Updated project metadata. Whether muscle mitochondrial dysfunction is the cause or consequence of metabolic disorders remains controversial. Herein, we demonstrate that inhibition of mitochondrial ATP synthase in muscle in vivo alters whole-body lipid homeostasis. Mice with restrained activity of the enzyme presented intrafiber lipid droplets, dysregulation of acyl-glycerides and higher visceral adipose tissue deposits, causing these animals to be prone to insulin resistance. This mitochondrial energy crisis increase lactate production, prevents fatty acid β-oxidation, and forces the catabolism of branched-chain amino acids (BCAA) to provide acetyl-CoA for de novo lipid synthesis. In turn, muscle acetyl-CoA accumulation feeds back to oxidative phosphorylation dysfunction through the acetylation-dependent inhibition of respiratory complex II that results in augmented ROS production. Finally, by screening 702 FDA-approved drugs, we identified edaravone as a potent mitochondrial antioxidant and enhancer. The edaravone-driven restoration of ROS and lipid homeostasis in skeletal muscle reestablished insulin sensitivity, thus suggesting that muscular mitochondrial perturbations are a direct cause in the setting of metabolic disorders and repurposing edaravone as a potential treatment for these diseases.