Perturbed Redox Signaling Exacerbates a Mitochondrial Myopathy

Alternative oxidases (AOXs) bypass respiratory complexes III and IV by transferring electrons from coenzyme Q 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 (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. Dogan et al. show that alternative oxidase attenuates ROS signaling in a COX-defective mitochondrial myopathy model, thus blunting ROS-dependent mitochondrial biogenesis and satellite cell recruitment. These findings must be considered in the treatment of mitochondrial myopathies, suggesting the need for careful assessment of antioxidant therapy.