https://wiki.oroboros.at/api.php?action=feedcontributions&user=Komlodi+Timea&feedformat=atomBioblast - User contributions [en]2024-03-29T14:40:34ZUser contributionsMediaWiki 1.36.1https://wiki.oroboros.at/index.php?title=Spielmann_2022_Mamm_Genome&diff=236325Spielmann 2022 Mamm Genome2023-03-05T17:30:32Z<p>Komlodi Timea: </p>
<hr />
<div>{{Publication<br />
|title=Spielmann N, Schenkl C, Komlódi T, da Silva-Buttkus P, Heyne E, Rohde J, Amarie OV, Rathkolb B, Gnaiger E, Doenst T, Fuchs H, Gailus-Durner V, de Angelis MH, Szibor M (2022) Knockout of the Complex III subunit Uqcrh causes bioenergetic impairment and cardiac contractile dysfunction. Mamm Genome 10.1007/s00335-022-09973-w<br />
|info=[https://pubmed.ncbi.nlm.nih.gov/36565314/ Open Access PMID:36565314]<br />
|authors=Spielmann Nadine, Schenkl Christina, Komlodi Timea, da Silva-Buttkus Patricia, Heyne Estelle, Rohde Jana, Amarie V Oana, Rathkolb Birgit, Gnaiger Erich, Doenst Torsten, Fuchs Helmut, Gailus-Durner Valérie, de Angelis Martin H, Szibor Marten<br />
|year=2022<br />
|journal=Mamm Genome<br />
|abstract=Ubiquinol cytochrome c reductase hinge protein (UQCRH) is required for the electron transfer between cytochrome c1 and c of the mitochondrial cytochrome bc1 Complex (CIII). A two-exon deletion in the human UQCRH gene has recently been identified as the cause for a rare familial mitochondrial disorder. Deletion of the corresponding gene in the mouse (Uqcrh-KO) resulted in striking biochemical and clinical similarities including impairment of CIII, failure to thrive, elevated blood glucose levels, and early death. Here, we set out to test how global ablation of the murine Uqcrh affects cardiac morphology and contractility, and bioenergetics. Hearts from Uqcrh-KO mutant mice appeared macroscopically considerably smaller compared to wildtype littermate controls despite similar geometries as confirmed by transthoracic echocardiography (TTE). Relating TTE-assessed heart to body mass revealed the development of subtle cardiac enlargement, but histopathological analysis showed no excess collagen deposition. Nonetheless, Uqcrh-KO hearts developed pronounced contractile dysfunction. To assess mitochondrial functions, we used the high-resolution respirometer NextGen-O2k allowing measurement of mitochondrial respiratory capacity through the electron transfer system (ETS) simultaneously with the redox state of ETS-reactive coenzyme Q (Q), or production of reactive oxygen species (ROS). Compared to wildtype littermate controls, we found decreased mitochondrial respiratory capacity and more reduced Q in Uqcrh-KO, indicative for an impaired ETS. Yet, mitochondrial ROS production was not generally increased. Taken together, our data suggest that Uqcrh-KO leads to cardiac contractile dysfunction at 9 weeks of age, which is associated with impaired bioenergetics but not with mitochondrial ROS production. Global ablation of the Uqcrh gene results in functional impairment of CIII associated with metabolic dysfunction and postnatal developmental arrest immediately after weaning from the mother. Uqcrh-KO mice show dramatically elevated blood glucose levels and decreased ability of isolated cardiac mitochondria to consume oxygen (O2). Impaired development (failure to thrive) after weaning manifests as a deficiency in the gain of body mass and growth of internal organ including the heart. The relative heart mass seemingly increases when organ mass calculated from transthoracic echocardiography (TTE) is normalized to body mass. Notably, the heart shows no signs of collagen deposition, yet does develop a contractile dysfunction reflected by a decrease in ejection fraction and fractional shortening.<br />
}}<br />
{{Labeling<br />
|area=Respiration, Genetic knockout;overexpression<br />
|injuries=Oxidative stress;RONS, Mitochondrial disease<br />
|organism=Mouse<br />
|tissues=Heart<br />
|preparations=Intact organism, Isolated mitochondria<br />
|enzymes=Complex III<br />
|topics=ADP, mt-Membrane potential, Redox state, Substrate, Q-junction effect<br />
|couplingstates=LEAK, OXPHOS, ET<br />
|pathways=N, S, NS, ROX<br />
|instruments=NextGen-O2k<br />
}}</div>Komlodi Timeahttps://wiki.oroboros.at/index.php?title=Spielmann_2022_Mamm_Genome&diff=236324Spielmann 2022 Mamm Genome2023-03-05T17:27:22Z<p>Komlodi Timea: </p>
<hr />
<div>{{Publication<br />
|title=Spielmann N, Schenkl C, Komlódi T, da Silva-Buttkus P, Heyne E, Rohde J, Amarie OV, Rathkolb B, Gnaiger E, Doenst T, Fuchs H, Gailus-Durner V, de Angelis MH, Szibor M (2022) Knockout of the Complex III subunit Uqcrh causes bioenergetic impairment and cardiac contractile dysfunction. Mamm Genome 10.1007/s00335-022-09973-w<br />
|info=[https://pubmed.ncbi.nlm.nih.gov/36565314/ Open Access PMID:36565314]<br />
|authors=Spielmann N, Schenkl C, Komlodi Timea, da Silva-Buttkus P, Heyne E, Rohde J, Amarie OV, Rathkolb B, Gnaiger Erich, Doenst T, Fuchs H, Gailus-Durner V, de Angelis MH, Szibor Marten<br />
|year=2022<br />
|journal=Mamm Genome<br />
|abstract=Ubiquinol cytochrome c reductase hinge protein (UQCRH) is required for the electron transfer between cytochrome c1 and c of the mitochondrial cytochrome bc1 Complex (CIII). A two-exon deletion in the human UQCRH gene has recently been identified as the cause for a rare familial mitochondrial disorder. Deletion of the corresponding gene in the mouse (Uqcrh-KO) resulted in striking biochemical and clinical similarities including impairment of CIII, failure to thrive, elevated blood glucose levels, and early death. Here, we set out to test how global ablation of the murine Uqcrh affects cardiac morphology and contractility, and bioenergetics. Hearts from Uqcrh-KO mutant mice appeared macroscopically considerably smaller compared to wildtype littermate controls despite similar geometries as confirmed by transthoracic echocardiography (TTE). Relating TTE-assessed heart to body mass revealed the development of subtle cardiac enlargement, but histopathological analysis showed no excess collagen deposition. Nonetheless, Uqcrh-KO hearts developed pronounced contractile dysfunction. To assess mitochondrial functions, we used the high-resolution respirometer NextGen-O2k allowing measurement of mitochondrial respiratory capacity through the electron transfer system (ETS) simultaneously with the redox state of ETS-reactive coenzyme Q (Q), or production of reactive oxygen species (ROS). Compared to wildtype littermate controls, we found decreased mitochondrial respiratory capacity and more reduced Q in Uqcrh-KO, indicative for an impaired ETS. Yet, mitochondrial ROS production was not generally increased. Taken together, our data suggest that Uqcrh-KO leads to cardiac contractile dysfunction at 9 weeks of age, which is associated with impaired bioenergetics but not with mitochondrial ROS production. Global ablation of the Uqcrh gene results in functional impairment of CIII associated with metabolic dysfunction and postnatal developmental arrest immediately after weaning from the mother. Uqcrh-KO mice show dramatically elevated blood glucose levels and decreased ability of isolated cardiac mitochondria to consume oxygen (O2). Impaired development (failure to thrive) after weaning manifests as a deficiency in the gain of body mass and growth of internal organ including the heart. The relative heart mass seemingly increases when organ mass calculated from transthoracic echocardiography (TTE) is normalized to body mass. Notably, the heart shows no signs of collagen deposition, yet does develop a contractile dysfunction reflected by a decrease in ejection fraction and fractional shortening.<br />
}}<br />
{{Labeling<br />
|area=Respiration, Genetic knockout;overexpression<br />
|injuries=Oxidative stress;RONS, Mitochondrial disease<br />
|organism=Mouse<br />
|tissues=Heart<br />
|preparations=Intact organism, Isolated mitochondria<br />
|enzymes=Complex III<br />
|topics=ADP, mt-Membrane potential, Redox state, Substrate, Q-junction effect<br />
|couplingstates=LEAK, OXPHOS, ET<br />
|pathways=N, S, NS, ROX<br />
|instruments=NextGen-O2k<br />
}}</div>Komlodi Timeahttps://wiki.oroboros.at/index.php?title=Spielmann_2022_Mamm_Genome&diff=236323Spielmann 2022 Mamm Genome2023-03-05T17:25:06Z<p>Komlodi Timea: </p>
<hr />
<div>{{Publication<br />
|title=Spielmann N, Schenkl C, Komlódi T, da Silva-Buttkus P, Heyne E, Rohde J, Amarie OV, Rathkolb B, Gnaiger E, Doenst T, Fuchs H, Gailus-Durner V, de Angelis MH, Szibor M (2022) Knockout of the Complex III subunit Uqcrh causes bioenergetic impairment and cardiac contractile dysfunction. Mamm Genome 10.1007/s00335-022-09973-w<br />
|info=[https://pubmed.ncbi.nlm.nih.gov/36565314/ Open Access PMID:36565314]<br />
|authors=Spielmann N, Schenkl C, Komlodi Timea, da Silva-Buttkus P, Heyne E, Rohde J, Amarie OV, Rathkolb B, Gnaiger Erich, Doenst T, Fuchs H, Gailus-Durner V, de Angelis MH, Szibor Marten<br />
|year=2022<br />
|journal=Mamm Genome<br />
|abstract=Ubiquinol cytochrome c reductase hinge protein (UQCRH) is required for the electron transfer between cytochrome c1 and c of the mitochondrial cytochrome bc1 Complex (CIII). A two-exon deletion in the human UQCRH gene has recently been identified as the cause for a rare familial mitochondrial disorder. Deletion of the corresponding gene in the mouse (Uqcrh-KO) resulted in striking biochemical and clinical similarities including impairment of CIII, failure to thrive, elevated blood glucose levels, and early death. Here, we set out to test how global ablation of the murine Uqcrh affects cardiac morphology and contractility, and bioenergetics. Hearts from Uqcrh-KO mutant mice appeared macroscopically considerably smaller compared to wildtype littermate controls despite similar geometries as confirmed by transthoracic echocardiography (TTE). Relating TTE-assessed heart to body mass revealed the development of subtle cardiac enlargement, but histopathological analysis showed no excess collagen deposition. Nonetheless, Uqcrh-KO hearts developed pronounced contractile dysfunction. To assess mitochondrial functions, we used the high-resolution respirometer NextGen-O2k allowing measurement of mitochondrial respiratory capacity through the electron transfer system (ETS) simultaneously with the redox state of ETS-reactive coenzyme Q (Q), or production of reactive oxygen species (ROS). Compared to wildtype littermate controls, we found decreased mitochondrial respiratory capacity and more reduced Q in Uqcrh-KO, indicative for an impaired ETS. Yet, mitochondrial ROS production was not generally increased. Taken together, our data suggest that Uqcrh-KO leads to cardiac contractile dysfunction at 9 weeks of age, which is associated with impaired bioenergetics but not with mitochondrial ROS production. Global ablation of the Uqcrh gene results in functional impairment of CIII associated with metabolic dysfunction and postnatal developmental arrest immediately after weaning from the mother. Uqcrh-KO mice show dramatically elevated blood glucose levels and decreased ability of isolated cardiac mitochondria to consume oxygen (O2). Impaired development (failure to thrive) after weaning manifests as a deficiency in the gain of body mass and growth of internal organ including the heart. The relative heart mass seemingly increases when organ mass calculated from transthoracic echocardiography (TTE) is normalized to body mass. Notably, the heart shows no signs of collagen deposition, yet does develop a contractile dysfunction reflected by a decrease in ejection fraction and fractional shortening.<br />
}}<br />
{{Labeling}}</div>Komlodi Timeahttps://wiki.oroboros.at/index.php?title=Spielmann_2022_Mamm_Genome&diff=236322Spielmann 2022 Mamm Genome2023-03-05T17:23:39Z<p>Komlodi Timea: Created page with "{{Publication |title=Spielmann N, Schenkl C, Komlódi T, da Silva-Buttkus P, Heyne E, Rohde J, Amarie OV, Rathkolb B, Gnaiger E, Doenst T, Fuchs H, Gailus-Durner V, de Angelis..."</p>
<hr />
<div>{{Publication<br />
|title=Spielmann N, Schenkl C, Komlódi T, da Silva-Buttkus P, Heyne E, Rohde J, Amarie OV, Rathkolb B, Gnaiger E, Doenst T, Fuchs H, Gailus-Durner V, de Angelis MH, Szibor M (2022) Knockout of the Complex III subunit Uqcrh causes bioenergetic impairment and cardiac contractile dysfunction. Mamm Genome 10.1007/s00335-022-09973-w<br />
|info=[https://pubmed.ncbi.nlm.nih.gov/36565314/ Open Access PMID:36565314]<br />
|authors=Spielmann N, Schenkl C, Komlódi T, da Silva-Buttkus P, Heyne E, Rohde J, Amarie OV, Rathkolb B, Gnaiger E, Doenst T, Fuchs H, Gailus-Durner V, de Angelis MH, Szibor M<br />
|year=2022<br />
|journal=Mamm Genome<br />
|abstract=Ubiquinol cytochrome c reductase hinge protein (UQCRH) is required for the electron transfer between cytochrome c1 and c of the mitochondrial cytochrome bc1 Complex (CIII). A two-exon deletion in the human UQCRH gene has recently been identified as the cause for a rare familial mitochondrial disorder. Deletion of the corresponding gene in the mouse (Uqcrh-KO) resulted in striking biochemical and clinical similarities including impairment of CIII, failure to thrive, elevated blood glucose levels, and early death. Here, we set out to test how global ablation of the murine Uqcrh affects cardiac morphology and contractility, and bioenergetics. Hearts from Uqcrh-KO mutant mice appeared macroscopically considerably smaller compared to wildtype littermate controls despite similar geometries as confirmed by transthoracic echocardiography (TTE). Relating TTE-assessed heart to body mass revealed the development of subtle cardiac enlargement, but histopathological analysis showed no excess collagen deposition. Nonetheless, Uqcrh-KO hearts developed pronounced contractile dysfunction. To assess mitochondrial functions, we used the high-resolution respirometer NextGen-O2k allowing measurement of mitochondrial respiratory capacity through the electron transfer system (ETS) simultaneously with the redox state of ETS-reactive coenzyme Q (Q), or production of reactive oxygen species (ROS). Compared to wildtype littermate controls, we found decreased mitochondrial respiratory capacity and more reduced Q in Uqcrh-KO, indicative for an impaired ETS. Yet, mitochondrial ROS production was not generally increased. Taken together, our data suggest that Uqcrh-KO leads to cardiac contractile dysfunction at 9 weeks of age, which is associated with impaired bioenergetics but not with mitochondrial ROS production. Global ablation of the Uqcrh gene results in functional impairment of CIII associated with metabolic dysfunction and postnatal developmental arrest immediately after weaning from the mother. Uqcrh-KO mice show dramatically elevated blood glucose levels and decreased ability of isolated cardiac mitochondria to consume oxygen (O2). Impaired development (failure to thrive) after weaning manifests as a deficiency in the gain of body mass and growth of internal organ including the heart. The relative heart mass seemingly increases when organ mass calculated from transthoracic echocardiography (TTE) is normalized to body mass. Notably, the heart shows no signs of collagen deposition, yet does develop a contractile dysfunction reflected by a decrease in ejection fraction and fractional shortening.<br />
}}<br />
{{Labeling}}</div>Komlodi Timeahttps://wiki.oroboros.at/index.php?title=Goretzki_2022_Int_J_Mol_Sci&diff=235383Goretzki 2022 Int J Mol Sci2023-01-19T08:57:52Z<p>Komlodi Timea: </p>
<hr />
<div>{{Publication<br />
|title=Goretzki A, Lin YJ, Zimmermann J, Rainer H, Junker AC, Wolfheimer S, Vieths S, Scheurer S and Schülke S (2022) Role of Glycolysis and Fatty Acid Synthesis in the Activation and T Cell-Modulating Potential of Dendritic Cells Stimulated with a TLR5-Ligand Allergen Fusion Protein. Int J Mol Sci 23:12695.<br />
|info=[https://pubmed.ncbi.nlm.nih.gov/36293550/ PMID: 36293550 Open Access]<br />
|authors=Goretzki A, Lin YJ,Zimmermann J, Rainer H, Junker AC, Wolfheimer S, Vieths S, Scheurer S and Schülke S<br />
|year=2022<br />
|journal=Int J Mol Sci<br />
|abstract=Trained immune responses, based on metabolic and epigenetic changes in innate immune cells, are de facto innate immune memory and, therefore, are of great interest in vaccine development. In previous studies, the recombinant fusion protein rFlaA:Betv1, combining the adjuvant and toll-like receptor (TLR)5-ligand flagellin (FlaA) and the major birch pollen allergen Bet v 1 into a single molecule, significantly suppressed allergic sensitization in vivo while also changing the metabolism of myeloid dendritic cells (mDCs). Within this study, the immune-metabolic effects of rFlaA:Betv1 during mDC activation were elucidated. In line with results for other well-characterized TLR-ligands, rFlaA:Betv1 increased glycolysis while suppressing oxidative phosphorylation to different extents, making rFlaA:Betv1 a suitable model to study the immune-metabolic effects of TLR-adjuvanted vaccines. In vitro pretreatment of mDCs with cerulenin (inhibitor of fatty acid biosynthesis) led to a decrease in both rFlaA:Betv1-induced anti-inflammatory cytokine Interleukin (IL) 10 and T helper cell type (TH) 1-related cytokine IL-12p70, while the pro-inflammatory cytokine IL 1β was unaffected. Interestingly, pretreatment with the glutaminase inhibitor BPTES resulted in an increase in IL-1β, but decreased IL-12p70 secretion while leaving IL-10 unchanged. Inhibition of the glycolytic enzyme hexokinase-2 by 2-deoxyglucose led to a decrease in all investigated cytokines (IL-10, IL-12p70, and IL-1β). Inhibitors of mitochondrial respiration had no effect on rFlaA:Betv1-induced IL-10 level, but either enhanced the secretion of IL-1β (oligomycin) or decreased IL-12p70 (antimycin A). In extracellular flux measurements, mDCs showed a strongly enhanced glycolysis after rFlaA:Betv1 stimulation, which was slightly increased after respiratory shutdown using antimycin A. rFlaA:Betv1-stimulated mDCs secreted directly antimicrobial substances in a mTOR- and fatty acid metabolism-dependent manner. In co-cultures of rFlaA:Betv1-stimulated mDCs with CD4+ T cells, the suppression of Bet v 1-specific TH2 responses was shown to depend on fatty acid synthesis. The effector function of rFlaA:Betv1-activated mDCs mainly relies on glycolysis, with fatty acid synthesis also significantly contributing to rFlaA:Betv1-mediated cytokine secretion, the production of antimicrobial molecules, and the modulation of T cell responses.<br />
}}<br />
{{Labeling}}</div>Komlodi Timeahttps://wiki.oroboros.at/index.php?title=Lin_2017_Neuro_Oncol&diff=235382Lin 2017 Neuro Oncol2023-01-19T08:38:45Z<p>Komlodi Timea: Created page with "{{Publication |title=Lin H, Patel S, Affleck VS, Wilson I, Turnbull DM, Joshi AR, Maxwell R, Stoll EA (2017) Fatty acid oxidation is required for the respiration and prolifera..."</p>
<hr />
<div>{{Publication<br />
|title=Lin H, Patel S, Affleck VS, Wilson I, Turnbull DM, Joshi AR, Maxwell R, Stoll EA (2017) Fatty acid oxidation is required for the respiration and proliferation of malignant glioma cells. Neuro Oncol 19:43-54.<br />
|info=[https://pubmed.ncbi.nlm.nih.gov/27365097/ PMID:27365097 Open Access]<br />
|authors=Lin H, Patel S, Affleck VS, Wilson I, Turnbull DM, Joshi AR, Maxwell R, Stoll EA<br />
|year=2017<br />
|journal=Neuro Oncol<br />
|abstract=Background: Glioma is the most common form of primary malignant brain tumor in adults, with approximately 4 cases per 100 000 people each year. Gliomas, like many tumors, are thought to primarily metabolize glucose for energy production; however, the reliance upon glycolysis has recently been called into question. In this study, we aimed to identify the metabolic fuel requirements of human glioma cells.<br />
<br />
Methods: We used database searches and tissue culture resources to evaluate genotype and protein expression, tracked oxygen consumption rates to study metabolic responses to various substrates, performed histochemical techniques and fluorescence-activated cell sorting-based mitotic profiling to study cellular proliferation rates, and employed an animal model of malignant glioma to evaluate a new therapeutic intervention.<br />
<br />
Results: We observed the presence of enzymes required for fatty acid oxidation within human glioma tissues. In addition, we demonstrated that this metabolic pathway is a major contributor to aerobic respiration in primary-cultured cells isolated from human glioma and grown under serum-free conditions. Moreover, inhibiting fatty acid oxidation reduces proliferative activity in these primary-cultured cells and prolongs survival in a syngeneic mouse model of malignant glioma.<br />
<br />
Conclusions: Fatty acid oxidation enzymes are present and active within glioma tissues. Targeting this metabolic pathway reduces energy production and cellular proliferation in glioma cells. The drug etomoxir may provide therapeutic benefit to patients with malignant glioma. In addition, the expression of fatty acid oxidation enzymes may provide prognostic indicators for clinical practice.<br />
|keywords=etomoxir; fatty acid oxidation; glioblastoma; glioma; metabolism.<br />
|editor=Komlodi T<br />
}}<br />
{{Labeling<br />
|additional=MitoFit 2021 Etomoxir<br />
}}<br />
== Cited ==<br />
{{Template:Cited by Silva 2021 MitoFit Etomoxir}}</div>Komlodi Timeahttps://wiki.oroboros.at/index.php?title=Pike_2011_Biochim_Biophys_Acta&diff=235364Pike 2011 Biochim Biophys Acta2023-01-18T11:08:13Z<p>Komlodi Timea: /* Cited */</p>
<hr />
<div>{{Publication<br />
|title=Pike LS, Smift AL, Croteau NJ, Ferrick DA, Wu M (2011) Inhibition of fatty acid oxidation by etomoxir impairs NADPH production and increases reactive oxygen species resulting in ATP depletion and cell death in human glioblastoma cells. https://doi.org/10.1016/j.bbabio.2010.10.022<br />
|info=Biochim Biophys Acta 1807:726-34. [https://pubmed.ncbi.nlm.nih.gov/21692241/ PMID: 21692241 Open Access]<br />
|authors=Pike LS, Smift AL, Croteau NJ, Ferrick DA, Wu M<br />
|year=2011<br />
|journal=Biochim Biophys Acta<br />
|abstract=Normal differentiated cells rely primarily on mitochondrial oxidative phosphorylation to produce adenosine triphosphate (ATP) to maintain their viability and functions by using three major bioenergetic fuels: glucose, glutamine and fatty acids. Many cancer cells, however, rely on aerobic glycolysis for their growth and survival, and recent studies indicate that some cancer cells depend on glutamine as well. This altered metabolism in cancers occurs through oncogene activation or loss of tumor suppressor genes in multiple signaling pathways, including the phosphoinositide 3-kinase and Myc pathways. Relatively little is known, however, about the role of fatty acids as a bioenergetic fuel in growth and survival of cancer cells. Here, we report that human glioblastoma SF188 cells oxidize fatty acids and that inhibition of fatty acid β-oxidation by etomoxir, a carnitine palmitoyltransferase 1 inhibitor, markedly reduces cellular ATP levels and viability. We also found that inhibition of fatty acid oxidation controls the NADPH level. In the presence of reactive oxygen species scavenger tiron, however, ATP depletion is prevented without restoring fatty acid oxidation. This suggests that oxidative stress may lead to bioenergetic failure and cell death. Our work provides evidence that mitochondrial fatty acid oxidation may provide NADPH for defense against oxidative stress and prevent ATP loss and cell death.<br />
|editor=Gnaiger E<br />
}}<br />
{{Labeling<br />
|area=Respiration<br />
|diseases=Cancer<br />
|tissues=Other cell lines<br />
|preparations=Intact cells<br />
|couplingstates=ROUTINE<br />
|pathways=F<br />
|additional=MitoFit 2021 Etomoxir<br />
}}<br />
__TOC__<br />
<br />
== Cited ==<br />
{{Template:Cited by Silva 2021 MitoFit Etomoxir}}<br />
<br />
Communicated by [[Gnaiger E]] (2023-01-17)<br />
<br />
<br />
=== Critical ===<br />
:::: Pike et al (2011) is cited with critical consideration of off-target side effects of etoxomir:<br />
::::* Silva FSG, Komlodi T, Garcia-Souza LF, Bento G, Doerrier C, Oliveira PJ, Gnaiger E (2019) Can fatty acid oxidation be specifically blocked by the CPT1 inhibitor etomoxir? - [[Silva 2019 ESCI2019 |»Bioblast link«]]<br />
<br />
::::* Goretzki A, Lin YJ, Zimmermann J, Rainer H, Junker AC, Wolfheimer S, Vieths S, Scheurer S, Schülke S. Role of Glycolysis and Fatty Acid Synthesis in the Activation and T Cell-Modulating Potential of Dendritic Cells Stimulated with a TLR5-Ligand Allergen Fusion Protein. Int J Mol Sci. 2022 Oct 21;23(20):12695. https://doi.org/10.3390/ijms232012695. PMID: 36293550<br />
:::::::: Ref 12: "Inhibition of fatty acid metabolism was achieved through pretreatment with either cerulenin to block fatty acid synthase [11] or etomoxir to block fatty acid oxidation by inhibiting carnitine palmitoyltransferase 1 [12]. .. Cerulenin slightly reduced the expression levels of CD40 and CD69 by approx. 60% and 50%, respectively, while etomoxir had no effect on the expression levels of the investigated surface markers. .. This effect was abolished when the cells were either pretreated with the mTOR-inhibitor rapamycin or the inhibitors of fatty acid metabolism cerulenin or etomoxir. .. We further analyzed the contribution of fatty acid metabolism to the observed activation of mDCs by rFlaA:Betv1. Metabolically, only inhibition of fatty acid synthesis by cerulenin slightly reduced glycolysis (while having no effect on OCR). Moreover, cerulenin pretreatment dose-dependently suppressed the rFlaA:Betv1-induced IL-10- and IL-12p70 secretion, while IL-1β secretion remained unchanged. In contrast, etomoxir pretreatment slightly reduced mitochondrial oxygen consumption and interfered with antimicrobial activity otherwise observed in supernatants of rFlaA:Betv1-stimulated mDCs, but had no impact on the investigated ECAR, cytokine secretion, or expression of co-stimulatory molecules. Etomoxir concentrations greater than 5 µM were recently shown to induce mitochondrial stress associated with ROS production in human T cells independently of its effect on carnitine palmitoyltransferase 1 (CPT1a) [29]. On the basis of these results, similar '''off-target effects of etomoxir in mDCs cannot be excluded. Therefore, our results obtained in mDCs pre-treated with etomoxir have to be interpreted cautiously'''. .. 10, 50, or 100 µM etomoxir"<br />
<br />
::::* Sainero-Alcolado L, Liaño-Pons J, Ruiz-Pérez MV, Arsenian-Henriksson M. Targeting mitochondrial metabolism for precision medicine in cancer. Cell Death Differ. 2022 Jul;29(7):1304-1317. doi: 10.1038/s41418-022-01022-y. Epub 2022 Jul 13. PMID: 35831624<br />
<br />
:::::::: Ref 81: "Etomoxir further induces cell death of glioblastoma cells in vitro [81] and delays tumor apparition and progression in a glioblastoma mouse model [82]. However, '''toxicity, off-target effects on ETC Complex I, and the high doses needed, limits its potential for clinical applications'''."<br />
<br />
::::* Yao CH, Liu GY, Wang R, Moon SH, Gross RW, Patti GJ (2018) Identifying off-target effects of etomoxir reveals that carnitine palmitoyltransferase I is essential for cancer cell proliferation independent of β-oxidation. PLoS Biol 16:2003782.<br />
:::::::: Ref 15: It is common in cancer studies to use etomoxir at hundreds of micromolar concentrations [5, 15, 18, 25, 26]. .. Given that studies evaluating the role of CPT1 in cancer have commonly used concentrations of etomoxir at the hundreds of micromolar or even 1 mM level [15], <br />
:::::::: Here we show that when FAO was reduced approximately 90% by pharmacological inhibition of carnitine palmitoyltransferase I (CPT1) with low concentrations of etomoxir, the proliferation rate of various cancer cells was unaffected. Efforts to pharmacologically inhibit FAO more than 90% revealed that high concentrations of etomoxir (200 μM) have an off-target effect of inhibiting complex I of the electron transport chain. <br />
<br />
=== Belief in a paradigm ===<br />
<br />
:::: Pike et al (2011) is cited many times without sufficiently taking into account off-target side effects of etoxomir:<br />
<br />
::::* Gaca-Tabaszewska M, Bogusiewicz J, Bojko B. Metabolomic and Lipidomic Profiling of Gliomas-A New Direction in Personalized Therapies. Cancers (Basel). 2022 Oct 14;14(20):5041. doi: 10.3390/cancers14205041. PMID: 36291824<br />
:::::::: "Many studies, including those focused on gliomas, have proposed FAO as a very good potential target for new drugs. As such, researchers have considered etomoxir as a CPT-1a inhibitor, as it slows the proliferation of glioma cells and prolongs the patient’s time of survival [73]. .. Promising results have been obtained from clinical trials examining the combined use of etomoxir and reradiation to target hypoxia and improve treatment efficiency for cancers such as lung adenocarcinoma or prostate cancer [76]. In addition, Taib et al. [77] observed the significant inhibition of cell proliferation when etomoxir was applied alongside oleic acid in GBM and astrocytic cells [77]. To date, most studies in this area have employed in vitro experiments using gliomas or other cancer cells; however, the literature also contains clinical trials and animal studies demonstrating the inhibitory effects of etomoxir treatment in neurodegenerative diseases, such as Parkinson’s or Alzheimer’s disease [78]. Thus, we can assume that BBB crossing is an issue that can be overcome in the case of etomoxir and that more trials examining the use of this drug to treat gliomas are forthcoming."<br />
<br />
::::* Shim JK, Choi S, Yoon SJ, Choi RJ, Park J, Lee EH, Cho HJ, Lee S, Teo WY, Moon JH, Kim HS, Kim EH, Cheong JH, Chang JH, Yook JI, Kang SG (2022) Etomoxir, a carnitine palmitoyltransferase 1 inhibitor, combined with temozolomide reduces stemness and invasiveness in patient-derived glioblastoma tumorspheres. Cancer Cell Int 22:309. doi: 10.1186/s12935-022-02731-7. PMID: 36221088<br />
:::::::: "The importance of fatty acid oxidation (FAO) in the bioenergetics of glioblastoma (GBM) is being realized. Etomoxir (ETO), a carnitine palmitoyltransferase 1 (CPT1) inhibitor exerts cytotoxic effects in GBM, which involve interrupting the FAO pathway. We hypothesized that FAO inhibition could affect the outcomes of current standard temozolomide (TMZ) chemotherapy against GBM."<br />
<br />
::::* Wang CY, Wang CH, Mai RT, Chen TW, Li CW, Chao CH (2022) Mutant p53-microRNA-200c-ZEB2-Axis-Induced CPT1C Elevation Contributes to Metabolic Reprogramming and Tumor Progression in Basal-Like Breast Cancers. Front Oncol 12:940402. doi: 10.3389/fonc.2022.940402. PMID: 35936710<br />
:::::::: "To quantify the FAO activity which contributes to total cellular oxygen consumption, a “basal ratio” (the ratio between FAO-mediated OCR and total OCR) was assigned by the following equation: [(basal respiration of the vehicle group–basal respiration of the ETO group)/basal respiration of the vehicle group] x 100 %. As shown in Figure 1G , the basal ratio of control cells is around 13%, which means FAO contributes to 13 % of cellular oxygen consumption, whereas it was at least doubled in Mutp53-bearing MCF12A cells. .. to understand whether FAO is involved in Mutp53-promoted tumor properties, we suppressed cellular FAO activity with etomoxir (ETO), the pan-CPT1 inhibitor. The p53-R273H and p53-R280K MCF-12A cells were pretreated with ETO (50 and 100 μmol/L) for seven days, .."<br />
<br />
::::* Jiang N, Xie B, Xiao W, Fan M, Xu S, Duan Y, Hamsafar Y, Evans AC, Huang J, Zhou W, Lin X, Ye N, Wanggou S, Chen W, Jing D, Fragoso RC, Dugger BN, Wilson PF, Coleman MA, Xia S, Li X, Sun LQ, Monjazeb AM, Wang A, Murphy WJ, Kung HJ, Lam KS, Chen HW, Li JJ (2022) Fatty acid oxidation fuels glioblastoma radioresistance with CD47-mediated immune evasion. Nat Commun 13:1511. doi: 10.1038/s41467-022-29137-3. PMID: 35314680<br />
:::::::: "Inhibition of FAO by CPT1 inhibitor etomoxir or CRISPR-generated CPT1A−/−, CPT2−/−, ACAD9−/− cells demonstrate that FAO-derived acetyl-CoA upregulates CD47 transcription via NF-κB/RelA acetylation. Blocking FAO impairs tumor growth and reduces CD47 anti-phagocytosis. Etomoxir combined with anti-CD47 antibody synergizes radiation control of regrown tumors with boosted macrophage phagocytosis. These results demonstrate that enhanced fat acid metabolism promotes aggressive growth of GBM with CD47-mediated immune evasion. .. cells treated with CPT1A inhibitor etomoxir (ET; 200 µM, 24 h). .. To inhibit FAO, CPT1 inhibitor etomoxir was added into the testing wells 0.5 h before detection."<br />
<br />
::::* Wu Y, Li Y, Lv G, Bu W (2022) Redox dyshomeostasis strategy for tumor therapy based on nanomaterials chemistry. Chem Sci 13:2202-17. doi: 10.1039/d1sc06315d. PMID: 35310479<br />
::::::::Ref 62: "Besides azobenzene, etomoxir, a carnitine palmitoyltransferase 1 inhibitor, can also decrease NADPH levels, thereby reducing the GSH content by inhibiting fatty acid oxidation.62"</div>Komlodi Timeahttps://wiki.oroboros.at/index.php?title=Wu_2022_Chem_Sci&diff=235363Wu 2022 Chem Sci2023-01-18T10:04:09Z<p>Komlodi Timea: Created page with "{{Publication |title=Wu Y, Li Y, Lv G, Bu W (2022) Redox dyshomeostasis strategy for tumor therapy based on nanomaterials chemistry. Chem Sci 13:2202-2217. |info=[https://pubm..."</p>
<hr />
<div>{{Publication<br />
|title=Wu Y, Li Y, Lv G, Bu W (2022) Redox dyshomeostasis strategy for tumor therapy based on nanomaterials chemistry. Chem Sci 13:2202-2217.<br />
|info=[https://pubmed.ncbi.nlm.nih.gov/35310479/ PMID:35310479 Open Access]<br />
|authors=Wu Y, Li Y, Lv G, Bu W<br />
|year=2022<br />
|journal=Chem Sci<br />
|abstract=Redox homeostasis, as an innate cellular defense mechanism, not only contributes to malignant transformation and metastasis of tumors, but also seriously restricts reactive oxygen species (ROS)-mediated tumor therapies, such as chemotherapy, radiotherapy, photodynamic therapy (PDT), and chemodynamic therapy (CDT). Therefore, the development of the redox dyshomeostasis (RDH) strategy based on nanomaterials chemistry is of great significance for developing highly efficient tumor therapy. This review will firstly introduce the basic definition and function of cellular redox homeostasis and RDH. Subsequently, the current representative progress of the nanomaterial-based RDH strategy for tumor therapy is evaluated, summarized and discussed. This strategy can be categorized into three groups: (1) regulation of oxidizing species; (2) regulation of reducing species and (3) regulation of both of them. Furthermore, the current limitations and potential future directions for this field will be briefly discussed. We expect that this review could attract positive attention in the chemistry, materials science, and biomedicine fields and further promote their interdisciplinary integration.<br />
}}<br />
{{Labeling<br />
|additional=MitoFit 2021 Etomoxir<br />
}}<br />
== Cited ==<br />
{{Template:Cited by Silva 2021 MitoFit Etomoxir}}</div>Komlodi Timeahttps://wiki.oroboros.at/index.php?title=Jiang_2022_Nat_Commun&diff=235362Jiang 2022 Nat Commun2023-01-18T09:29:21Z<p>Komlodi Timea: Created page with "{{Publication |title=Jiang N, Xie B, Xiao W, Fan M, Xu S, Duan Y, Hamsafar Y, Evans AC, Huang J, Zhou W, Lin X, Ye N, Wanggou S, Chen W, Jing D, Fragoso RC, Dugger BN, Wilson..."</p>
<hr />
<div>{{Publication<br />
|title=Jiang N, Xie B, Xiao W, Fan M, Xu S, Duan Y, Hamsafar Y, Evans AC, Huang J, Zhou W, Lin X, Ye N, Wanggou S, Chen W, Jing D, Fragoso RC, Dugger BN, Wilson PF, Coleman MA, Xia S, Li X, Sun LQ, Monjazeb AM, Wang A, Murphy WJ, Kung HJ, Lam KS, Chen HW, Li JJ. (2022) Fatty acid oxidation fuels glioblastoma radioresistance with CD47-mediated immune evasion. Nat Commun 13:1511.<br />
|info=[https://pubmed.ncbi.nlm.nih.gov/35314680/ PMID:35314680 Open Access]<br />
|authors=Jiang N, Xie B, Xiao W, Fan M, Xu S, Duan Y, Hamsafar Y, Evans AC, Huang J, Zhou W, Lin X, Ye N, Wanggou S, Chen W, Jing D, Fragoso RC, Dugger BN, Wilson PF, Coleman MA, Xia S, Li X, Sun LQ, Monjazeb AM, Wang A, Murphy WJ, Kung HJ, Lam KS, Chen HW, Li JJ.<br />
|year=2022<br />
|journal=Nat Commun<br />
|abstract=Glioblastoma multiforme (GBM) remains the top challenge to radiotherapy with only 25% one-year survival after diagnosis. Here, we reveal that co-enhancement of mitochondrial fatty acid oxidation (FAO) enzymes (CPT1A, CPT2 and ACAD9) and immune checkpoint CD47 is dominant in recurrent GBM patients with poor prognosis. A glycolysis-to-FAO metabolic rewiring is associated with CD47 anti-phagocytosis in radioresistant GBM cells and regrown GBM after radiation in syngeneic mice. Inhibition of FAO by CPT1 inhibitor etomoxir or CRISPR-generated CPT1A-/-, CPT2-/-, ACAD9-/- cells demonstrate that FAO-derived acetyl-CoA upregulates CD47 transcription via NF-κB/RelA acetylation. Blocking FAO impairs tumor growth and reduces CD47 anti-phagocytosis. Etomoxir combined with anti-CD47 antibody synergizes radiation control of regrown tumors with boosted macrophage phagocytosis. These results demonstrate that enhanced fat acid metabolism promotes aggressive growth of GBM with CD47-mediated immune evasion. The FAO-CD47 axis may be targeted to improve GBM control by eliminating the radioresistant phagocytosis-proofing tumor cells in GBM radioimmunotherapy.<br />
}}<br />
{{Labeling}}<br />
== Cited ==<br />
{{Template:Cited by Silva 2021 MitoFit Etomoxir}}</div>Komlodi Timeahttps://wiki.oroboros.at/index.php?title=Wang_2022_Front_Oncol&diff=235361Wang 2022 Front Oncol2023-01-18T09:02:37Z<p>Komlodi Timea: Created page with "{{Publication |title=Wang CY, Wang CH, Mai RT, Chen TW, Li CW, Chao CH (2022) Mutant p53-microRNA-200c-ZEB2-Axis-Induced CPT1C Elevation Contributes to Metabolic Reprogramming..."</p>
<hr />
<div>{{Publication<br />
|title=Wang CY, Wang CH, Mai RT, Chen TW, Li CW, Chao CH (2022) Mutant p53-microRNA-200c-ZEB2-Axis-Induced CPT1C Elevation Contributes to Metabolic Reprogramming and Tumor Progression in Basal-Like Breast Cancers. Front Oncol 12:940402.<br />
|info=[https://pubmed.ncbi.nlm.nih.gov/35936710/ PMID:35936710 Open Access]<br />
|authors=Wang CY, Wang CH, Mai RT, Chen TW, Li CW, Chao CH<br />
|year=2022<br />
|journal=Front Oncol<br />
|abstract=TP53 is mutated in more than 80% of basal-like breast cancers (BLBCs). BLBCs with TP53 mutation are usually high-grade and have worse responses to chemotherapy, leading to poor clinical outcomes. Wild-type p53 (WTp53) is well-accepted to promote fatty acid oxidation (FAO); however, in this study, we demonstrate that mutant p53 (Mutp53) enhances FAO activity through constitutively upregulating CPT1C via dysregulating the miR-200c-ZEB2 axis. Sustained CPT1C expression contributes to the metabolic preference of FAO, epithelial-mesenchymal transition (EMT) phenotypes, migration, invasion, and cancer stemness in BLBC, which is mediated by modulating the redox status. Furthermore, interference of CPT1C expression impairs tumor growth and pulmonary colonization of BLBC cells in vivo, and even postpones the occurrence of spontaneous metastasis, resulting in a prolonged disease-specific survival (DSS). Consistently, clinical validation reveals that high CPT1C is observed in breast cancer patients with metastasis and is correlated with poor overall, disease-free, progression-free, and disease-specific survival in BLBC patients. Together, unlike WTp53 which transiently transactivates CPT1C, Mutp53 provides long-term benefits through sustaining CPT1C expression by disturbing the miR-200c-ZEB2 axis, which potentiates FAO and facilitates tumor progression in BLBC, suggesting that targeting Mutp53-CPT1C-driven metabolic reprogramming is promising to serve as novel therapeutic strategies for BLBC in the future.<br />
}}<br />
{{Labeling<br />
|additional=MitoFit 2021 Etomoxir<br />
}}<br />
== Cited ==<br />
{{Template:Cited by Silva 2021 MitoFit Etomoxir}}</div>Komlodi Timeahttps://wiki.oroboros.at/index.php?title=Shim_2022_Cancer_Cell_Int&diff=235360Shim 2022 Cancer Cell Int2023-01-18T08:58:29Z<p>Komlodi Timea: Created page with "{{Publication |title=Shim JK, Choi S, Yoon SJ, Choi RJ, Park J, Lee EH, Cho HJ, Lee S, Teo WY, Moon JH, Kim HS, Kim EH, Cheong JH, Chang JH, Yook JI, Kang SG. (2022) Etomoxir,..."</p>
<hr />
<div>{{Publication<br />
|title=Shim JK, Choi S, Yoon SJ, Choi RJ, Park J, Lee EH, Cho HJ, Lee S, Teo WY, Moon JH, Kim HS, Kim EH, Cheong JH, Chang JH, Yook JI, Kang SG. (2022) Etomoxir, a carnitine palmitoyltransferase 1 inhibitor, combined with temozolomide reduces stemness and invasiveness in patient-derived glioblastoma tumorspheres. Cancer Cell Int 22:309.<br />
|info=[https://pubmed.ncbi.nlm.nih.gov/36221088/ PMID:36221088 Open Access]<br />
|authors=Shim JK, Choi S, Yoon SJ, Choi RJ, Park J, Lee EH, Cho HJ, Lee S, Teo WY, Moon JH, Kim HS, Kim EH, Cheong JH, Chang JH, Yook JI, Kang SG.<br />
|year=2022<br />
|journal=Cancer Cell Int<br />
|abstract=Introduction: The importance of fatty acid oxidation (FAO) in the bioenergetics of glioblastoma (GBM) is being realized. Etomoxir (ETO), a carnitine palmitoyltransferase 1 (CPT1) inhibitor exerts cytotoxic effects in GBM, which involve interrupting the FAO pathway. We hypothesized that FAO inhibition could affect the outcomes of current standard temozolomide (TMZ) chemotherapy against GBM.<br />
<br />
Methods: The FAO-related gene expression was compared between GBM and the tumor-free cortex. Using four different GBM tumorspheres (TSs), the effects of ETO and/or TMZ was analyzed on cell viability, tricarboxylate (TCA) cycle intermediates and adenosine triphosphate (ATP) production to assess metabolic changes. Alterations in tumor stemness, invasiveness, and associated transcriptional changes were also measured. Mouse orthotopic xenograft model was used to elucidate the combinatory effect of TMZ and ETO.<br />
<br />
Results: GBM tissues exhibited overexpression of FAO-related genes, especially CPT1A, compared to the tumor-free cortex. The combined use of ETO and TMZ further inhibited TCA cycle and ATP production than single uses. This combination treatment showed superior suppression effects compared to treatment with individual agents on the viability, stemness, and invasiveness of GBM TSs, as well as better downregulation of FAO-related gene expression. The results of in vivo study showed prolonged survival outcomes in the combination treatment group.<br />
<br />
Conclusion: ETO, an FAO inhibitor, causes a lethal energy reduction in the GBM TSs. When used in combination with TMZ, ETO effectively reduces GBM cell stemness and invasiveness and further improves survival. These results suggest a potential novel treatment option for GBM.<br />
}}<br />
{{Labeling<br />
|additional=MitoFit 2021 Etomoxir<br />
}}<br />
== Cited ==<br />
{{Template:Cited by Silva 2021 MitoFit Etomoxir}}</div>Komlodi Timeahttps://wiki.oroboros.at/index.php?title=Sainero-Alcolado_2022_Cell_Death_Differ&diff=235359Sainero-Alcolado 2022 Cell Death Differ2023-01-18T08:54:50Z<p>Komlodi Timea: Created page with "{{Publication |title=Sainero-Alcolado L, Liaño-Pons J, Ruiz-Pérez MV, Arsenian-Henriksson M (2022) Targeting mitochondrial metabolism for precision medicine in cancer. Cell..."</p>
<hr />
<div>{{Publication<br />
|title=Sainero-Alcolado L, Liaño-Pons J, Ruiz-Pérez MV, Arsenian-Henriksson M (2022) Targeting mitochondrial metabolism for precision medicine in cancer. Cell Death Differ 29:1304-1317.<br />
|info=[https://pubmed.ncbi.nlm.nih.gov/35831624/ PMID: 35831624 Open Access]<br />
|authors=Sainero-Alcolado L, Liaño-Pons J, Ruiz-Pérez MV, Arsenian-Henriksson M<br />
|year=2022<br />
|journal=Cell Death Differ<br />
|abstract=During decades, the research field of cancer metabolism was based on the Warburg effect, described almost one century ago. Lately, the key role of mitochondria in cancer development has been demonstrated. Many mitochondrial pathways including oxidative phosphorylation, fatty acid, glutamine, and one carbon metabolism are altered in tumors, due to mutations in oncogenes and tumor suppressor genes, as well as in metabolic enzymes. This results in metabolic reprogramming that sustains rapid cell proliferation and can lead to an increase in reactive oxygen species used by cancer cells to maintain pro-tumorigenic signaling pathways while avoiding cellular death. The knowledge acquired on the importance of mitochondrial cancer metabolism is now being translated into clinical practice. Detailed genomic, transcriptomic, and metabolomic analysis of tumors are necessary to develop more precise treatments. The successful use of drugs targeting metabolic mitochondrial enzymes has highlighted the potential for their use in precision medicine and many therapeutic candidates are in clinical trials. However, development of efficient personalized drugs has proved challenging and the combination with other strategies such as chemocytotoxic drugs, immunotherapy, and ketogenic or calorie restriction diets is likely necessary to boost their potential. In this review, we summarize the main mitochondrial features, metabolic pathways, and their alterations in different cancer types. We also present an overview of current inhibitors, highlight enzymes that are attractive targets, and discuss challenges with translation of these approaches into clinical practice. The role of mitochondria in cancer is indisputable and presents several attractive targets for both tailored and personalized cancer therapy.<br />
}}<br />
{{Labeling<br />
|additional=MitoFit 2021 Etomoxir<br />
}}<br />
== Cited ==<br />
{{Template:Cited by Silva 2021 MitoFit Etomoxir}}</div>Komlodi Timeahttps://wiki.oroboros.at/index.php?title=Pike_2011_Biochim_Biophys_Acta&diff=235358Pike 2011 Biochim Biophys Acta2023-01-18T08:48:12Z<p>Komlodi Timea: </p>
<hr />
<div>{{Publication<br />
|title=Pike LS, Smift AL, Croteau NJ, Ferrick DA, Wu M (2011) Inhibition of fatty acid oxidation by etomoxir impairs NADPH production and increases reactive oxygen species resulting in ATP depletion and cell death in human glioblastoma cells. https://doi.org/10.1016/j.bbabio.2010.10.022<br />
|info=Biochim Biophys Acta 1807:726-34. [https://pubmed.ncbi.nlm.nih.gov/21692241/ PMID: 21692241 Open Access]<br />
|authors=Pike LS, Smift AL, Croteau NJ, Ferrick DA, Wu M<br />
|year=2011<br />
|journal=Biochim Biophys Acta<br />
|abstract=Normal differentiated cells rely primarily on mitochondrial oxidative phosphorylation to produce adenosine triphosphate (ATP) to maintain their viability and functions by using three major bioenergetic fuels: glucose, glutamine and fatty acids. Many cancer cells, however, rely on aerobic glycolysis for their growth and survival, and recent studies indicate that some cancer cells depend on glutamine as well. This altered metabolism in cancers occurs through oncogene activation or loss of tumor suppressor genes in multiple signaling pathways, including the phosphoinositide 3-kinase and Myc pathways. Relatively little is known, however, about the role of fatty acids as a bioenergetic fuel in growth and survival of cancer cells. Here, we report that human glioblastoma SF188 cells oxidize fatty acids and that inhibition of fatty acid β-oxidation by etomoxir, a carnitine palmitoyltransferase 1 inhibitor, markedly reduces cellular ATP levels and viability. We also found that inhibition of fatty acid oxidation controls the NADPH level. In the presence of reactive oxygen species scavenger tiron, however, ATP depletion is prevented without restoring fatty acid oxidation. This suggests that oxidative stress may lead to bioenergetic failure and cell death. Our work provides evidence that mitochondrial fatty acid oxidation may provide NADPH for defense against oxidative stress and prevent ATP loss and cell death.<br />
|editor=Gnaiger E<br />
}}<br />
{{Labeling<br />
|area=Respiration<br />
|diseases=Cancer<br />
|tissues=Other cell lines<br />
|preparations=Intact cells<br />
|couplingstates=ROUTINE<br />
|pathways=F<br />
|additional=MitoFit 2021 Etomoxir<br />
}}<br />
__TOC__<br />
<br />
== Cited ==<br />
Communicated by [[Gnaiger E]] (2023-01-17)<br />
{{Template:Cited by Silva 2021 MitoFit Etomoxir}}<br />
<br />
=== Critical ===<br />
:::: Pike et al (2011) is cited with critical consideration of off-target side effects of etoxomir:<br />
::::* Silva FSG, Komlodi T, Garcia-Souza LF, Bento G, Doerrier C, Oliveira PJ, Gnaiger E (2019) Can fatty acid oxidation be specifically blocked by the CPT1 inhibitor etomoxir? - [[Silva 2019 ESCI2019 |»Bioblast link«]]<br />
<br />
::::* Goretzki A, Lin YJ, Zimmermann J, Rainer H, Junker AC, Wolfheimer S, Vieths S, Scheurer S, Schülke S. Role of Glycolysis and Fatty Acid Synthesis in the Activation and T Cell-Modulating Potential of Dendritic Cells Stimulated with a TLR5-Ligand Allergen Fusion Protein. Int J Mol Sci. 2022 Oct 21;23(20):12695. https://doi.org/10.3390/ijms232012695. PMID: 36293550<br />
:::::::: Ref 12: "Inhibition of fatty acid metabolism was achieved through pretreatment with either cerulenin to block fatty acid synthase [11] or etomoxir to block fatty acid oxidation by inhibiting carnitine palmitoyltransferase 1 [12]. .. Cerulenin slightly reduced the expression levels of CD40 and CD69 by approx. 60% and 50%, respectively, while etomoxir had no effect on the expression levels of the investigated surface markers. .. This effect was abolished when the cells were either pretreated with the mTOR-inhibitor rapamycin or the inhibitors of fatty acid metabolism cerulenin or etomoxir. .. We further analyzed the contribution of fatty acid metabolism to the observed activation of mDCs by rFlaA:Betv1. Metabolically, only inhibition of fatty acid synthesis by cerulenin slightly reduced glycolysis (while having no effect on OCR). Moreover, cerulenin pretreatment dose-dependently suppressed the rFlaA:Betv1-induced IL-10- and IL-12p70 secretion, while IL-1β secretion remained unchanged. In contrast, etomoxir pretreatment slightly reduced mitochondrial oxygen consumption and interfered with antimicrobial activity otherwise observed in supernatants of rFlaA:Betv1-stimulated mDCs, but had no impact on the investigated ECAR, cytokine secretion, or expression of co-stimulatory molecules. Etomoxir concentrations greater than 5 µM were recently shown to induce mitochondrial stress associated with ROS production in human T cells independently of its effect on carnitine palmitoyltransferase 1 (CPT1a) [29]. On the basis of these results, similar '''off-target effects of etomoxir in mDCs cannot be excluded. Therefore, our results obtained in mDCs pre-treated with etomoxir have to be interpreted cautiously'''. .. 10, 50, or 100 µM etomoxir"<br />
<br />
::::* Sainero-Alcolado L, Liaño-Pons J, Ruiz-Pérez MV, Arsenian-Henriksson M. Targeting mitochondrial metabolism for precision medicine in cancer. Cell Death Differ. 2022 Jul;29(7):1304-1317. doi: 10.1038/s41418-022-01022-y. Epub 2022 Jul 13. PMID: 35831624<br />
<br />
:::::::: Ref 81: "Etomoxir further induces cell death of glioblastoma cells in vitro [81] and delays tumor apparition and progression in a glioblastoma mouse model [82]. However, '''toxicity, off-target effects on ETC Complex I, and the high doses needed, limits its potential for clinical applications'''."<br />
<br />
::::* Yao CH, Liu GY, Wang R, Moon SH, Gross RW, Patti GJ (2018) Identifying off-target effects of etomoxir reveals that carnitine palmitoyltransferase I is essential for cancer cell proliferation independent of β-oxidation. PLoS Biol 16:2003782.<br />
:::::::: Ref 15: It is common in cancer studies to use etomoxir at hundreds of micromolar concentrations [5, 15, 18, 25, 26]. .. Given that studies evaluating the role of CPT1 in cancer have commonly used concentrations of etomoxir at the hundreds of micromolar or even 1 mM level [15], <br />
:::::::: Here we show that when FAO was reduced approximately 90% by pharmacological inhibition of carnitine palmitoyltransferase I (CPT1) with low concentrations of etomoxir, the proliferation rate of various cancer cells was unaffected. Efforts to pharmacologically inhibit FAO more than 90% revealed that high concentrations of etomoxir (200 μM) have an off-target effect of inhibiting complex I of the electron transport chain. <br />
<br />
=== Belief in a paradigm ===<br />
<br />
:::: Pike et al (2011) is cited many times without sufficiently taking into account off-target side effects of etoxomir:<br />
<br />
::::* Gaca-Tabaszewska M, Bogusiewicz J, Bojko B. Metabolomic and Lipidomic Profiling of Gliomas-A New Direction in Personalized Therapies. Cancers (Basel). 2022 Oct 14;14(20):5041. doi: 10.3390/cancers14205041. PMID: 36291824<br />
:::::::: "Many studies, including those focused on gliomas, have proposed FAO as a very good potential target for new drugs. As such, researchers have considered etomoxir as a CPT-1a inhibitor, as it slows the proliferation of glioma cells and prolongs the patient’s time of survival [73]. .. Promising results have been obtained from clinical trials examining the combined use of etomoxir and reradiation to target hypoxia and improve treatment efficiency for cancers such as lung adenocarcinoma or prostate cancer [76]. In addition, Taib et al. [77] observed the significant inhibition of cell proliferation when etomoxir was applied alongside oleic acid in GBM and astrocytic cells [77]. To date, most studies in this area have employed in vitro experiments using gliomas or other cancer cells; however, the literature also contains clinical trials and animal studies demonstrating the inhibitory effects of etomoxir treatment in neurodegenerative diseases, such as Parkinson’s or Alzheimer’s disease [78]. Thus, we can assume that BBB crossing is an issue that can be overcome in the case of etomoxir and that more trials examining the use of this drug to treat gliomas are forthcoming."<br />
<br />
::::* Shim JK, Choi S, Yoon SJ, Choi RJ, Park J, Lee EH, Cho HJ, Lee S, Teo WY, Moon JH, Kim HS, Kim EH, Cheong JH, Chang JH, Yook JI, Kang SG (2022) Etomoxir, a carnitine palmitoyltransferase 1 inhibitor, combined with temozolomide reduces stemness and invasiveness in patient-derived glioblastoma tumorspheres. Cancer Cell Int 22:309. doi: 10.1186/s12935-022-02731-7. PMID: 36221088<br />
:::::::: "The importance of fatty acid oxidation (FAO) in the bioenergetics of glioblastoma (GBM) is being realized. Etomoxir (ETO), a carnitine palmitoyltransferase 1 (CPT1) inhibitor exerts cytotoxic effects in GBM, which involve interrupting the FAO pathway. We hypothesized that FAO inhibition could affect the outcomes of current standard temozolomide (TMZ) chemotherapy against GBM."<br />
<br />
::::* Wang CY, Wang CH, Mai RT, Chen TW, Li CW, Chao CH (2022) Mutant p53-microRNA-200c-ZEB2-Axis-Induced CPT1C Elevation Contributes to Metabolic Reprogramming and Tumor Progression in Basal-Like Breast Cancers. Front Oncol 12:940402. doi: 10.3389/fonc.2022.940402. PMID: 35936710<br />
:::::::: "To quantify the FAO activity which contributes to total cellular oxygen consumption, a “basal ratio” (the ratio between FAO-mediated OCR and total OCR) was assigned by the following equation: [(basal respiration of the vehicle group–basal respiration of the ETO group)/basal respiration of the vehicle group] x 100 %. As shown in Figure 1G , the basal ratio of control cells is around 13%, which means FAO contributes to 13 % of cellular oxygen consumption, whereas it was at least doubled in Mutp53-bearing MCF12A cells. .. to understand whether FAO is involved in Mutp53-promoted tumor properties, we suppressed cellular FAO activity with etomoxir (ETO), the pan-CPT1 inhibitor. The p53-R273H and p53-R280K MCF-12A cells were pretreated with ETO (50 and 100 μmol/L) for seven days, .."<br />
<br />
::::* Jiang N, Xie B, Xiao W, Fan M, Xu S, Duan Y, Hamsafar Y, Evans AC, Huang J, Zhou W, Lin X, Ye N, Wanggou S, Chen W, Jing D, Fragoso RC, Dugger BN, Wilson PF, Coleman MA, Xia S, Li X, Sun LQ, Monjazeb AM, Wang A, Murphy WJ, Kung HJ, Lam KS, Chen HW, Li JJ (2022) Fatty acid oxidation fuels glioblastoma radioresistance with CD47-mediated immune evasion. Nat Commun 13:1511. doi: 10.1038/s41467-022-29137-3. PMID: 35314680<br />
:::::::: "Inhibition of FAO by CPT1 inhibitor etomoxir or CRISPR-generated CPT1A−/−, CPT2−/−, ACAD9−/− cells demonstrate that FAO-derived acetyl-CoA upregulates CD47 transcription via NF-κB/RelA acetylation. Blocking FAO impairs tumor growth and reduces CD47 anti-phagocytosis. Etomoxir combined with anti-CD47 antibody synergizes radiation control of regrown tumors with boosted macrophage phagocytosis. These results demonstrate that enhanced fat acid metabolism promotes aggressive growth of GBM with CD47-mediated immune evasion. .. cells treated with CPT1A inhibitor etomoxir (ET; 200 µM, 24 h). .. To inhibit FAO, CPT1 inhibitor etomoxir was added into the testing wells 0.5 h before detection."<br />
<br />
::::* Wu Y, Li Y, Lv G, Bu W (2022) Redox dyshomeostasis strategy for tumor therapy based on nanomaterials chemistry. Chem Sci 13:2202-17. doi: 10.1039/d1sc06315d. PMID: 35310479<br />
::::::::Ref 62: "Besides azobenzene, etomoxir, a carnitine palmitoyltransferase 1 inhibitor, can also decrease NADPH levels, thereby reducing the GSH content by inhibiting fatty acid oxidation.62"</div>Komlodi Timeahttps://wiki.oroboros.at/index.php?title=Goretzki_2022_Int_J_Mol_Sci&diff=235357Goretzki 2022 Int J Mol Sci2023-01-18T08:46:28Z<p>Komlodi Timea: Created page with "{{Publication |title=Goretzki A, Lin YJ, Zimmermann J, Rainer H, Junker AC, Wolfheimer S, Vieths S, Scheurer S and Schülke S (2022) Role of Glycolysis and Fatty Acid Synthes..."</p>
<hr />
<div>{{Publication<br />
|title=Goretzki A, Lin YJ, Zimmermann J, Rainer H, Junker AC, Wolfheimer S, Vieths S, Scheurer S and Schülke S (2022) Role of Glycolysis and Fatty Acid Synthesis in the Activation and T Cell-Modulating Potential of Dendritic Cells Stimulated with a TLR5-Ligand Allergen Fusion Protein. Int J Mol Sci 23:12695.<br />
|info=[https://pubmed.ncbi.nlm.nih.gov/36293550/ PMID: 36293550 Open Access]<br />
|authors=Goretzki A, Lin YJ,Zimmermann J, Rainer H, Junker AC, Wolfheimer S, Vieths S, Scheurer S and Schülke S<br />
|year=2022<br />
|journal=Int J Mol Sci<br />
|abstract=Trained immune responses, based on metabolic and epigenetic changes in innate immune cells, are de facto innate immune memory and, therefore, are of great interest in vaccine development. In previous studies, the recombinant fusion protein rFlaA:Betv1, combining the adjuvant and toll-like receptor (TLR)5-ligand flagellin (FlaA) and the major birch pollen allergen Bet v 1 into a single molecule, significantly suppressed allergic sensitization in vivo while also changing the metabolism of myeloid dendritic cells (mDCs). Within this study, the immune-metabolic effects of rFlaA:Betv1 during mDC activation were elucidated. In line with results for other well-characterized TLR-ligands, rFlaA:Betv1 increased glycolysis while suppressing oxidative phosphorylation to different extents, making rFlaA:Betv1 a suitable model to study the immune-metabolic effects of TLR-adjuvanted vaccines. In vitro pretreatment of mDCs with cerulenin (inhibitor of fatty acid biosynthesis) led to a decrease in both rFlaA:Betv1-induced anti-inflammatory cytokine Interleukin (IL) 10 and T helper cell type (TH) 1-related cytokine IL-12p70, while the pro-inflammatory cytokine IL 1β was unaffected. Interestingly, pretreatment with the glutaminase inhibitor BPTES resulted in an increase in IL-1β, but decreased IL-12p70 secretion while leaving IL-10 unchanged. Inhibition of the glycolytic enzyme hexokinase-2 by 2-deoxyglucose led to a decrease in all investigated cytokines (IL-10, IL-12p70, and IL-1β). Inhibitors of mitochondrial respiration had no effect on rFlaA:Betv1-induced IL-10 level, but either enhanced the secretion of IL-1β (oligomycin) or decreased IL-12p70 (antimycin A). In extracellular flux measurements, mDCs showed a strongly enhanced glycolysis after rFlaA:Betv1 stimulation, which was slightly increased after respiratory shutdown using antimycin A. rFlaA:Betv1-stimulated mDCs secreted directly antimicrobial substances in a mTOR- and fatty acid metabolism-dependent manner. In co-cultures of rFlaA:Betv1-stimulated mDCs with CD4+ T cells, the suppression of Bet v 1-specific TH2 responses was shown to depend on fatty acid synthesis. The effector function of rFlaA:Betv1-activated mDCs mainly relies on glycolysis, with fatty acid synthesis also significantly contributing to rFlaA:Betv1-mediated cytokine secretion, the production of antimicrobial molecules, and the modulation of T cell responses.<br />
}}<br />
{{Labeling<br />
|additional=MitoFit 2021 Etomoxir<br />
}}<br />
== Cited by ==<br />
{{Template:Cited by Silva 2021 MitoFit Etomoxir}}</div>Komlodi Timeahttps://wiki.oroboros.at/index.php?title=Gaca-Tabaszewska_2022_Cancers_(Basel)&diff=235356Gaca-Tabaszewska 2022 Cancers (Basel)2023-01-18T08:32:45Z<p>Komlodi Timea: Created page with "{{Publication |title=Gaca-Tabaszewska M, Bogusiewicz J, and Bojko B (2022) Metabolomic and Lipidomic Profiling of Gliomas—A New Direction in Personalized Therapies. Cancers..."</p>
<hr />
<div>{{Publication<br />
|title=Gaca-Tabaszewska M, Bogusiewicz J, and Bojko B (2022) Metabolomic and Lipidomic Profiling of Gliomas—A New Direction in Personalized Therapies. Cancers (Basel) 14:5041.<br />
|info=[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9599495/ PMID: 36291824 Open Access]<br />
|authors=Gaca-Tabaszewska M, Bogusiewicz J, and Bojko B<br />
|year=2022<br />
|journal=Cancers (Basel)<br />
|abstract=Gliomas comprise an extremely diverse category of brain tumors that are difficult to diagnose and treat. As a result, scientists continue to search for new treatment solutions, with personalized medicine having emerged as a particularly promising therapeutic approach. Metabolomics and its sub-discipline, lipidomics, are two scientific fields well-suited to support this search. Metabolomics focuses on the physicochemical changes in the metabolome, which include all of the small endogenous and exogenous compounds in a biological system. As such, metabolic analysis can help identify important biochemical pathways which could be the targets for new therapeutic approaches. This review examines the new directions of personalized therapies for gliomas and how metabolomic and lipidomic analysis assists in developing these strategies and monitoring their effectiveness. The discussion of new strategies is preceded by a brief overview of the current “gold standard” treatment for gliomas and the obstacles that new treatment approaches must overcome.<br />
In addition to being the most common primary brain tumor, gliomas are also among the most difficult to diagnose and treat. At present, the “gold standard” in glioma treatment entails the surgical resection of the largest possible portion of the tumor, followed by temozolomide therapy and radiation. However, this approach does not always yield the desired results. Additionally, the ability to cross the blood-brain barrier remains a major challenge for new potential drugs. Thus, researchers continue to search for targeted therapies that can be individualized based on the specific characteristics of each case. Metabolic and lipidomic research may represent two of the best ways to achieve this goal, as they enable detailed insights into the changes in the profile of small molecules in a biological system/specimen. This article reviews the new approaches to glioma therapy based on the analysis of alterations to biochemical pathways, and it provides an overview of the clinical results that may support personalized therapies in the future.<br />
}}<br />
{{Labeling<br />
|additional=MitoFit 2021 Etomoxir<br />
}}<br />
== Cited by ==<br />
{{Template:Cited by Silva 2021 MitoFit Etomoxir}}</div>Komlodi Timeahttps://wiki.oroboros.at/index.php?title=Komlodi_Timea&diff=234515Komlodi Timea2022-11-30T08:21:46Z<p>Komlodi Timea: </p>
<hr />
<div>{{Person<br />
|lastname=Komlodi<br />
|firstname=Timea<br />
|title=PharmD,PhD [https://orcid.org/0000-0001-9876-1411 ORCID ID]<br />
|institution=[[File:KomlodiT.JPG|right|150px]] Department of Biochemistry Semmelweis University<br/>Timea joined [[Oroboros contact |Oroboros Instruments]] from February 2017 to February 2022. She continues her collaboration with [[AT Innsbruck Oroboros]] from her position at the Semmelweis University in Budapest.<br />
|address=Tüzolto Strett 37-47<br />
|area code=H - 1094<br />
|city=Budapest<br />
|country=Hungary<br />
|mailaddress=komlodi.timea@med.semmelweis-univ.hu<br />
}}<br />
{{Labelingperson<br />
|field of research=Basic<br />
}}<br />
{{EAGLE<br />
|COST = Member<br />
|COST WG1= WG1<br />
|COST WG4= WG4<br />
|COST ECI=ECI<br />
}}<br />
{{NextGen-O2k H2020-support}}<br />
<br />
<br />
__TOC__<br />
== Bioenergetics Communications ==<br />
::::* Timea Komlodi is Section Editor of the journal '''[[Bioenergetics Communications]]'''<br />
:::::'''Keywords:''' mitochondria, bioenergetics, reactive oxygen species, coenzyme Q redox <br />
<br />
== MitoEAGLE Short-Term Scientific Mission ==<br />
****: [[Short-Term_Scientific_Missions_MitoEAGLE#STSM_Grant_Period_1 |STSM Grant Period 1]]<br />
::: '''Motivation letter'''<br />
::::I am writing this letter to apply for the Short-Term Scientific Mission (STSM) covered by MitoEAGLE–COST Action CA15203 (1st Call for STSM Applications).<br />
::::My name is Tímea Komlódi. I studied at Semmelweis University at the Faculty of Pharmacy. After graduation, in 2013, I started working as a PhD student at the Semmelweis University in the Department of Medical Biochemistry, Hungary.<br />
::::My main topic of interest is energy metabolism and mitochondrial homeostasis under physiological and pathological conditions. Our group focuses mainly on neurodegenerative diseases like Alzheimer’s and Parkinson’s disease, which are attributed to mitochondrial dysfunction. I have experience in measurement of mitochondrial respiration, ATP synthesis, membrane potential, reactive oxygen species production and intra- and extramitochondrial pH detection.<br />
::::In the future I am planning to deepen my knowledge about mitochondria and to expand it towards cell lines. The STSM grant would give the opportunity to deal with mitochondrial physiology and cell lines at the Oroboros Instruments in Innsbruck. The focus of the STSM project is the standardization of protocols in mitochondrial respirometry which could contribute to the scientific objective of MitoEAGLE. During the 8-day STSM mission I could acquire new measurement protocols which could be applied in future projects. These are the planned program of the STSM mission: 1.) detection of reactive oxygen species production of permeabilized cells using fluorescent probes; 2.) determination of mitochondrial membrane potential with safranin, TMRM and TPP+; 3.) assessment of mitochondrial P/O ratio by measuring ATP levels fluorometrically.<br />
::::The STSM training would provide a platform for an international discussion and standardization of protocols, data and measurement techniques. Furthermore, the STSM project could be a basis of a flourishing cooperation with the Oroboros laboratory in Innsbruck in the near future.<br />
::::I would like to participate in the MitoEAGLE projects because it provides the opportunity to<br />
::::take part in data establishment and comparison of data between different research groups.<br />
::::Moreover, Oroboros laboratory would provide a platform with its instrumental background,with its protocols and with its international connections to the objectives and aim of MitoEAGLE.<br />
<br />
::: '''STSM request''': [http://wiki.oroboros.at/images/2/27/Komlodi_T_STSM_Request_CA15203.pdf ''download pdf'']<br />
== MitoEAGLE==<br />
<br />
****: '''Benefits for COST and for the COST Action MitoEAGLE'''<br />
<br />
:::: During my PhD I worked with brain, heart and liver mitochondria isolated from guinea pig and in this summer I started to deal with cultured cell lines<br />
<br />
<br />
<br />
<br />
== Participated at ==<br />
<br />
::::* [[Bioblast 2022|Bioblast 2022: BEC Inaugural Conference]]<br />
<br />
::::* [[FAT4BRAIN Workshop IOC151 Innsbruck AT]]<br />
::::* [[MiPNet 26.16 NextGen-O2k Summit 2021 Virtual|NextGen-O2k Summit 2021 Virtual]]<br />
::::* [[SHVM 2021 Virtual]]<br />
::::* [[FAT4BRAIN Advanced O2k-Workshop IOC149 Virtual]]<br />
::::* [[ESCI 2021 Virtual]]<br />
::::* [[MiPNet25.06 IOC145 Innsbruck AT|IOC145 Innsbruck AT]]<br />
::::* [[MiPNet25.03 IOC144 Innsbruck AT|IOC144 Innsbruck AT]]<br />
::::* [[IOC141|IOC141 Schroecken AT]]<br />
::::* [[IOC139| IOC139 Schroecken AT]]<br />
::::* [[ESCI 2019 Coimbra PT]]<br />
::::* [[MitoEAGLE WG1 Coimbra 2019| MitoEAGLE WG1 2019 Coimbra PT]]<br />
::::* [[MitoEAGLE_Innsbruck_2018-11-19| MitoEAGLE 2018 Innsbruck AT]] (local organizer)<br />
::::* [[IOC134|IOC134 Schroecken AT]]<br />
::::* [[IOC133|IOC133 Innsbruck AT]]<br />
::::* [[IOC132|IOC132 Budapest HU]]<br />
::::* [[IOC127|IOC127 Szeged HU]]<br />
::::* [[MitoFit Workshop ATP 2017 Innsbruck AT]]<br />
::::* [[MiP2017/MitoEAGLE Hradec Kralove CZ|MitoEAGLE 2017 Hradec Kralove CZ]]<br />
::::* [[IOC124| IOC124 Schroecken AT]]<br />
::::* [[MiPschool Obergurgl 2017| MiPschool 2017 Obergurgl AT]]<br />
::::* [[MitoEAGLE Barcelona 2017| MitoEAGLE 2017 Barcelona ES]]<br />
::::* [[MiP2014 | MiP2014 Obergurgl AT]]<br />
::::* [[IOC116 | IOC116 Innsbruck AT]]<br />
<br />
== Visiting scientist in the Oroboros O2k-Laboratory ==<br />
<br />
:::: [[Image:O2k-Network.png|left|40px|link=O2k-Network|O2k-Network]]<br />
[[Komlodi Timea| Timea Komlòdi ]]: Visiting scientist at the [[Oroboros Laboratories: visiting scientists |Oroboros O2k-Laboratory]]<br />
::::::* 2016, November 21 to 28</div>Komlodi Timeahttps://wiki.oroboros.at/index.php?title=Komlodi_Timea&diff=234514Komlodi Timea2022-11-30T08:20:44Z<p>Komlodi Timea: </p>
<hr />
<div>{{Person<br />
|lastname=Komlodi<br />
|firstname=Timea<br />
|title=PharmD,PhD [https://orcid.org/0000-0001-9876-1411 ORCID ID]<br />
|institution=[[File:KomlodiT.JPG|right|150px]] Department of BiochemistrySemmelweis University<br/>Timea joined [[Oroboros contact |Oroboros Instruments]] from February 2017 to February 2022. She continues her collaboration with [[AT Innsbruck Oroboros]] from her position at the Semmelweis University in Budapest.<br />
|address=Tüzolto Strett 37-47<br />
|area code=H - 1094<br />
|city=Budapest<br />
|country=Hungary<br />
|mailaddress=komlodi.timea@med.semmelweis-univ.hu<br />
}}<br />
{{Labelingperson<br />
|field of research=Basic<br />
}}<br />
{{EAGLE<br />
|COST = Member<br />
|COST WG1= WG1<br />
|COST WG4= WG4<br />
|COST ECI=ECI<br />
}}<br />
{{NextGen-O2k H2020-support}}<br />
<br />
<br />
__TOC__<br />
== Bioenergetics Communications ==<br />
::::* Timea Komlodi is Section Editor of the journal '''[[Bioenergetics Communications]]'''<br />
:::::'''Keywords:''' mitochondria, bioenergetics, reactive oxygen species, coenzyme Q redox <br />
<br />
== MitoEAGLE Short-Term Scientific Mission ==<br />
****: [[Short-Term_Scientific_Missions_MitoEAGLE#STSM_Grant_Period_1 |STSM Grant Period 1]]<br />
::: '''Motivation letter'''<br />
::::I am writing this letter to apply for the Short-Term Scientific Mission (STSM) covered by MitoEAGLE–COST Action CA15203 (1st Call for STSM Applications).<br />
::::My name is Tímea Komlódi. I studied at Semmelweis University at the Faculty of Pharmacy. After graduation, in 2013, I started working as a PhD student at the Semmelweis University in the Department of Medical Biochemistry, Hungary.<br />
::::My main topic of interest is energy metabolism and mitochondrial homeostasis under physiological and pathological conditions. Our group focuses mainly on neurodegenerative diseases like Alzheimer’s and Parkinson’s disease, which are attributed to mitochondrial dysfunction. I have experience in measurement of mitochondrial respiration, ATP synthesis, membrane potential, reactive oxygen species production and intra- and extramitochondrial pH detection.<br />
::::In the future I am planning to deepen my knowledge about mitochondria and to expand it towards cell lines. The STSM grant would give the opportunity to deal with mitochondrial physiology and cell lines at the Oroboros Instruments in Innsbruck. The focus of the STSM project is the standardization of protocols in mitochondrial respirometry which could contribute to the scientific objective of MitoEAGLE. During the 8-day STSM mission I could acquire new measurement protocols which could be applied in future projects. These are the planned program of the STSM mission: 1.) detection of reactive oxygen species production of permeabilized cells using fluorescent probes; 2.) determination of mitochondrial membrane potential with safranin, TMRM and TPP+; 3.) assessment of mitochondrial P/O ratio by measuring ATP levels fluorometrically.<br />
::::The STSM training would provide a platform for an international discussion and standardization of protocols, data and measurement techniques. Furthermore, the STSM project could be a basis of a flourishing cooperation with the Oroboros laboratory in Innsbruck in the near future.<br />
::::I would like to participate in the MitoEAGLE projects because it provides the opportunity to<br />
::::take part in data establishment and comparison of data between different research groups.<br />
::::Moreover, Oroboros laboratory would provide a platform with its instrumental background,with its protocols and with its international connections to the objectives and aim of MitoEAGLE.<br />
<br />
::: '''STSM request''': [http://wiki.oroboros.at/images/2/27/Komlodi_T_STSM_Request_CA15203.pdf ''download pdf'']<br />
== MitoEAGLE==<br />
<br />
****: '''Benefits for COST and for the COST Action MitoEAGLE'''<br />
<br />
:::: During my PhD I worked with brain, heart and liver mitochondria isolated from guinea pig and in this summer I started to deal with cultured cell lines<br />
<br />
<br />
<br />
<br />
== Participated at ==<br />
<br />
::::* [[Bioblast 2022|Bioblast 2022: BEC Inaugural Conference]]<br />
<br />
::::* [[FAT4BRAIN Workshop IOC151 Innsbruck AT]]<br />
::::* [[MiPNet 26.16 NextGen-O2k Summit 2021 Virtual|NextGen-O2k Summit 2021 Virtual]]<br />
::::* [[SHVM 2021 Virtual]]<br />
::::* [[FAT4BRAIN Advanced O2k-Workshop IOC149 Virtual]]<br />
::::* [[ESCI 2021 Virtual]]<br />
::::* [[MiPNet25.06 IOC145 Innsbruck AT|IOC145 Innsbruck AT]]<br />
::::* [[MiPNet25.03 IOC144 Innsbruck AT|IOC144 Innsbruck AT]]<br />
::::* [[IOC141|IOC141 Schroecken AT]]<br />
::::* [[IOC139| IOC139 Schroecken AT]]<br />
::::* [[ESCI 2019 Coimbra PT]]<br />
::::* [[MitoEAGLE WG1 Coimbra 2019| MitoEAGLE WG1 2019 Coimbra PT]]<br />
::::* [[MitoEAGLE_Innsbruck_2018-11-19| MitoEAGLE 2018 Innsbruck AT]] (local organizer)<br />
::::* [[IOC134|IOC134 Schroecken AT]]<br />
::::* [[IOC133|IOC133 Innsbruck AT]]<br />
::::* [[IOC132|IOC132 Budapest HU]]<br />
::::* [[IOC127|IOC127 Szeged HU]]<br />
::::* [[MitoFit Workshop ATP 2017 Innsbruck AT]]<br />
::::* [[MiP2017/MitoEAGLE Hradec Kralove CZ|MitoEAGLE 2017 Hradec Kralove CZ]]<br />
::::* [[IOC124| IOC124 Schroecken AT]]<br />
::::* [[MiPschool Obergurgl 2017| MiPschool 2017 Obergurgl AT]]<br />
::::* [[MitoEAGLE Barcelona 2017| MitoEAGLE 2017 Barcelona ES]]<br />
::::* [[MiP2014 | MiP2014 Obergurgl AT]]<br />
::::* [[IOC116 | IOC116 Innsbruck AT]]<br />
<br />
== Visiting scientist in the Oroboros O2k-Laboratory ==<br />
<br />
:::: [[Image:O2k-Network.png|left|40px|link=O2k-Network|O2k-Network]]<br />
[[Komlodi Timea| Timea Komlòdi ]]: Visiting scientist at the [[Oroboros Laboratories: visiting scientists |Oroboros O2k-Laboratory]]<br />
::::::* 2016, November 21 to 28</div>Komlodi Timeahttps://wiki.oroboros.at/index.php?title=Chalmers_2003_J_Biol_Chem&diff=234373Chalmers 2003 J Biol Chem2022-11-24T13:17:41Z<p>Komlodi Timea: </p>
<hr />
<div>{{Publication<br />
|title=Chalmers S, Nicholls DG (2003) The relationship between free and total calcium concentrations in the matrix of liver and brain mitochondria. J Biol Chem 278(21):19062-70.<br />
|info=[https://pubmed.ncbi.nlm.nih.gov/12660243/?from_single_result=Chalmers%2C+S.+%26+Nicholls%2C+D.+G.+%282003%29%2C+%27The+relationship+between+free+and+total+calcium+concentrations+in+the+matrix+of+liver+and+brain+mitochondria.%27%2C+J+Biol+Chem+278%2821%29%2C+19062--+19070&expanded_search_query=Chalmers%2C+S.+%26+Nicholls%2C+D.+G.+%282003%29%2C+%27The+relationship+between+free+and+total+calcium+concentrations+in+the+matrix+of+liver+and+brain+mitochondria.%27%2C+J+Biol+Chem+278%2821%29%2C+19062--+19070 PMID: 12660243 Open Access]<br />
|authors=Chalmers S, Nicholls DG<br />
|year=2003<br />
|journal=J Biol Chem<br />
|abstract=Three sequential phases of mitochondrial calcium accumulation can be distinguished: matrix dehydrogenase regulation, buffering of extramitochondrial free calcium, and finally activation of the permeability transition. Relationships between these phases, free and total matrix calcium concentration, and phosphate concentration are investigated in rat liver and brain mitochondria. Slow, continuous calcium infusion is employed to avoid transient bioenergetic consequences of bolus additions. Liver and brain mitochondria undergo permeability transitions at precise matrix calcium loads that are independent of infusion rate. Cytochrome c release precedes the permeability transition. Cyclosporin A enhances the loading capacity in the presence or absence of acetoacetate. A remarkably constant free matrix calcium concentration, in the range 1-5 microM as monitored by matrix-loaded fura2-FF, was observed when total matrix calcium was increased from 10 to at least 500 nmol of calcium/mg of protein. Increasing phosphate decreased both the free matrix calcium and the matrix calcium-loading capacity. Thus the permeability transition is not triggered by a critical matrix free calcium concentration. The rate of hydrogen peroxide detection by Amplex Red decreased during calcium infusion arguing against a role for oxidative stress in permeability pore activation in this model. A transition between a variable and buffered matrix free calcium concentration occurred at 10 nmol of total matrix calcium/mg protein. The solubility product of amorphous Ca3(PO4)2 is consistent with the observed matrix free calcium concentration, and the matrix pH is proposed to play the major role in maintaining the low matrix free calcium concentration.<br />
|keywords=free calcium, liver, brain<br />
|editor=[[Cecatto C]]<br />
}}<br />
{{Labeling<br />
|organism=Rat<br />
|tissues=Nervous system, Liver<br />
|topics=Calcium, mt-Membrane potential, Phosphate, Redox state<br />
|additional=2020-05, Ca-list, MitoFit 2022 pmF<br />
}}<br />
== Cited by ==<br />
{{Template:Cited by Komlodi 2022 MitoFit pmF}}</div>Komlodi Timeahttps://wiki.oroboros.at/index.php?title=Rolfe_1994_Biochim_Biophys_Acta&diff=234372Rolfe 1994 Biochim Biophys Acta2022-11-24T10:36:31Z<p>Komlodi Timea: </p>
<hr />
<div>{{Publication<br />
|title=Rolfe DF, Hulbert AJ, Brand MD (1994) Characteristics of mitochondrial proton leak and control of oxidative phosphorylation in the major oxygen-consuming tissues of the rat. Biochim Biophys Acta 1188:405-16.<br />
|info=[https://pubmed.ncbi.nlm.nih.gov/7803454/ PMID:7803454]<br />
|authors=Rolfe DF, Hulbert AJ, Brand MD<br />
|year=1994<br />
|journal=Biochim Biophys Acta<br />
|abstract=Maintenance of an electrochemical proton gradient across the mitochondrial inner membrane against the significant proton permeability of the membrane accounts for 25-30% of resting oxygen consumption in hepatocytes. It has been proposed that proton leak could be a significant contributor to resting metabolic rate in mammals if it were present in other tissues. Mitochondria were isolated from the major oxygen-consuming tissues (liver, kidney, brain and skeletal muscle) of the rat. In each tissue, the mitochondria showed significant proton leak with the same characteristic non-linear dependence on membrane potential. Liver and kidney mitochondria showed similar membrane proton permeability per mg of mitochondrial protein; brain and muscle permeabilities were greater when expressed in this way. Differences in the kinetic response of the substrate oxidation and phosphorylating systems to membrane potential were observed. The substrate oxidation system was more active in kidney, brain and skeletal muscle mitochondria than in liver mitochondria per mg of mitochondrial protein. Liver and kidney phosphorylating systems were less active than brain and skeletal muscle per mg of mitochondrial protein. The control of oxidative phosphorylation was also assessed. The distribution of control in mitochondria isolated from the four tissue types was found to be similar.<br />
}}<br />
{{Labeling<br />
|additional=MitoFit 2021 Tissue normoxia, MitoFit 2022 pmF<br />
}}<br />
== Cited by ==<br />
{{Template:Cited by Komlodi 2021 MitoFit Tissue normoxia}}<br />
{{Template:Cited by Komlodi 2022 MitoFit pmF}}</div>Komlodi Timeahttps://wiki.oroboros.at/index.php?title=Rolfe_1994_Biochim_Biophys_Acta&diff=234371Rolfe 1994 Biochim Biophys Acta2022-11-24T10:25:10Z<p>Komlodi Timea: </p>
<hr />
<div>{{Publication<br />
|title=Rolfe DF, Hulbert AJ, Brand MD (1994) Characteristics of mitochondrial proton leak and control of oxidative phosphorylation in the major oxygen-consuming tissues of the rat. Biochim Biophys Acta 1188:405-16.<br />
|info=[https://pubmed.ncbi.nlm.nih.gov/7803454/ PMID:7803454]<br />
|authors=Rolfe DF, Hulbert AJ, Brand MD<br />
|year=1994<br />
|journal=Biochim Biophys Acta<br />
|abstract=Maintenance of an electrochemical proton gradient across the mitochondrial inner membrane against the significant proton permeability of the membrane accounts for 25-30% of resting oxygen consumption in hepatocytes. It has been proposed that proton leak could be a significant contributor to resting metabolic rate in mammals if it were present in other tissues. Mitochondria were isolated from the major oxygen-consuming tissues (liver, kidney, brain and skeletal muscle) of the rat. In each tissue, the mitochondria showed significant proton leak with the same characteristic non-linear dependence on membrane potential. Liver and kidney mitochondria showed similar membrane proton permeability per mg of mitochondrial protein; brain and muscle permeabilities were greater when expressed in this way. Differences in the kinetic response of the substrate oxidation and phosphorylating systems to membrane potential were observed. The substrate oxidation system was more active in kidney, brain and skeletal muscle mitochondria than in liver mitochondria per mg of mitochondrial protein. Liver and kidney phosphorylating systems were less active than brain and skeletal muscle per mg of mitochondrial protein. The control of oxidative phosphorylation was also assessed. The distribution of control in mitochondria isolated from the four tissue types was found to be similar.<br />
}}<br />
{{Labeling<br />
|additional=MitoFit 2021 Tissue normoxia, Komlodi 2022 MitoFit<br />
}}<br />
== Cited by ==<br />
{{Template:Cited by Komlodi 2021 MitoFit Tissue normoxia}}<br />
{{Template:Cited by Komlodi 2022 MitoFit pmF}}</div>Komlodi Timeahttps://wiki.oroboros.at/index.php?title=Rolfe_1994_Biochim_Biophys_Acta&diff=234370Rolfe 1994 Biochim Biophys Acta2022-11-24T10:24:11Z<p>Komlodi Timea: </p>
<hr />
<div>{{Publication<br />
|title=Rolfe DF, Hulbert AJ, Brand MD (1994) Characteristics of mitochondrial proton leak and control of oxidative phosphorylation in the major oxygen-consuming tissues of the rat. Biochim Biophys Acta 1188:405-16.<br />
|info=[https://pubmed.ncbi.nlm.nih.gov/7803454/ PMID:7803454]<br />
|authors=Rolfe DF, Hulbert AJ, Brand MD<br />
|year=1994<br />
|journal=Biochim Biophys Acta<br />
|abstract=Maintenance of an electrochemical proton gradient across the mitochondrial inner membrane against the significant proton permeability of the membrane accounts for 25-30% of resting oxygen consumption in hepatocytes. It has been proposed that proton leak could be a significant contributor to resting metabolic rate in mammals if it were present in other tissues. Mitochondria were isolated from the major oxygen-consuming tissues (liver, kidney, brain and skeletal muscle) of the rat. In each tissue, the mitochondria showed significant proton leak with the same characteristic non-linear dependence on membrane potential. Liver and kidney mitochondria showed similar membrane proton permeability per mg of mitochondrial protein; brain and muscle permeabilities were greater when expressed in this way. Differences in the kinetic response of the substrate oxidation and phosphorylating systems to membrane potential were observed. The substrate oxidation system was more active in kidney, brain and skeletal muscle mitochondria than in liver mitochondria per mg of mitochondrial protein. Liver and kidney phosphorylating systems were less active than brain and skeletal muscle per mg of mitochondrial protein. The control of oxidative phosphorylation was also assessed. The distribution of control in mitochondria isolated from the four tissue types was found to be similar.<br />
}}<br />
{{Labeling<br />
|additional=MitoFit 2021 Tissue normoxia, Komlodi 2022 MitoFit<br />
}}<br />
== Cited by ==<br />
{{Template:Cited by Komlodi 2021 MitoFit Tissue normoxia}}<br />
{{Template:Cited by Komlodi 2022 MitoFit }}</div>Komlodi Timeahttps://wiki.oroboros.at/index.php?title=Rolfe_1994_Biochim_Biophys_Acta&diff=234369Rolfe 1994 Biochim Biophys Acta2022-11-24T10:23:38Z<p>Komlodi Timea: </p>
<hr />
<div>{{Publication<br />
|title=Rolfe DF, Hulbert AJ, Brand MD (1994) Characteristics of mitochondrial proton leak and control of oxidative phosphorylation in the major oxygen-consuming tissues of the rat. Biochim Biophys Acta 1188:405-16.<br />
|info=[https://pubmed.ncbi.nlm.nih.gov/7803454/ PMID:7803454]<br />
|authors=Rolfe DF, Hulbert AJ, Brand MD<br />
|year=1994<br />
|journal=Biochim Biophys Acta<br />
|abstract=Maintenance of an electrochemical proton gradient across the mitochondrial inner membrane against the significant proton permeability of the membrane accounts for 25-30% of resting oxygen consumption in hepatocytes. It has been proposed that proton leak could be a significant contributor to resting metabolic rate in mammals if it were present in other tissues. Mitochondria were isolated from the major oxygen-consuming tissues (liver, kidney, brain and skeletal muscle) of the rat. In each tissue, the mitochondria showed significant proton leak with the same characteristic non-linear dependence on membrane potential. Liver and kidney mitochondria showed similar membrane proton permeability per mg of mitochondrial protein; brain and muscle permeabilities were greater when expressed in this way. Differences in the kinetic response of the substrate oxidation and phosphorylating systems to membrane potential were observed. The substrate oxidation system was more active in kidney, brain and skeletal muscle mitochondria than in liver mitochondria per mg of mitochondrial protein. Liver and kidney phosphorylating systems were less active than brain and skeletal muscle per mg of mitochondrial protein. The control of oxidative phosphorylation was also assessed. The distribution of control in mitochondria isolated from the four tissue types was found to be similar.<br />
}}<br />
{{Labeling<br />
|additional=MitoFit 2021 Tissue normoxia, Komlodi 2022 MitoFit<br />
}}<br />
== Cited by ==<br />
{{Template:Cited by Komlodi 2021 MitoFit Tissue normoxia}}</div>Komlodi Timeahttps://wiki.oroboros.at/index.php?title=Votyakova_2004_Arch_Biochem_Biophys&diff=230623Votyakova 2004 Arch Biochem Biophys2022-07-21T12:18:35Z<p>Komlodi Timea: </p>
<hr />
<div>{{Publication<br />
|title=Votyakova TV, Reynolds IJ (2004) Detection of hydrogen peroxide with Amplex Red: interference by NADH and reduced glutathione auto-oxidation. Arch Biochem Biophys 431:138-44.<br />
|info=[https://pubmed.ncbi.nlm.nih.gov/15464736/ PMID:15464736]<br />
|authors=Votyakova TV, Reynolds IJ<br />
|year=2004<br />
|journal=Arch Biochem Biophys<br />
|abstract=We report here that reduced pyridine nucleotides and reduced glutathione result in an oxidation of Amplex Red by dioxygen that is dependent on the presence of horseradish peroxidase (HRP). Concentrations of NADH and glutathione typically found in biological systems result in the oxidation of Amplex Red at a rate comparable to that produced, for example, by respiring mitochondria. The effects of NADH and glutathione in this assay system are likely to be the result of H(2)O(2) generation via a superoxide intermediate because both catalase and superoxide dismutase prevent the oxidation of Amplex Red. These results suggest caution in the assay of H(2)O(2) production in biological systems using the Amplex Red/HRP because the assay will also report the mobilization of NADH or glutathione. However, the interruption of this process by the addition of superoxide dismutase offers a simple and reliable method for establishing the source of the oxidant signal.<br />
}}<br />
== Cited by ==<br />
{{Template:Cited by Komlodi 2021 MitoFit AmR-O2}}<br />
{{Template:Cited by Komlodi 2021 MitoFit Tissue normoxia}}<br />
{{Labeling<br />
|additional=MitoFit 2021 AmR-O2, MitoFit 2021 Tissue normoxia<br />
}}</div>Komlodi Timeahttps://wiki.oroboros.at/index.php?title=Auger_2015_Front_Cell_Dev_Biol&diff=228062Auger 2015 Front Cell Dev Biol2022-05-31T16:23:43Z<p>Komlodi Timea: </p>
<hr />
<div>{{Publication<br />
|title=Auger C, Alhasawi A, Contavadoo M, Appanna VD (2015) Dysfunctional mitochondrial bioenergetics and the pathogenesis of hepatic disorders. Front Cell Dev Biol 3:40.<br />
|info=[https://pubmed.ncbi.nlm.nih.gov/26161384/ PMID:26161384 Open Access]<br />
|authors=Auger C, Alhasawi A, Contavadoo M, Appanna VD<br />
|year=2015<br />
|journal=Front Cell Dev Biol<br />
|abstract=The liver is involved in a variety of critical biological functions including the homeostasis of glucose, fatty acids, amino acids, and the synthesis of proteins that are secreted in the blood. It is also at the forefront in the detoxification of noxious metabolites that would otherwise upset the functioning of the body. As such, this vital component of the mammalian system is exposed to a notable quantity of toxicants on a regular basis. It therefore comes as no surprise that there are over a hundred disparate hepatic disorders, encompassing such afflictions as fatty liver disease, hepatitis, and liver cancer. Most if not all of liver functions are dependent on energy, an ingredient that is primarily generated by the mitochondrion, the power house of all cells. This organelle is indispensable in providing adenosine triphosphate (ATP), a key effector of most biological processes. Dysfunctional mitochondria lead to a shortage in ATP, the leakage of deleterious reactive oxygen species (ROS), and the excessive storage of fats. Here we examine how incapacitated mitochondrial bioenergetics triggers the pathogenesis of various hepatic diseases. Exposure of liver cells to detrimental environmental hazards such as oxidative stress, metal toxicity, and various xenobiotics results in the inactivation of crucial mitochondrial enzymes and decreased ATP levels. The contribution of the latter to hepatic disorders and potential therapeutic cues to remedy these conditions are elaborated.<br />
}}<br />
== Cited by ==<br />
{{Template:Cited by Silva 2021 MitoFit Etomoxir}}<br />
{{Labeling<br />
|additional=MitoFit 2021 Etomoxir<br />
}}</div>Komlodi Timeahttps://wiki.oroboros.at/index.php?title=Auger_2015_Front_Cell_Dev_Biol&diff=228061Auger 2015 Front Cell Dev Biol2022-05-31T16:21:30Z<p>Komlodi Timea: Created page with "{{Publication |title=Auger C, Alhasawi A, Contavadoo M, Appanna VD (2015) Dysfunctional mitochondrial bioenergetics and the pathogenesis of hepatic disorders. Front Cell Dev..."</p>
<hr />
<div>{{Publication<br />
|title=Auger C, Alhasawi A, Contavadoo M, Appanna VD (2015) Dysfunctional mitochondrial bioenergetics and the pathogenesis of hepatic disorders. Front Cell Dev Biol 3:40.<br />
|info=[https://pubmed.ncbi.nlm.nih.gov/26161384/ PMID:26161384 Open Access]<br />
|authors=Auger C, Alhasawi A, Contavadoo M, Appanna VD<br />
|year=2015<br />
|journal=Front Cell Dev Biol<br />
|abstract=The liver is involved in a variety of critical biological functions including the homeostasis of glucose, fatty acids, amino acids, and the synthesis of proteins that are secreted in the blood. It is also at the forefront in the detoxification of noxious metabolites that would otherwise upset the functioning of the body. As such, this vital component of the mammalian system is exposed to a notable quantity of toxicants on a regular basis. It therefore comes as no surprise that there are over a hundred disparate hepatic disorders, encompassing such afflictions as fatty liver disease, hepatitis, and liver cancer. Most if not all of liver functions are dependent on energy, an ingredient that is primarily generated by the mitochondrion, the power house of all cells. This organelle is indispensable in providing adenosine triphosphate (ATP), a key effector of most biological processes. Dysfunctional mitochondria lead to a shortage in ATP, the leakage of deleterious reactive oxygen species (ROS), and the excessive storage of fats. Here we examine how incapacitated mitochondrial bioenergetics triggers the pathogenesis of various hepatic diseases. Exposure of liver cells to detrimental environmental hazards such as oxidative stress, metal toxicity, and various xenobiotics results in the inactivation of crucial mitochondrial enzymes and decreased ATP levels. The contribution of the latter to hepatic disorders and potential therapeutic cues to remedy these conditions are elaborated.<br />
}}<br />
{{Labeling<br />
|additional=MitoFit 2021 Etomoxir<br />
}}</div>Komlodi Timeahttps://wiki.oroboros.at/index.php?title=Tarasenko_2015_Biochim_Biophys_Acta&diff=228060Tarasenko 2015 Biochim Biophys Acta2022-05-31T16:19:53Z<p>Komlodi Timea: </p>
<hr />
<div>{{Publication<br />
|title=Tarasenko TN, Singh LN, Chatterji-Len M, Zerfas PM, Cusmano-Ozog K, McGuire PJ (2015) Kupffer cells modulate hepatic fatty acid oxidation during infection with PR8 influenza. Biochim Biophys Acta 1852:2391-401.<br />
|info=[https://pubmed.ncbi.nlm.nih.gov/26319418/ PMID:26319418 Open Access]<br />
|authors=Tarasenko TN, Singh LN, Chatterji-Len M, Zerfas PM, Cusmano-Ozog K, McGuire PJ<br />
|year=2015<br />
|journal=Biochim Biophys Acta<br />
|abstract=In response to infection, patients with inborn errors of metabolism may develop a functional deterioration termed metabolic decompensation. The biochemical hallmarks of this disruption of metabolic homeostasis are disease specific and may include acidosis, hyperammonemia or hypoglycemia. In a model system previously published by our group, we noted that during influenza infection, mice displayed a depression in hepatic mitochondrial enzymes involved in nitrogen metabolism. Based on these findings, we hypothesized that this normal adaptation may extend to other metabolic pathways, and as such, may impact various inborn errors of metabolism. Since the liver is a critical organ in inborn errors of metabolism, we carried out untargeted metabolomic profiling of livers using mass spectrometry in C57Bl/6 mice infected with influenza to characterize metabolic adaptation. Pathway analysis of metabolomic data revealed reductions in CoA synthesis, and long chain fatty acyl CoA and carnitine species. These metabolic adaptations coincided with a depression in hepatic long chain β-oxidation mRNA and protein. To our surprise, the metabolic changes observed occurred in conjunction with a hepatic innate immune response, as demonstrated by transcriptional profiling and flow cytometry. By employing an immunomodulation strategy to deplete Kupffer cells, we were able to improve the expression of multiple genes involved in β-oxidation. Based on these findings, we are the first to suggest that the role of the liver as an immunologic organ is central in the pathophysiology of hepatic metabolic decompensation in inborn errors of metabolism due to respiratory viral infection.<br />
}}<br />
== Cited by ==<br />
{{Template:Cited by Silva 2021 MitoFit Etomoxir}}<br />
{{Labeling<br />
|additional=MitoFit 2021 Etomoxir<br />
}}</div>Komlodi Timeahttps://wiki.oroboros.at/index.php?title=Tarasenko_2015_Biochim_Biophys_Acta&diff=228059Tarasenko 2015 Biochim Biophys Acta2022-05-31T16:19:21Z<p>Komlodi Timea: Created page with "{{Publication |title=Tarasenko TN, Singh LN, Chatterji-Len M, Zerfas PM, Cusmano-Ozog K, McGuire PJ (2015) Kupffer cells modulate hepatic fatty acid oxidation during infection..."</p>
<hr />
<div>{{Publication<br />
|title=Tarasenko TN, Singh LN, Chatterji-Len M, Zerfas PM, Cusmano-Ozog K, McGuire PJ (2015) Kupffer cells modulate hepatic fatty acid oxidation during infection with PR8 influenza. Biochim Biophys Acta 1852:2391-401.<br />
|info=[https://pubmed.ncbi.nlm.nih.gov/26319418/ PMID:26319418 Open Access]<br />
|authors=Tarasenko TN, Singh LN, Chatterji-Len M, Zerfas PM, Cusmano-Ozog K, McGuire PJ<br />
|year=2015<br />
|journal=Biochim Biophys Acta<br />
|abstract=In response to infection, patients with inborn errors of metabolism may develop a functional deterioration termed metabolic decompensation. The biochemical hallmarks of this disruption of metabolic homeostasis are disease specific and may include acidosis, hyperammonemia or hypoglycemia. In a model system previously published by our group, we noted that during influenza infection, mice displayed a depression in hepatic mitochondrial enzymes involved in nitrogen metabolism. Based on these findings, we hypothesized that this normal adaptation may extend to other metabolic pathways, and as such, may impact various inborn errors of metabolism. Since the liver is a critical organ in inborn errors of metabolism, we carried out untargeted metabolomic profiling of livers using mass spectrometry in C57Bl/6 mice infected with influenza to characterize metabolic adaptation. Pathway analysis of metabolomic data revealed reductions in CoA synthesis, and long chain fatty acyl CoA and carnitine species. These metabolic adaptations coincided with a depression in hepatic long chain β-oxidation mRNA and protein. To our surprise, the metabolic changes observed occurred in conjunction with a hepatic innate immune response, as demonstrated by transcriptional profiling and flow cytometry. By employing an immunomodulation strategy to deplete Kupffer cells, we were able to improve the expression of multiple genes involved in β-oxidation. Based on these findings, we are the first to suggest that the role of the liver as an immunologic organ is central in the pathophysiology of hepatic metabolic decompensation in inborn errors of metabolism due to respiratory viral infection.<br />
}}<br />
{{Labeling<br />
|additional=MitoFit 2021 Etomoxir<br />
}}</div>Komlodi Timeahttps://wiki.oroboros.at/index.php?title=Bastos_2019_Clin_Mol_Hepatol&diff=228058Bastos 2019 Clin Mol Hepatol2022-05-31T16:17:50Z<p>Komlodi Timea: </p>
<hr />
<div>{{Publication<br />
|title=Bastos KLM, Quaio CR, Lima FR, Araújo IM, Araújo CAT, Piazzon FB, Silva IDCG, Benevides GN, Tannuri AC, Tannuri U, Azevedo RA, Kim CA (2019) Biochemical profile in an infant with neonatal hemochromatosis shows evidence of impairment of mitochondrial long-chain fatty acid oxidation. Clin Mol Hepatol 25:86-91.<br />
|info=[https://pubmed.ncbi.nlm.nih.gov/30149691/ PMID:30149691 Open Access]<br />
|authors=Bastos KLM, Quaio CR, Lima FR, Araújo IM, Araújo CAT, Piazzon FB, Silva IDCG, Benevides GN, Tannuri AC, Tannuri U, Azevedo RA, Kim CA<br />
|year=2019<br />
|journal=Clin Mol Hepatol<br />
}}<br />
== Cited by ==<br />
{{Template:Cited by Silva 2021 MitoFit Etomoxir}}<br />
{{Labeling<br />
|additional=MitoFit 2021 Etomoxir<br />
}}</div>Komlodi Timeahttps://wiki.oroboros.at/index.php?title=Bastos_2019_Clin_Mol_Hepatol&diff=228057Bastos 2019 Clin Mol Hepatol2022-05-31T16:17:11Z<p>Komlodi Timea: Created page with "{{Publication |title=Bastos KLM, Quaio CR, Lima FR, Araújo IM, Araújo CAT, Piazzon FB, Silva IDCG, Benevides GN, Tannuri AC, Tannuri U, Azevedo RA, Kim CA (2019) Biochemical..."</p>
<hr />
<div>{{Publication<br />
|title=Bastos KLM, Quaio CR, Lima FR, Araújo IM, Araújo CAT, Piazzon FB, Silva IDCG, Benevides GN, Tannuri AC, Tannuri U, Azevedo RA, Kim CA (2019) Biochemical profile in an infant with neonatal hemochromatosis shows evidence of impairment of mitochondrial long-chain fatty acid oxidation. Clin Mol Hepatol 25:86-91.<br />
|info=[https://pubmed.ncbi.nlm.nih.gov/30149691/ PMID:30149691 Open Access]<br />
|authors=Bastos KLM, Quaio CR, Lima FR, Araújo IM, Araújo CAT, Piazzon FB, Silva IDCG, Benevides GN, Tannuri AC, Tannuri U, Azevedo RA, Kim CA<br />
|year=2019<br />
|journal=Clin Mol Hepatol<br />
}}<br />
{{Labeling<br />
|additional=MitoFit 2021 Etomoxir<br />
}}</div>Komlodi Timeahttps://wiki.oroboros.at/index.php?title=Rector_2010_J_Hepatol&diff=228056Rector 2010 J Hepatol2022-05-31T16:12:25Z<p>Komlodi Timea: </p>
<hr />
<div>{{Publication<br />
|title=Rector RS, Thyfault JP, Uptergrove GM, Morris EM, Naples SP, Borengasser SJ, Mikus CR, Laye MJ, Laughlin MH, Booth FW, Ibdah JA (2010) Mitochondrial dysfunction precedes insulin resistance and hepatic steatosis and contributes to the natural history of non-alcoholic fatty liver disease in an obese rodent model. J Hepatol 52:727-36.<br />
|info=[https://pubmed.ncbi.nlm.nih.gov/20347174/ PMID:20347174 Open Access]<br />
|authors=Rector RS, Thyfault JP, Uptergrove GM, Morris EM, Naples SP, Borengasser SJ, Mikus CR, Laye MJ, Laughlin MH, Booth FW, Ibdah JA<br />
|year=2010<br />
|journal=J Hepatol<br />
|abstract=Background & aims: In this study, we sought to determine the temporal relationship between hepatic mitochondrial dysfunction, hepatic steatosis and insulin resistance, and to examine their potential role in the natural progression of non-alcoholic fatty liver disease (NAFLD) utilising a sedentary, hyperphagic, obese, Otsuka Long-Evans Tokushima Fatty (OLETF) rat model.<br />
<br />
Methods: OLETF rats and their non-hyperphagic control Long-Evans Tokushima Otsuka (LETO) rats were sacrificed at 5, 8, 13, 20, and 40 weeks of age (n=6-8 per group).<br />
<br />
Results: At 5 weeks of age, serum insulin and glucose and hepatic triglyceride (TG) concentrations did not differ between animal groups; however, OLETF animals displayed significant (p<0.01) hepatic mitochondrial dysfunction as measured by reduced hepatic carnitine palmitoyl-CoA transferase-1 activity, fatty acid oxidation, and cytochrome c protein content compared with LETO rats. Hepatic TG levels were significantly elevated by 8 weeks of age, and insulin resistance developed by 13 weeks in the OLETF rats. NAFLD progressively worsened to include hepatocyte ballooning, perivenular fibrosis, 2.5-fold increase in serum ALT, hepatic mitochondrial ultrastructural abnormalities, and increased hepatic oxidative stress in the OLETF animals at later ages. Measures of hepatic mitochondrial content and function including beta-hydroxyacyl-CoA dehydrogenase activity, citrate synthase activity, and immunofluorescence staining for mitochondrial carbamoyl phosphate synthetase-1, progressively worsened and were significantly reduced at 40 weeks in OLETF rats compared to LETO animals.<br />
<br />
Conclusions: Our study documents that hepatic mitochondrial dysfunction precedes the development of NAFLD and insulin resistance in the OLETF rats. This evidence suggests that progressive mitochondrial dysfunction contributes to the natural history of obesity-associated NAFLD.<br />
}}<br />
== Cited by ==<br />
{{Template:Cited by Silva 2021 MitoFit Etomoxir}}<br />
{{Labeling<br />
|additional=MitoFit 2021 Etomoxir<br />
}}</div>Komlodi Timeahttps://wiki.oroboros.at/index.php?title=Rector_2010_J_Hepatol&diff=228055Rector 2010 J Hepatol2022-05-31T16:11:35Z<p>Komlodi Timea: Created page with "{{Publication |title=Rector RS, Thyfault JP, Uptergrove GM, Morris EM, Naples SP, Borengasser SJ, Mikus CR, Laye MJ, Laughlin MH, Booth FW, Ibdah JA (2010) Mitochondrial dysfu..."</p>
<hr />
<div>{{Publication<br />
|title=Rector RS, Thyfault JP, Uptergrove GM, Morris EM, Naples SP, Borengasser SJ, Mikus CR, Laye MJ, Laughlin MH, Booth FW, Ibdah JA (2010) Mitochondrial dysfunction precedes insulin resistance and hepatic steatosis and contributes to the natural history of non-alcoholic fatty liver disease in an obese rodent model. J Hepatol 52:727-36.<br />
|info=[https://pubmed.ncbi.nlm.nih.gov/20347174/ PMID:20347174 Open Access]<br />
|authors=Rector RS, Thyfault JP, Uptergrove GM, Morris EM, Naples SP, Borengasser SJ, Mikus CR, Laye MJ, Laughlin MH, Booth FW, Ibdah JA<br />
|year=2010<br />
|journal=J Hepatol<br />
|abstract=Background & aims: In this study, we sought to determine the temporal relationship between hepatic mitochondrial dysfunction, hepatic steatosis and insulin resistance, and to examine their potential role in the natural progression of non-alcoholic fatty liver disease (NAFLD) utilising a sedentary, hyperphagic, obese, Otsuka Long-Evans Tokushima Fatty (OLETF) rat model.<br />
<br />
Methods: OLETF rats and their non-hyperphagic control Long-Evans Tokushima Otsuka (LETO) rats were sacrificed at 5, 8, 13, 20, and 40 weeks of age (n=6-8 per group).<br />
<br />
Results: At 5 weeks of age, serum insulin and glucose and hepatic triglyceride (TG) concentrations did not differ between animal groups; however, OLETF animals displayed significant (p<0.01) hepatic mitochondrial dysfunction as measured by reduced hepatic carnitine palmitoyl-CoA transferase-1 activity, fatty acid oxidation, and cytochrome c protein content compared with LETO rats. Hepatic TG levels were significantly elevated by 8 weeks of age, and insulin resistance developed by 13 weeks in the OLETF rats. NAFLD progressively worsened to include hepatocyte ballooning, perivenular fibrosis, 2.5-fold increase in serum ALT, hepatic mitochondrial ultrastructural abnormalities, and increased hepatic oxidative stress in the OLETF animals at later ages. Measures of hepatic mitochondrial content and function including beta-hydroxyacyl-CoA dehydrogenase activity, citrate synthase activity, and immunofluorescence staining for mitochondrial carbamoyl phosphate synthetase-1, progressively worsened and were significantly reduced at 40 weeks in OLETF rats compared to LETO animals.<br />
<br />
Conclusions: Our study documents that hepatic mitochondrial dysfunction precedes the development of NAFLD and insulin resistance in the OLETF rats. This evidence suggests that progressive mitochondrial dysfunction contributes to the natural history of obesity-associated NAFLD.<br />
}}<br />
{{Labeling<br />
|additional=MitoFit 2021 Etomoxir<br />
}}</div>Komlodi Timeahttps://wiki.oroboros.at/index.php?title=Makrecka-Kuka_2017_Sci_Rep&diff=227998Makrecka-Kuka 2017 Sci Rep2022-05-31T07:44:29Z<p>Komlodi Timea: </p>
<hr />
<div>{{Publication<br />
|title=Makrecka-Kuka M, Sevostjanovs E, Vilks K, Volska K, Antone U, Kuka J, Makarova E, Pugovics O, Dambrova M, Liepinsh E (2017) Plasma acylcarnitine concentrations reflect the acylcarnitine profile in cardiac tissues. Sci Rep 7:17528.<br />
|info=[https://pubmed.ncbi.nlm.nih.gov/29235526/ PMID:29235526 Open Access]<br />
|authors=Makrecka-Kuka M, Sevostjanovs E, Vilks K, Volska K, Antone U, Kuka J, Makarova E, Pugovics O, Dambrova M, Liepinsh E<br />
|year=2017<br />
|journal=Sci Rep<br />
|abstract=Increased plasma concentrations of acylcarnitines (ACs) are suggested as a marker of metabolism disorders. The aim of the present study was to clarify which tissues are responsible for changes in the AC pool in plasma. The concentrations of medium- and long-chain ACs were changing during the fed-fast cycle in rat heart, muscles and liver. After 60 min running exercise, AC content was increased in fasted mice muscles, but not in plasma or heart. After glucose bolus administration in fasted rats, the AC concentrations in plasma decreased after 30 min but then began to increase, while in the muscles and liver, the contents of medium- and long-chain ACs were unchanged or even increased. Only the heart showed a decrease in medium- and long-chain AC contents that was similar to that observed in plasma. In isolated rat heart, but not isolated-contracting mice muscles, the significant efflux of medium- and long-chain ACs was observed. The efflux was reduced by 40% after the addition of glucose and insulin to the perfusion solution. Overall, these results indicate that during fed-fast cycle shifting the heart determines the medium- and long-chain AC profile in plasma, due to a rapid response to the availability of circulating energy substrates.<br />
}}<br />
== Cited by ==<br />
{{Template:Cited by Silva 2021 MitoFit Etomoxir}}<br />
{{Labeling<br />
|additional=MitoFit 2021 Etomoxir<br />
}}</div>Komlodi Timeahttps://wiki.oroboros.at/index.php?title=Makrecka-Kuka_2017_Sci_Rep&diff=227997Makrecka-Kuka 2017 Sci Rep2022-05-31T07:43:29Z<p>Komlodi Timea: Created page with "{{Publication |title=Makrecka-Kuka M, Sevostjanovs E, Vilks K, Volska K, Antone U, Kuka J, Makarova E, Pugovics O, Dambrova M, Liepinsh E (2017) Plasma acylcarnitine concentr..."</p>
<hr />
<div>{{Publication<br />
|title=Makrecka-Kuka M, Sevostjanovs E, Vilks K, Volska K, Antone U, Kuka J, Makarova E, Pugovics O, Dambrova M, Liepinsh E (2017) Plasma acylcarnitine concentrations reflect the acylcarnitine profile in cardiac tissues. Sci Rep 7:17528.<br />
|info=[https://pubmed.ncbi.nlm.nih.gov/29235526/ PMID:29235526 Open Access]<br />
|authors=Makrecka-Kuka M, Sevostjanovs E, Vilks K, Volska K, Antone U, Kuka J, Makarova E, Pugovics O, Dambrova M, Liepinsh E<br />
|year=2017<br />
|journal=Sci Rep<br />
|abstract=Increased plasma concentrations of acylcarnitines (ACs) are suggested as a marker of metabolism disorders. The aim of the present study was to clarify which tissues are responsible for changes in the AC pool in plasma. The concentrations of medium- and long-chain ACs were changing during the fed-fast cycle in rat heart, muscles and liver. After 60 min running exercise, AC content was increased in fasted mice muscles, but not in plasma or heart. After glucose bolus administration in fasted rats, the AC concentrations in plasma decreased after 30 min but then began to increase, while in the muscles and liver, the contents of medium- and long-chain ACs were unchanged or even increased. Only the heart showed a decrease in medium- and long-chain AC contents that was similar to that observed in plasma. In isolated rat heart, but not isolated-contracting mice muscles, the significant efflux of medium- and long-chain ACs was observed. The efflux was reduced by 40% after the addition of glucose and insulin to the perfusion solution. Overall, these results indicate that during fed-fast cycle shifting the heart determines the medium- and long-chain AC profile in plasma, due to a rapid response to the availability of circulating energy substrates.<br />
}}<br />
{{Labeling<br />
|additional=MitoFit 2021 Etomoxir<br />
}}</div>Komlodi Timeahttps://wiki.oroboros.at/index.php?title=Bunting_1989_Biophys_J&diff=227955Bunting 1989 Biophys J2022-05-30T18:12:22Z<p>Komlodi Timea: </p>
<hr />
<div>{{Publication<br />
|title=Bunting JR, Phan TV, Kamali E, Dowben RM (1989) Fluorescent cationic probes of mitochondria. Metrics and mechanism of interaction. Biophys J 56:979-93.<br />
|info=[https://pubmed.ncbi.nlm.nih.gov/2605307/ PMID:2605307 Open Access]<br />
|authors=Bunting JR, Phan TV, Kamali E, Dowben RM<br />
|year=1989<br />
|journal=Biophys J<br />
|abstract=Mitochondria strongly accumulate amphiphilic cations. We report here a study of the association of respiring rat liver mitochondria with several fluorescent cationic dyes from differing structural classes. Using gravimetric and fluorometric analysis of dye partition, we find that dyes and mitochondria interact in three ways: (a) uptake with fluorescence quenching, (b) uptake without change in fluorescence intensity, and (c) lack of uptake. For dyes that quench upon uptake, the extent of quenching correlates with the degree of aggregation of the dye to dimers, as predicted by theory (Tomov, T.C. 1986. J. Biochem. Biophys. Methods. 13:29-38). Also predicted is the relationship observed between quenching and the mitochondria concentration when constant dye is titrated with mitochondria. Not predicted is the relationship observed between quenching and dye concentration when constant mitochondria are titrated with dye. Because a limit to dye uptake exists, in this case, the degree of quenching decreases as dye is added. A Langmuir isotherm analysis gives phenomenological parameters that predict quenching when it is observed as a function of dye concentration. By allowing for a decrease in membrane potential, caused by incorporation of cationic dye into the lipid bilayer, a modification of the Tomov theory predicts the dye titration data. We present a model of cationic dye-mitochondria interaction and discuss the use of these as probes of mitochondrial membrane potential.<br />
}}<br />
== Cited by ==<br />
{{Template:Cited by Komlodi 2022 MitoFit pmF}}<br />
{{Labeling<br />
|additional=MitoFit 2022 pmF<br />
}}</div>Komlodi Timeahttps://wiki.oroboros.at/index.php?title=Bunting_1989_Biophys_J&diff=227954Bunting 1989 Biophys J2022-05-30T18:11:44Z<p>Komlodi Timea: Created page with "{{Publication |title=Bunting JR, Phan TV, Kamali E, Dowben RM (1989) Fluorescent cationic probes of mitochondria. Metrics and mechanism of interaction. Biophys J 56:979-93. |i..."</p>
<hr />
<div>{{Publication<br />
|title=Bunting JR, Phan TV, Kamali E, Dowben RM (1989) Fluorescent cationic probes of mitochondria. Metrics and mechanism of interaction. Biophys J 56:979-93.<br />
|info=[https://pubmed.ncbi.nlm.nih.gov/2605307/ PMID:2605307 Open Access]<br />
|authors=Bunting JR, Phan TV, Kamali E, Dowben RM<br />
|year=1989<br />
|journal=Biophys J<br />
|abstract=Mitochondria strongly accumulate amphiphilic cations. We report here a study of the association of respiring rat liver mitochondria with several fluorescent cationic dyes from differing structural classes. Using gravimetric and fluorometric analysis of dye partition, we find that dyes and mitochondria interact in three ways: (a) uptake with fluorescence quenching, (b) uptake without change in fluorescence intensity, and (c) lack of uptake. For dyes that quench upon uptake, the extent of quenching correlates with the degree of aggregation of the dye to dimers, as predicted by theory (Tomov, T.C. 1986. J. Biochem. Biophys. Methods. 13:29-38). Also predicted is the relationship observed between quenching and the mitochondria concentration when constant dye is titrated with mitochondria. Not predicted is the relationship observed between quenching and dye concentration when constant mitochondria are titrated with dye. Because a limit to dye uptake exists, in this case, the degree of quenching decreases as dye is added. A Langmuir isotherm analysis gives phenomenological parameters that predict quenching when it is observed as a function of dye concentration. By allowing for a decrease in membrane potential, caused by incorporation of cationic dye into the lipid bilayer, a modification of the Tomov theory predicts the dye titration data. We present a model of cationic dye-mitochondria interaction and discuss the use of these as probes of mitochondrial membrane potential.<br />
}}<br />
{{Labeling<br />
|additional=MitoFit 2022 pmF<br />
}}</div>Komlodi Timeahttps://wiki.oroboros.at/index.php?title=Scaduto_1999&diff=227953Scaduto 19992022-05-30T18:10:27Z<p>Komlodi Timea: </p>
<hr />
<div>{{Publication<br />
|title=Scaduto Jr RC,Grotyohann LW (1999) Measurement of mitochondrial membrane potential using fluorescent rhodamine derivatives. Biophys J 76:469-77.<br />
|info=[https://pubmed.ncbi.nlm.nih.gov/9876159/ PMID:9876159 Open Access]<br />
|authors=Scaduto Jr RC,Grotyohann LW<br />
|year=1999<br />
|journal=Biophys J<br />
|abstract=We investigated the use of rhodamine 123 (R123), tetramethylrhodamine methyl ester (TMRM), and tetramethylrhodamine ethyl ester (TMRE) as fluorescent probes to monitor the membrane potential of mitochondria. These indicator dyes are lipophilic cations accumulated by mitochondria in proportion to DeltaPsi. Upon accumulation, all three dyes exhibit a red shift in both their absorption and fluorescence emission spectra. The fluorescence intensity is quenched when the dyes are accumulated by mitochondria. These properties have been used to develop a method to dynamically monitor DeltaPsi of isolated rat heart mitochondria using a ratio fluorescence approach. All three dyes bound to the inner and outer aspects of the inner mitochondrial membrane and, as a result, were accumulated by mitochondria in a greater quantity than predicted by the Nernst equation. Binding to mitochondria was temperature-dependent and the degree of binding was in the order of TMRE > R123 > TMRM. The internal and external partition coefficients for binding were determined to correct for binding in the calculation of DeltaPsi. All three dyes suppressed mitochondrial respiratory control to some extent. Inhibition of respiration was greatest with TMRE, followed by R123 and TMRM. When used at low concentrations, TMRM did not suppress respiration. The use of these dyes and ratio fluorescence techniques affords a simple method for measurement of DeltaPsi of isolated mitochondria. We also applied this approach to the isolated perfused heart to determine whether DeltaPsi could be monitored in an intact tissue. Wavelength scanning of the surface fluorescence of the heart under various conditions after accumulation of TMRM indicated that the mitochondrial matrix-induced wavelength shift of TMRM also occurs in the heart cytosol, eliminating the use of this approach in the intact heart.<br />
}}<br />
== Cited by ==<br />
{{Template:Cited by Komlodi 2022 MitoFit pmF}}<br />
{{Labeling<br />
|additional=MitoFit 2022 pmF<br />
}}</div>Komlodi Timeahttps://wiki.oroboros.at/index.php?title=Scaduto_1999&diff=227952Scaduto 19992022-05-30T18:09:26Z<p>Komlodi Timea: Created page with "{{Publication |title=Scaduto Jr RC,Grotyohann LW (1999) Measurement of mitochondrial membrane potential using fluorescent rhodamine derivatives. Biophys J 76:469-77. |info=[ht..."</p>
<hr />
<div>{{Publication<br />
|title=Scaduto Jr RC,Grotyohann LW (1999) Measurement of mitochondrial membrane potential using fluorescent rhodamine derivatives. Biophys J 76:469-77.<br />
|info=[https://pubmed.ncbi.nlm.nih.gov/9876159/ PMID:9876159 Open Access]<br />
|authors=Scaduto Jr RC,Grotyohann LW<br />
|year=1999<br />
|journal=Biophys J<br />
|abstract=We investigated the use of rhodamine 123 (R123), tetramethylrhodamine methyl ester (TMRM), and tetramethylrhodamine ethyl ester (TMRE) as fluorescent probes to monitor the membrane potential of mitochondria. These indicator dyes are lipophilic cations accumulated by mitochondria in proportion to DeltaPsi. Upon accumulation, all three dyes exhibit a red shift in both their absorption and fluorescence emission spectra. The fluorescence intensity is quenched when the dyes are accumulated by mitochondria. These properties have been used to develop a method to dynamically monitor DeltaPsi of isolated rat heart mitochondria using a ratio fluorescence approach. All three dyes bound to the inner and outer aspects of the inner mitochondrial membrane and, as a result, were accumulated by mitochondria in a greater quantity than predicted by the Nernst equation. Binding to mitochondria was temperature-dependent and the degree of binding was in the order of TMRE > R123 > TMRM. The internal and external partition coefficients for binding were determined to correct for binding in the calculation of DeltaPsi. All three dyes suppressed mitochondrial respiratory control to some extent. Inhibition of respiration was greatest with TMRE, followed by R123 and TMRM. When used at low concentrations, TMRM did not suppress respiration. The use of these dyes and ratio fluorescence techniques affords a simple method for measurement of DeltaPsi of isolated mitochondria. We also applied this approach to the isolated perfused heart to determine whether DeltaPsi could be monitored in an intact tissue. Wavelength scanning of the surface fluorescence of the heart under various conditions after accumulation of TMRM indicated that the mitochondrial matrix-induced wavelength shift of TMRM also occurs in the heart cytosol, eliminating the use of this approach in the intact heart.<br />
}}<br />
{{Labeling<br />
|additional=MitoFit 2022 pmF<br />
}}</div>Komlodi Timeahttps://wiki.oroboros.at/index.php?title=Rosenthal_1987&diff=227764Rosenthal 19872022-05-28T08:04:27Z<p>Komlodi Timea: </p>
<hr />
<div>{{Publication<br />
|title=Rosenthal RE, Hamud F, Fiskum G, Varghese PJ, Sharpe S (1987) Cerebral ischemia and reperfusion: prevention of brain mitochondrial injury by lidoflazine. J Cereb Blood Flow Metab 7:752-8.<br />
|info=[https://pubmed.ncbi.nlm.nih.gov/3693430/ PMID:3693430 Open Access]<br />
|authors=Rosenthal RE, Hamud F, Fiskum G, Varghese PJ, Sharpe S<br />
|year=1987<br />
|journal=J Cereb Blood Flow Metab<br />
|abstract=Mitochondrial degradation is implicated in the irreversible cell damage that can occur during cerebral ischemia and reperfusion. In this study, the effects of 10 min of ventricular fibrillation and 100 min of spontaneous circulation on brain mitochondrial function was studied in dogs in the absence and presence of pretreatment with the Ca2+ antagonist lidoflazine. Twenty-three beagles were separated into four experimental groups: (i) nonischemic controls (ii) those undergoing 10-min ventricular fibrillation, (iii) those undergoing 10-min ventricular fibrillation pretreated with 1 mg/kg lidoflazine i.v., and (iv) those undergoing 10-min ventricular fibrillation followed by spontaneous circulation for 100 min. Brain mitochondria were isolated and tested for their ability to respire and accumulate calcium in a physiological test medium. There was a 35% decrease in the rate of phosphorylating respiration (ATP production) following 10 min of complete cerebral ischemia. Those animals pretreated with lidoflazine showed significantly less decline in phosphorylating respiration (16%) when compared with nontreated dogs. Resting and uncoupled respiration also declined following 10 min of fibrillatory arrest. One hundred minutes of spontaneous circulation following 10 min of ventricular fibrillation and 3 min of open-chest cardiac massage provided complete recovery of normal mitochondrial respiration. Energy-dependent Ca2+ accumulation by isolated brain mitochondria was unimpaired by 10 min of complete cerebral ischemia. However, by 100 min after resuscitation, there was a small, but significant rise in the capacity for mitochondrial Ca2+ sequestration when compared to either control or fibrillated groups.<br />
}}<br />
== Cited by ==<br />
{{Template:Cited by Komlodi 2022 MitoFit pmF}}<br />
<br />
{{Labeling<br />
|additional=MitoFit 2022 pmF<br />
}}</div>Komlodi Timeahttps://wiki.oroboros.at/index.php?title=Rosenthal_1987&diff=227763Rosenthal 19872022-05-28T08:04:00Z<p>Komlodi Timea: </p>
<hr />
<div>{{Publication<br />
|title=Rosenthal RE, Hamud F, Fiskum G, Varghese PJ, Sharpe S (1987) Cerebral ischemia and reperfusion: prevention of brain mitochondrial injury by lidoflazine. J Cereb Blood Flow Metab 7:752-8.<br />
|info=[https://pubmed.ncbi.nlm.nih.gov/3693430/ PMID:3693430 Open Access]<br />
|authors=Rosenthal RE, Hamud F, Fiskum G, Varghese PJ, Sharpe S<br />
|year=1987<br />
|journal=J Cereb Blood Flow Metab<br />
|abstract=Mitochondrial degradation is implicated in the irreversible cell damage that can occur during cerebral ischemia and reperfusion. In this study, the effects of 10 min of ventricular fibrillation and 100 min of spontaneous circulation on brain mitochondrial function was studied in dogs in the absence and presence of pretreatment with the Ca2+ antagonist lidoflazine. Twenty-three beagles were separated into four experimental groups: (i) nonischemic controls (ii) those undergoing 10-min ventricular fibrillation, (iii) those undergoing 10-min ventricular fibrillation pretreated with 1 mg/kg lidoflazine i.v., and (iv) those undergoing 10-min ventricular fibrillation followed by spontaneous circulation for 100 min. Brain mitochondria were isolated and tested for their ability to respire and accumulate calcium in a physiological test medium. There was a 35% decrease in the rate of phosphorylating respiration (ATP production) following 10 min of complete cerebral ischemia. Those animals pretreated with lidoflazine showed significantly less decline in phosphorylating respiration (16%) when compared with nontreated dogs. Resting and uncoupled respiration also declined following 10 min of fibrillatory arrest. One hundred minutes of spontaneous circulation following 10 min of ventricular fibrillation and 3 min of open-chest cardiac massage provided complete recovery of normal mitochondrial respiration. Energy-dependent Ca2+ accumulation by isolated brain mitochondria was unimpaired by 10 min of complete cerebral ischemia. However, by 100 min after resuscitation, there was a small, but significant rise in the capacity for mitochondrial Ca2+ sequestration when compared to either control or fibrillated groups.<br />
}}<br />
{{Labeling<br />
|additional=MitoFit 2022 pmF<br />
}}<br />
== Cited by ==<br />
{{Template:Cited by Komlodi 2022 MitoFit pmF}}</div>Komlodi Timeahttps://wiki.oroboros.at/index.php?title=Rosenthal_1987&diff=227762Rosenthal 19872022-05-28T08:03:47Z<p>Komlodi Timea: </p>
<hr />
<div>{{Publication<br />
|title=Rosenthal RE, Hamud F, Fiskum G, Varghese PJ, Sharpe S (1987) Cerebral ischemia and reperfusion: prevention of brain mitochondrial injury by lidoflazine. J Cereb Blood Flow Metab 7:752-8.<br />
|info=[https://pubmed.ncbi.nlm.nih.gov/3693430/ PMID:3693430 Open Access]<br />
|authors=Rosenthal RE, Hamud F, Fiskum G, Varghese PJ, Sharpe S<br />
|year=1987<br />
|journal=J Cereb Blood Flow Metab<br />
|abstract=Mitochondrial degradation is implicated in the irreversible cell damage that can occur during cerebral ischemia and reperfusion. In this study, the effects of 10 min of ventricular fibrillation and 100 min of spontaneous circulation on brain mitochondrial function was studied in dogs in the absence and presence of pretreatment with the Ca2+ antagonist lidoflazine. Twenty-three beagles were separated into four experimental groups: (i) nonischemic controls (ii) those undergoing 10-min ventricular fibrillation, (iii) those undergoing 10-min ventricular fibrillation pretreated with 1 mg/kg lidoflazine i.v., and (iv) those undergoing 10-min ventricular fibrillation followed by spontaneous circulation for 100 min. Brain mitochondria were isolated and tested for their ability to respire and accumulate calcium in a physiological test medium. There was a 35% decrease in the rate of phosphorylating respiration (ATP production) following 10 min of complete cerebral ischemia. Those animals pretreated with lidoflazine showed significantly less decline in phosphorylating respiration (16%) when compared with nontreated dogs. Resting and uncoupled respiration also declined following 10 min of fibrillatory arrest. One hundred minutes of spontaneous circulation following 10 min of ventricular fibrillation and 3 min of open-chest cardiac massage provided complete recovery of normal mitochondrial respiration. Energy-dependent Ca2+ accumulation by isolated brain mitochondria was unimpaired by 10 min of complete cerebral ischemia. However, by 100 min after resuscitation, there was a small, but significant rise in the capacity for mitochondrial Ca2+ sequestration when compared to either control or fibrillated groups.<br />
}}<br />
== Cited by ==<br />
{{Template:Cited by Komlodi 2022 MitoFit pmF}}<br />
{{Labeling}}</div>Komlodi Timeahttps://wiki.oroboros.at/index.php?title=Rosenthal_1987&diff=227761Rosenthal 19872022-05-28T08:03:26Z<p>Komlodi Timea: Created page with "{{Publication |title=Rosenthal RE, Hamud F, Fiskum G, Varghese PJ, Sharpe S (1987) Cerebral ischemia and reperfusion: prevention of brain mitochondrial injury by lidoflazine...."</p>
<hr />
<div>{{Publication<br />
|title=Rosenthal RE, Hamud F, Fiskum G, Varghese PJ, Sharpe S (1987) Cerebral ischemia and reperfusion: prevention of brain mitochondrial injury by lidoflazine. J Cereb Blood Flow Metab 7:752-8.<br />
|info=[https://pubmed.ncbi.nlm.nih.gov/3693430/ PMID:3693430 Open Access]<br />
|authors=Rosenthal RE, Hamud F, Fiskum G, Varghese PJ, Sharpe S<br />
|year=1987<br />
|journal=J Cereb Blood Flow Metab<br />
|abstract=Mitochondrial degradation is implicated in the irreversible cell damage that can occur during cerebral ischemia and reperfusion. In this study, the effects of 10 min of ventricular fibrillation and 100 min of spontaneous circulation on brain mitochondrial function was studied in dogs in the absence and presence of pretreatment with the Ca2+ antagonist lidoflazine. Twenty-three beagles were separated into four experimental groups: (i) nonischemic controls (ii) those undergoing 10-min ventricular fibrillation, (iii) those undergoing 10-min ventricular fibrillation pretreated with 1 mg/kg lidoflazine i.v., and (iv) those undergoing 10-min ventricular fibrillation followed by spontaneous circulation for 100 min. Brain mitochondria were isolated and tested for their ability to respire and accumulate calcium in a physiological test medium. There was a 35% decrease in the rate of phosphorylating respiration (ATP production) following 10 min of complete cerebral ischemia. Those animals pretreated with lidoflazine showed significantly less decline in phosphorylating respiration (16%) when compared with nontreated dogs. Resting and uncoupled respiration also declined following 10 min of fibrillatory arrest. One hundred minutes of spontaneous circulation following 10 min of ventricular fibrillation and 3 min of open-chest cardiac massage provided complete recovery of normal mitochondrial respiration. Energy-dependent Ca2+ accumulation by isolated brain mitochondria was unimpaired by 10 min of complete cerebral ischemia. However, by 100 min after resuscitation, there was a small, but significant rise in the capacity for mitochondrial Ca2+ sequestration when compared to either control or fibrillated groups.<br />
}}<br />
{{Labeling}}</div>Komlodi Timeahttps://wiki.oroboros.at/index.php?title=Bradford_1976_Anal_Biochem&diff=227760Bradford 1976 Anal Biochem2022-05-28T08:01:21Z<p>Komlodi Timea: </p>
<hr />
<div>{{Publication<br />
|title=Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248-54.<br />
|info=[https://pubmed.ncbi.nlm.nih.gov/942051/ PMID:942051]<br />
|authors=Bradford MM<br />
|year=1976<br />
|journal=Anal Biochem<br />
|abstract=A protein determination method which involves the binding of Coomassie Brilliant Blue G-250 to protein is described. The binding of the dye to protein causes a shift in the absorption maximum of the dye from 465 to 595 nm, and it is the increase in absorption at 595 nm which is monitored. This assay is very reproducible and rapid with the dye binding process virtually complete in approximately 2 min with good color stability for 1 hr. There is little or no interference from cations such as sodium or potassium nor from carbohydrates such as sucrose. A small amount of color is developed in the presence of strongly alkaline buffering agents, but the assay may be run accurately by the use of proper buffer controls. The only components found to give excessive interfering color in the assay are relatively large amounts of detergents such as sodium dodecyl sulfate, Triton X-100, and commercial glassware detergents. Interference by small amounts of detergent may be eliminated by the use of proper controls.<br />
}}<br />
== Cited by ==<br />
{{Template:Cited by Komlodi 2021 MitoFit AmR}}<br />
{{Template:Cited by Komlodi 2022 MitoFit pmF}}<br />
{{Labeling<br />
|additional=MitoFit 2021 AmR, MitoFit 2022 pmF<br />
}}</div>Komlodi Timeahttps://wiki.oroboros.at/index.php?title=Patel_1999_Biochim_Biophys_Acta&diff=226923Patel 1999 Biochim Biophys Acta2022-05-05T12:34:38Z<p>Komlodi Timea: </p>
<hr />
<div>{{Publication<br />
|title=Patel RP, McAndrew J, Sellak H, White CR, Jo H, Freeman BA, Darley-Usmar VM (1999) Biological aspects of reactive nitrogen species. Biochim Biophys Acta 1411:385-400.<br />
|info=[https://pubmed.ncbi.nlm.nih.gov/10320671/ PMID:10320671 Open Access]<br />
|authors=Patel RP, McAndrew J, Sellak H, White CR, Jo H, Freeman BA, Darley-Usmar VM<br />
|year=1999<br />
|journal=Biochim Biophys Acta<br />
|abstract=Nitric oxide (NO) plays an important role as a cell-signalling molecule, anti-infective agent and, as most recently recognised, an antioxidant. The metabolic fate of NO gives rise to a further series of compounds, collectively known as the reactive nitrogen species (RNS), which possess their own unique characteristics. In this review we discuss this emerging aspect of the NO field in the context of the formation of the RNS and what is known about their effects on biological systems. While much of the insight into the RNS has been gained from the extensive chemical characterisation of these species, to reveal biological consequences this approach must be complemented by direct measures of physiological function. Although we do not know the consequences of many of the dominant chemical reactions of RNS an intriguing aspect is now emerging. This review will illustrate how, when specificity and amplification through cell signalling mechanisms are taken into account, the less significant reactions, in terms of yield or rates, can explain many of the biological responses of exposure of cells or physiological systems to RNS.<br />
}}<br />
== Cited by ==<br />
<br />
{{Labeling<br />
|additional=<br />
}}</div>Komlodi Timeahttps://wiki.oroboros.at/index.php?title=Radi_2018_Proc_Natl_Acad_Sci_U_S_A&diff=226922Radi 2018 Proc Natl Acad Sci U S A2022-05-05T12:34:26Z<p>Komlodi Timea: </p>
<hr />
<div>{{Publication<br />
|title=Radi R (2018) Oxygen radicals, nitric oxide, and peroxynitrite: Redox pathways in molecular medicine. Proc Natl Acad Sci U S A 115:5839-48. doi: 10.1073/pnas.1804932115<br />
|info=[https://pubmed.ncbi.nlm.nih.gov/29802228/ PMID: 29802228 Open Access]<br />
|authors=Radi R<br />
|year=2018<br />
|journal=Proc Natl Acad Sci U S A<br />
|abstract=Oxygen-derived free radicals and related oxidants are ubiquitous and short-lived intermediates formed in aerobic organisms throughout life. These reactive species participate in redox reactions leading to oxidative modifications in biomolecules, among which proteins and lipids are preferential targets. Despite a broad array of enzymatic and nonenzymatic antioxidant systems in mammalian cells and microbes, excess oxidant formation causes accumulation of new products that may compromise cell function and structure leading to cell degeneration and death. Oxidative events are associated with pathological conditions and the process of normal aging. Notably, physiological levels of oxidants also modulate cellular functions via homeostatic redox-sensitive cell signaling cascades. On the other hand, nitric oxide (•NO), a free radical and weak oxidant, represents a master physiological regulator via reversible interactions with heme proteins. The bioavailability and actions of •NO are modulated by its fast reaction with superoxide radical ([Formula: see text]), which yields an unusual and reactive peroxide, peroxynitrite, representing the merging of the oxygen radicals and •NO pathways. In this Inaugural Article, I summarize early and remarkable developments in free radical biochemistry and the later evolution of the field toward molecular medicine; this transition includes our contributions disclosing the relationship of •NO with redox intermediates and metabolism. The biochemical characterization, identification, and quantitation of peroxynitrite and its role in disease processes have concentrated much of our attention. Being a mediator of protein oxidation and nitration, lipid peroxidation, mitochondrial dysfunction, and cell death, peroxynitrite represents both a pathophysiologically relevant endogenous cytotoxin and a cytotoxic effector against invading pathogens.<br />
|editor=Gnaiger E<br />
}}<br />
== Cited by ==<br />
{{Template:Cited by Komlodi 2021 MitoFit AmR}}<br />
{{Labeling<br />
|injuries=Oxidative stress;RONS<br />
|additional=MitoFit 2021 AmR<br />
}}</div>Komlodi Timeahttps://wiki.oroboros.at/index.php?title=Template:Cited_by_Komlodi_2022_MitoFit_ROS_review&diff=226650Template:Cited by Komlodi 2022 MitoFit ROS review2022-04-25T11:57:20Z<p>Komlodi Timea: </p>
<hr />
<div>::::* Komlódi T, Gnaiger E (2022) Discrepancy on oxygen dependence of mitochondrial ROS production - review. MitoFit Preprints 2022 (''in prep'').</div>Komlodi Timeahttps://wiki.oroboros.at/index.php?title=Sies_1997_Exp_Physiol&diff=226649Sies 1997 Exp Physiol2022-04-25T11:50:31Z<p>Komlodi Timea: </p>
<hr />
<div>{{Publication<br />
|title=Sies H (1997) Oxidative stress: oxidants and antioxidants. Exp Physiol 82:291-5.<br />
|info=[https://pubmed.ncbi.nlm.nih.gov/9129943/ PMID:9129943 Open Access]<br />
|authors=Sies H<br />
|year=1997<br />
|journal=Exp Physiol<br />
|abstract=An imbalance between oxidants and antioxidants in favour of the oxidants, potentially leading to damage, is termed 'oxidative stress'. Oxidants are formed as a normal product of aerobic metabolism but can be produced at elevated rates under pathophysiological conditions. Antioxidant defense involves several strategies, both enzymatic and non-enzymatic. In the lipid phase, tocopherols and carotenes as well as oxy-carotenoids are of interest, as are vitamin A and ubiquinols. In the aqueous phase, there are ascorbate, glutathione and other compounds. In addition to the cytosol, the nuclear and mitochondrial matrices and extracellular fluids are protected. Overall, these low molecular mass antioxidant molecules add significantly to the defense provided by the enzymes superoxide dismutase, catalase and glutathione peroxidases.<br />
}}<br />
== Cited by ==<br />
{{Template:Cited by Komlodi 2021 MitoFit AmR-O2}}<br />
{{Template:Cited by Komlodi 2022 MitoFit ROS review}}<br />
{{Labeling<br />
|additional=MitoFit 2021 AmR-O2, MitoFit 2022 ROS review<br />
}}</div>Komlodi Timeahttps://wiki.oroboros.at/index.php?title=Archer_1993_Circ_Res&diff=226648Archer 1993 Circ Res2022-04-25T11:46:22Z<p>Komlodi Timea: </p>
<hr />
<div>{{Publication<br />
|title=Archer SL, Huang J, Henry T, Peterson D, Weir EK (1993) A redox-based O<sub>2</sub> sensor in rat pulmonary vasculature. Circ Res 73:1100-12.<br />
|info=[https://pubmed.ncbi.nlm.nih.gov/8222081/ PMID:8222081 Open Access]<br />
|authors=Archer SL, Huang J, Henry T, Peterson D, Weir EK<br />
|year=1993<br />
|journal=Circ Res<br />
|abstract=The effector mechanism of hypoxic pulmonary vasoconstriction (HPV) involves K+ channel inhibition with subsequent membrane depolarization. It remains uncertain how hypoxia modulates K<sup>+</sup> channel activity. The similar effects of hypoxia and mitochondrial electron transport chain (ETC) inhibitors on metabolism and vascular tone suggest a common mechanism of action. ETC inhibitors and hypoxia may alter cell redox status by causing an accumulation of electron donors from the Krebs cycle and by decreasing the production of activated O<sub>2</sub> species (AOS) by the ETC. We hypothesized that this shift toward a more reduced redox state elicits vasoconstriction by inhibition of K<sup>+</sup> channels. Pulmonary artery pressure and AOS, measured simultaneously using enhanced chemiluminescence, were studied in isolated perfused rat lungs during exposure to hypoxia, proximal ETC inhibitors (rotenone and antimycin A), and a distal ETC inhibitor (cyanide). Patch-clamp measurements of whole-cell K+ currents were made on freshly isolated rat pulmonary vascular smooth muscle cells during exposure to hypoxia and ETC inhibitors. Hypoxia, rotenone, and antimycin A decreased lung chemiluminescence (-62 +/- 12, -46 +/- 7, and -148 +/- 36 counts/0.1 s, respectively) and subsequently increased pulmonary artery pressure (+14 +/- 2, +13 +/- 3, and +21 +/- 3 mm Hg, respectively). These agents reversibly inhibited an outward, ATP-independent, K+ current in pulmonary vascular smooth muscle cells. Antimycin A and rotenone abolished subsequent HPV. In contrast, cyanide increased AOS and did not alter K<sup>+</sup> currents or inhibit HPV. The initial effect of rotenone, antimycin A, and hypoxia was a change in redox status (evident as a decrease in production of AOS). This was associated with the reversible inhibition of an ATP-independent K<sup>+</sup> channel and vasoconstriction. These findings are consistent with the existence of a redox-based O<sub>2</sub> sensor in the pulmonary vasculature.<br />
}}<br />
== Cited by ==<br />
{{Template:Cited by Komlodi 2021 MitoFit AmR}}<br />
{{Template:Cited by Komlodi 2022 MitoFit ROS review}}<br />
{{Labeling<br />
|additional=MitoFit 2021 AmR, MitoFit 2022 ROS review<br />
}}</div>Komlodi Timeahttps://wiki.oroboros.at/index.php?title=Paniker_1970_Biochim_Biophys_Acta&diff=226647Paniker 1970 Biochim Biophys Acta2022-04-25T11:40:32Z<p>Komlodi Timea: </p>
<hr />
<div>{{Publication<br />
|title=Paniker NV, Srivastava SK, Beutler E (1970) Glutathione metabolism of the red cells. Effect of glutathione reductase deficiency on the stimulation of hexose monophosphate shunt under oxidative stress. Biochim Biophys Acta 215:456-60.<br />
|info=[https://pubmed.ncbi.nlm.nih.gov/5507367/ PMID:5507367]<br />
|authors=Paniker NV, Srivastava SK, Beutler E<br />
|year=1970<br />
|journal=Biochim Biophys Acta<br />
}}<br />
== Cited by ==<br />
{{Template:Cited by Komlodi 2021 MitoFit AmR-O2}}<br />
{{Template:Cited by Komlodi 2021 MitoFit AmR}}<br />
{{Template:Cited by Komlodi 2022 MitoFit ROS review}}<br />
{{Labeling<br />
|additional=MitoFit 2021 AmR-O2, MitoFit 2021 AmR, MitoFit 2022 ROS review<br />
}}</div>Komlodi Timeahttps://wiki.oroboros.at/index.php?title=Sies_2021_Redox_Biol&diff=226646Sies 2021 Redox Biol2022-04-25T11:36:50Z<p>Komlodi Timea: </p>
<hr />
<div>{{Publication<br />
|title=Sies H (2021) Oxidative eustress: On constant alert for redox homeostasis. Redox Biol 41:101867.<br />
|info=[https://pubmed.ncbi.nlm.nih.gov/33657525/ PMID:33657525 Open Access]<br />
|authors=Sies H<br />
|year=2021<br />
|journal=Redox Biol<br />
|abstract=In the open metabolic system, redox-related signaling requires continuous monitoring and fine-tuning of the steady-state redox set point. The ongoing oxidative metabolism is a persistent challenge, denoted as oxidative eustress, which operates within a physiological range that has been called the 'Homeodynamic Space', the 'Goldilocks Zone' or the 'Golden Mean'. Spatiotemporal control of redox signaling is achieved by compartmentalized generation and removal of oxidants. The cellular landscape of H2O2, the major redox signaling molecule, is characterized by orders-of-magnitude concentration differences between organelles. This concentration pattern is mirrored by the pattern of oxidatively modified proteins, exemplified by S-glutathionylated proteins. The review presents the conceptual background for short-term (non-transcriptional) and longer-term (transcriptional/translational) homeostatic mechanisms of stress and stress responses. The redox set point is a variable moving target value, modulated by circadian rhythm and by external influence, summarily denoted as exposome, which includes nutrition and lifestyle factors. Emerging fields of cell-specific and tissue-specific redox regulation in physiological settings are briefly presented, including new insight into the role of oxidative eustress in embryonal development and lifespan, skeletal muscle and exercise, sleep-wake rhythm, and the function of the nervous system with aspects leading to psychobiology.<br />
}}<br />
== Cited by ==<br />
{{Template:Cited by Komlodi 2021 MitoFit AmR}}<br />
{{Template:Cited by Komlodi 2022 MitoFit ROS review}}<br />
{{Labeling<br />
|additional=MitoFit 2021 AmR, MitoFit 2022 ROS review<br />
}}</div>Komlodi Timeahttps://wiki.oroboros.at/index.php?title=Sies_2020_Nat_Rev_Mol_Cell_Biol&diff=226645Sies 2020 Nat Rev Mol Cell Biol2022-04-25T11:35:25Z<p>Komlodi Timea: </p>
<hr />
<div>{{Publication<br />
|title=Sies H, Jones DP (2020) Reactive oxygen species (ROS) as pleiotropic physiological signalling agents. Nat Rev Mol Cell Biol 21:363-83.<br />
|info=[https://pubmed.ncbi.nlm.nih.gov/32231263/ PMID:32231263]<br />
|authors=Sies H, Jones DP<br />
|year=2020<br />
|journal=Nat Rev Mol Cell Biol<br />
|abstract=‘Reactive oxygen species’ (ROS) is an umbrella term for an array of derivatives of molecular oxygen that occur as a normal attribute of aerobic life. Elevated formation of the different ROS leads to molecular damage, denoted as ‘oxidative distress’. Here we focus on ROS at physiological levels and their central role in redox signalling via different post-translational modifications, denoted as ‘oxidative eustress’. Two species, hydrogen peroxide (H2O2) and the superoxide anion radical (O2·−), are key redox signalling agents generated under the control of growth factors and cytokines by more than 40 enzymes, prominently including NADPH oxidases and the mitochondrial electron transport chain. At the low physiological levels in the nanomolar range, H2O2 is the major agent signalling through specific protein targets, which engage in metabolic regulation and stress responses to support cellular adaptation to a changing environment and stress. In addition, several other reactive species are involved in redox signalling, for instance nitric oxide, hydrogen sulfide and oxidized lipids. Recent methodological advances permit the assessment of molecular interactions of specific ROS molecules with specific targets in redox signalling pathways. Accordingly, major advances have occurred in understanding the role of these oxidants in physiology and disease, including the nervous, cardiovascular and immune systems, skeletal muscle and metabolic regulation as well as ageing and cancer. In the past, unspecific elimination of ROS by use of low molecular mass antioxidant compounds was not successful in counteracting disease initiation and progression in clinical trials. However, controlling specific ROS-mediated signalling pathways by selective targeting offers a perspective for a future of more refined redox medicine. This includes enzymatic defence systems such as those controlled by the stress-response transcription factors NRF2 and nuclear factor-κB, the role of trace elements such as selenium, the use of redox drugs and the modulation of environmental factors collectively known as the exposome (for example, nutrition, lifestyle and irradiation).<br />
}}<br />
== Cited by ==<br />
{{Template:Cited by Komlodi 2021 MitoFit AmR-O2}}<br />
{{Template:Cited by Komlodi 2021 MitoFit AmR}}<br />
{{Template:Cited by Komlodi 2021 MitoFit Tissue normoxia}}<br />
{{Template:Cited by Komlodi 2022 MitoFit ROS review}}<br />
{{Labeling<br />
|additional=MitoFit 2021 AmR-O2, MitoFit 2021 AmR, MitoFit 2022 ROS review<br />
}}</div>Komlodi Timea