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

Abstract

It 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.

• Authors: Cristina Sánchez-González, Cristina Nuevo-Tapioles, Juan Cruz Herrero Martín, Marta P Pereira, Sandra Serrano Sanz, Ana Ramírez de Molina, José M Cuezva, Laura Formentini
• Journal: The EMBO journal (EMBO J) Vol. 39 Issue 14 Pg. e103812 (07 15 2020) ISSN: 1460-2075 [Electronic] England
• PMID: 32488939 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 The Authors. Published under the terms of the CC BY 4.0 license.

Chemical References

• Amino Acids, Branched-Chain

Topics

• Amino Acids, Branched-Chain (metabolism)
• Animals
• Lipogenesis
• Mice
• Mice, Transgenic
• Muscle, Skeletal (metabolism)
• Oxidative Phosphorylation