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Herein, we demonstrate that\n                    <jats:italic>in\u00a0vivo<\/jats:italic>\n                    inhibition of mitochondrial ATP synthase in muscle alters whole\u2010body lipid homeostasis. Mice with restrained mitochondrial ATP synthase activity presented intrafiber lipid droplets, dysregulation of acyl\u2010glycerides, and higher visceral adipose tissue deposits, poising these animals to insulin resistance. This mitochondrial energy crisis increases lactate production, prevents fatty acid \u03b2\u2010oxidation, and forces the catabolism of branched\u2010chain amino acids (BCAA) to provide acetyl\u2010CoA for\n                    <jats:italic>de novo<\/jats:italic>\n                    lipid synthesis. In turn, muscle accumulation of acetyl\u2010CoA leads to acetylation\u2010dependent inhibition of mitochondrial respiratory complex II enhancing oxidative phosphorylation dysfunction which results in augmented ROS production. By screening 702 FDA\u2010approved drugs, we identified edaravone as a potent mitochondrial antioxidant and enhancer. Edaravone administration restored ROS and lipid homeostasis in skeletal muscle and reinstated insulin sensitivity. Our results suggest that muscular mitochondrial perturbations are causative of metabolic disorders and that edaravone is a potential treatment for these diseases.\n                  <\/jats:p>","DOI":"10.15252\/embj.2019103812","type":"journal-article","created":{"date-parts":[[2020,6,3]],"date-time":"2020-06-03T05:48:28Z","timestamp":1591163308000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":57,"title":["Dysfunctional oxidative phosphorylation shunts branched\u2010chain amino acid catabolism onto lipogenesis in skeletal muscle"],"prefix":"10.1038","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2710-2317","authenticated-orcid":false,"given":"Cristina","family":"S\u00e1nchez\u2010Gonz\u00e1lez","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5809-2030","authenticated-orcid":false,"given":"Cristina","family":"Nuevo\u2010Tapioles","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan Cruz","family":"Herrero Mart\u00edn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9347-957X","authenticated-orcid":false,"given":"Marta P","family":"Pereira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Serrano Sanz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Ram\u00edrez de Molina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1118-248X","authenticated-orcid":false,"given":"Jos\u00e9 M","family":"Cuezva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5641-821X","authenticated-orcid":false,"given":"Laura","family":"Formentini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,6,3]]},"reference":[{"key":"BFEMBJ2019103812_CR1","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1016\/j.molcel.2008.10.021","volume":"32","author":"R Acin\u2010Perez","year":"2008","unstructured":"Acin\u2010Perez R, Fernandez\u2010Silva P, Peleato ML, Perez\u2010Martos A, Enriquez JA (2008) Respiratory active mitochondrial supercomplexes. 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