Jacovetti 2024 Mol Metab: Difference between revisions
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|keywords=Insulin secretion, Mitochondrial OXPHOS, Mitochondrial tRNA-derived fragments | |keywords=Insulin secretion, Mitochondrial OXPHOS, Mitochondrial tRNA-derived fragments | ||
|editor=[[Plangger M]] | |editor=[[Plangger M]] | ||
|mipnetlab=CH Lausanne Place N | |||
}} | }} | ||
{{Labeling | {{Labeling | ||
|area=Respiration | |area=Respiration, mtDNA;mt-genetics | ||
|diseases=Diabetes | |||
|organism=Rat | |||
|tissues=Islet cell;pancreas;thymus | |||
|preparations=Permeabilized cells | |||
|topics=mt-Membrane potential | |||
|couplingstates=LEAK, OXPHOS | |||
|pathways=N, S, NS, ROX | |||
|instruments=Oxygraph-2k | |instruments=Oxygraph-2k | ||
|additional=2024-05 | |additional=2024-05 | ||
}} | }} |
Latest revision as of 13:22, 8 May 2024
Jacovetti C, Donnelly C, Menoud V, Suleiman M, Cosentino C, Sobel J, Wu K, Bouzakri K, Marchetti P, Guay C, Kayser B, Regazzi R (2024) The mitochondrial tRNA-derived fragment, mt-tRF-LeuTAA, couples mitochondrial metabolism to insulin secretion. Mol Metab [Epub ahead of print]. https://doi.org/10.1016/j.ecoenv.2024.116423 |
Jacovetti Cecile, Donnelly Chris, Menoud Veronique, Suleiman Mara, Cosentino Cristina, Sobel Jonathan, Wu Kejing, Bouzakri Karim, Marchetti Piero, Guay Claudiane, Kayser Bengt, Regazzi Romano (2024) Mol Metab
Abstract: The contribution of the mitochondrial electron transfer system to insulin secretion involves more than just energy provision. We identified a small RNA fragment (mt-tRF-LeuTAA) derived from the cleavage of a mitochondrially-encoded tRNA that is conserved between mice and humans. The role of mitochondrially-encoded tRNA-derived fragments remains unknown. This study aimed to characterize the impact of mt-tRF-LeuTAA, on mitochondrial metabolism and pancreatic islet functions.
We used antisense oligonucleotides to reduce mt-tRF-LeuTAA levels in primary rat and human islet cells, as well as in insulin-secreting cell lines. We performed a joint transcriptome and proteome analysis upon mt-tRF-LeuTAA inhibition. Additionally, we employed pull-down assays followed by mass spectrometry to identify direct interactors of the fragment. Finally, we characterized the impact of mt-tRF-LeuTAA silencing on the coupling between mitochondrial metabolism and insulin secretion using high-resolution respirometry and insulin secretion assays.
Our study unveils a modulation of mt-tRF-LeuTAA levels in pancreatic islets in different Type 2 diabetes models and in response to changes in nutritional status. The level of the fragment is finely tuned by the mechanistic target of rapamycin complex 1. Located within mitochondria, mt-tRF-LeuTAA interacts with core subunits and assembly factors of respiratory complexes of the electron transfer system. Silencing of mt-tRF-LeuTAA in islet cells limits the inner mitochondrial membrane potential and impairs mitochondrial oxidative phosphorylation, predominantly by affecting the Succinate (via Complex II)-linked electron transfer pathway. Lowering mt-tRF-LeuTAA impairs insulin secretion of rat and human pancreatic ร-cells.
Our findings indicate that mt-tRF-LeuTAA interacts with electron transfer system complexes and is a pivotal regulator of mitochondrial oxidative phosphorylation and its coupling to insulin secretion. โข Keywords: Insulin secretion, Mitochondrial OXPHOS, Mitochondrial tRNA-derived fragments โข Bioblast editor: Plangger M โข O2k-Network Lab: CH Lausanne Place N
Labels: MiParea: Respiration, mtDNA;mt-genetics
Pathology: Diabetes
Organism: Rat Tissue;cell: Islet cell;pancreas;thymus Preparation: Permeabilized cells
Regulation: mt-Membrane potential Coupling state: LEAK, OXPHOS Pathway: N, S, NS, ROX HRR: Oxygraph-2k
2024-05