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Title

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

AuthorsSánchez-González, Cristina; Nuevo-Tapioles, Cristina CSIC ORCID; Herrero-Martín, Juan C.; Pereira, Marta P. CSIC ORCID; Serrano-Sanz, Sandra; Ramírez de Molina, Ana; Cuezva, José M.; Formentini, Laura CSIC ORCID
KeywordsAcetyl-CoA
ATP synthase
Edaravone
Insulin resistance
Mitochondria
Issue Date3-Jun-2020
PublisherNature Publishing Group
CitationEMBO Journal 39 (2020)
AbstractIt is controversial whether mitochondrial dysfunction in skeletal muscle is the cause or consequence of metabolic disorders. Herein, we demonstrate that in vivo inhibition of mitochondrial ATP synthase in muscle alters whole-body lipid homeostasis. Mice with restrained mitochondrial ATP synthase activity presented intrafiber lipid droplets, dysregulation of acyl-glycerides, and higher visceral adipose tissue deposits, poising these animals to insulin resistance. This mitochondrial energy crisis increases 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 accumulation of acetyl-CoA leads to acetylation-dependent inhibition of mitochondrial respiratory complex II enhancing oxidative phosphorylation dysfunction which results in augmented ROS production. By screening 702 FDA-approved 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.
Publisher version (URL)http://dx.doi.org/10.15252/embj.2019103812
URIhttp://hdl.handle.net/10261/236076
Identifiersdoi: 10.15252/embj.2019103812
issn: 1460-2075
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