Perturbed Redox Signaling Exacerbates a Mitochondrial Myopathy.

TitlePerturbed Redox Signaling Exacerbates a Mitochondrial Myopathy.
Publication TypeJournal Article
Year of Publication2018
AuthorsDogan, SAnil, Cerutti, R, Benincá, C, Brea-Calvo, G, Jacobs, HTrevor, Zeviani, M, Szibor, M, Viscomi, C
JournalCell Metab
Date Published2018 Aug 09

Alternative oxidases (AOXs) bypass respiratory complexes III and IV by transferring electrons from coenzyme Q directly to O. They have therefore been proposed as a potential therapeutic tool for mitochondrial diseases. We crossed the severely myopathic skeletal muscle-specific COX15 knockout (KO) mouse with an AOX-transgenic mouse. Surprisingly, the double KO-AOX mutants had decreased lifespan and a substantial worsening of the myopathy compared with KO alone. Decreased ROS production in KO-AOX versus KO mice led to impaired AMPK/PGC-1α signaling and PAX7/MYOD-dependent muscle regeneration, blunting compensatory responses. Importantly, the antioxidant N-acetylcysteine 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.

Alternate JournalCell Metab.
Citation Key10.1016/j.cmet.2018.07.012
PubMed ID30122554