Dogan 2018 Cell Metab
|Dogan SA, Cerutti R, Benincá C, Brea-Calvo G, Jacobs HT, Zeviani M, Szibor M, Viscomi C (2018) Perturbed redox signaling exacerbates a mitochondrial myopathy. Cell Metab 28:764-77.|
Abstract: 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.
• Keywords: ROS, Alternative oxidase, Antioxidant, Autophagy, Mitochondrial biogenesis, Mitochondrial disease, Redox signaling, Satellite cells, Stress responses • Bioblast editor: Plangger M • O2k-Network Lab: FI Helsinki Jacobs HT, IT Padova Viscomi C, DE Jena Szibor M
Labels: MiParea: Respiration, Genetic knockout;overexpression Pathology: Myopathy Stress:Mitochondrial disease Organism: Mouse Tissue;cell: Skeletal muscle Preparation: Isolated mitochondria
Coupling state: LEAK, OXPHOS Pathway: N, S, CIV, ROX HRR: Oxygraph-2k, O2k-Fluorometer
2018-09, AmR, Safranin