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.