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Difference between revisions of "Heher 2022 Redox Biol"

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(Created page with "{{Publication |title=Heher P, Ganassi M, Weidinger A, Engquist EN, Pruller J, Nguyen TH, Tassin A, Declèves AE, Mamchaoui K, Banerji CRS, Grillari J, Kozlov AV, Zammit PS (20...")
 
 
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|keywords=Antioxidants, DUX4, Facioscapulohumeral muscular dystrophy, Hypoxia, Mitochondrial dysfunction, Reactive oxygen species
|keywords=Antioxidants, DUX4, Facioscapulohumeral muscular dystrophy, Hypoxia, Mitochondrial dysfunction, Reactive oxygen species
|editor=[[Plangger M]]
|editor=[[Plangger M]]
|mipnetlab=AT Vienna Kozlov AV
}}
}}
{{Labeling
{{Labeling

Latest revision as of 13:58, 5 December 2022

Publications in the MiPMap
Heher P, Ganassi M, Weidinger A, Engquist EN, Pruller J, Nguyen TH, Tassin A, Declèves AE, Mamchaoui K, Banerji CRS, Grillari J, Kozlov AV, Zammit PS (2022) Interplay between mitochondrial reactive oxygen species, oxidative stress and hypoxic adaptation in facioscapulohumeral muscular dystrophy: Metabolic stress as potential therapeutic target. https://doi.org/10.1016/j.redox.2022.102251

» Redox Biol 51:102251. PMID: 35248827 Open Access

Heher Philipp, Ganassi Massimo,  Weidinger Adelheid,  Engquist Elise N,  Pruller Johanna,  Nguyen Thuy Hang,  Tassin Alexandra,  Decleves Anne-Emilie,  Mamchaoui Kamel,  Banerji Christopher RS,  Grillari Johannes,  Kozlov Andrey V,  Zammit Peter S (2022) Redox Biol

Abstract: Facioscapulohumeral muscular dystrophy (FSHD) is characterised by descending skeletal muscle weakness and wasting. FSHD is caused by mis-expression of the transcription factor DUX4, which is linked to oxidative stress, a condition especially detrimental to skeletal muscle with its high metabolic activity and energy demands. Oxidative damage characterises FSHD and recent work suggests metabolic dysfunction and perturbed hypoxia signalling as novel pathomechanisms. However, redox biology of FSHD remains poorly understood, and integrating the complex dynamics of DUX4-induced metabolic changes is lacking. Here we pinpoint the kinetic involvement of altered mitochondrial ROS metabolism and impaired mitochondrial function in aetiology of oxidative stress in FSHD. Transcriptomic analysis in FSHD muscle biopsies reveals strong enrichment for pathways involved in mitochondrial complex I assembly, nitrogen metabolism, oxidative stress response and hypoxia signalling. We found elevated mitochondrial ROS (mitoROS) levels correlate with increases in steady-state mitochondrial membrane potential in FSHD myogenic cells. DUX4 triggers mitochondrial membrane polarisation prior to oxidative stress generation and apoptosis through mitoROS, and affects mitochondrial health through lipid peroxidation. We identify complex I as the primary target for DUX4-induced mitochondrial dysfunction, with strong correlation between complex I-linked respiration and cellular oxygenation/hypoxia signalling activity in environmental hypoxia. Thus, FSHD myogenesis is uniquely susceptible to hypoxia-induced oxidative stress as a consequence of metabolic mis-adaptation. Importantly, mitochondria-targeted antioxidants rescue FSHD pathology more effectively than conventional antioxidants, highlighting the central involvement of disturbed mitochondrial ROS metabolism. This work provides a pathomechanistic model by which DUX4-induced changes in oxidative metabolism impair muscle function in FSHD, amplified when metabolic adaptation to varying O2 tension is required. Keywords: Antioxidants, DUX4, Facioscapulohumeral muscular dystrophy, Hypoxia, Mitochondrial dysfunction, Reactive oxygen species Bioblast editor: Plangger M O2k-Network Lab: AT Vienna Kozlov AV


Labels: MiParea: Respiration  Pathology: Myopathy  Stress:Oxidative stress;RONS  Organism: Human  Tissue;cell: Skeletal muscle  Preparation: Permeabilized tissue 


Coupling state: LEAK, OXPHOS  Pathway: N, S  HRR: Oxygraph-2k 

2022-12