Dysfunctional oxidative phosphorylation shunts branched‐chain amino acid catabolism onto lipogenesis in skeletal muscle

• DOI: 10.15252/embj.2019103812
• Publication Date: 2020-06-03T09:48:28Z
• Authors: Cristina Sánchez‐...; Cristina Nuevo‐Ta...; Juan Cruz Herrero...; Marta P Pereira; Sandra Serrano Sanz; Ana Ramírez de Mo...; José M Cuezva; Laura Formentini
• Keywords: Lipogenesis; Catabolism; Dysfunctional family

It is controversial whether mitochondrial dysfunction in skeletal muscle the cause or consequence of metabolic disorders. Herein, we demonstrate that vivo inhibition ATP synthase alters whole-body lipid homeostasis. Mice with restrained activity presented intrafiber droplets, dysregulation acyl-glycerides, and higher visceral adipose tissue deposits, poising these animals to insulin resistance. This energy crisis increases lactate production, prevents fatty acid β-oxidation, forces catabolism branched-chain amino acids (BCAA) provide acetyl-CoA for de novo synthesis. In turn, accumulation leads acetylation-dependent respiratory complex II enhancing oxidative phosphorylation which results augmented ROS production. By screening 702 FDA-approved drugs, identified edaravone as a potent antioxidant enhancer. Edaravone administration restored homeostasis reinstated sensitivity. Our suggest muscular perturbations are causative disorders potential treatment diseases.