Perturbed Redox Signaling Exacerbates a Mitochondrial Myopathy.
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Dogan, S. A., Cerutti, R., Benincá, C., Brea-Calvo, G., Jacobs, H. T., Zeviani, M., Szibor, M., & et al. (2018). Perturbed Redox Signaling Exacerbates a Mitochondrial Myopathy.. Cell metabolism, 28 (5), 764-775.e5. https://doi.org/10.1016/j.cmet.2018.07.012
Alternative oxidases (AOX) bypass respiratory complexes III and IV by transferring electrons from CoQ directly to O2. They have therefore been proposed as a potential therapeutic tool for mitochondrial diseases. We crossed the severely myopathic skeletal muscle-specific COX15 knockout mouse (KO) with an AOX-transgenic mouse. Surprisingly, the double KO-AOX mutants had decreased lifespan and a substantial worsening of the myopathy compared to KO alone. Decreased ROS production in KOAOX vs. KO mice led to impaired AMPK/PGC-1 signaling and Pax7/MyoD-dependent muscle regeneration, blunting compensatory responses. Importantly, the antioxidant Nacetylcysteine had a similar effect, decreasing the lifespan of KO mice. Our findings have major implications for understanding pathogenic mechanisms in mitochondrial diseases and for the design of therapies, highlighting the benefits of ROS signaling and the potential hazards of antioxidant treatment.
Muscle, Skeletal, Animals, Mice, Inbred C57BL, Mice, Knockout, Mice, Mitochondrial Myopathies, Reactive Oxygen Species, Oxidoreductases, Mitochondrial Proteins, Plant Proteins, Signal Transduction, Oxidation-Reduction, Autophagy, Female, Male, Organelle Biogenesis
European Commission FP7 ERC Advanced Investigator Grants (AIG) (322424)
External DOI: https://doi.org/10.1016/j.cmet.2018.07.012
This record's URL: https://www.repository.cam.ac.uk/handle/1810/279931
Attribution 4.0 International (CC BY 4.0)
Licence URL: https://creativecommons.org/licenses/by/4.0/