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.

Muscle Proteomic Profile before and after Enzyme Replacement Therapy in Late-Onset Pompe Disease

“…This occurred before and after treatment and no significant changes on this pathways were observed comparing PRE- and POST-therapy. It is well-known that the electron transport chain capacity per mitochondria declines with age and disease [ 37 , 38 , 39 , 40 ]. In our case this decline has to be accounted for Pompe disease since controls were age-matched; thus additional intervention to recover, at least partially, the oxidative phosphorylation, could represent a possible target for this disorder.…”

Generation of mitochondrial reactive oxygen species is controlled by ATPase inhibitory factor 1 and regulates cognition

“…MAU : PleasenotethatasperPLOSstyle; donotusesac ice were humanely killed 4 hours later, and the hippocampus was weighed and flash-frozen at −80˚C. MitoB and MitoP were extracted with 60% acetonitrile/0.1% formic acid, and standard curves of MitoB and MitoP were prepared and spiked with the internal standards d 15…”

“…In fact, inhibition of the ATP synthase by the overexpression of the ATPase inhibitory factor 1 (IF1) confers increased resistance to toxic insults in different mouse tissues [12][13][14]. However, the expression of IF1 in mouse tissues that naturally do not express the protein is detrimental and results in metabolic syndrome [15] or in oncogenesis [14], strongly emphasizing the pivotal tissue-specific role of the mammalian ATP synthase/IF1 axis in cellular signaling.…”

“…For many years, IF1 has been considered to inhibit only the reverse activity of the enzyme to prevent the hydrolysis of cellular ATP when mitochondria become de-energized [18,19]. However, the overexpression of IF1 in cultured cells [20][21][22][23][24] or in mouse tissues [12][13][14][15] inhibits the ATP synthetic activity of the enzyme contributing to metabolic reprogramming to an enhanced glycolysis and the production of mtROS. Moreover, and in contrast to the idea that IF1 binds only to the ATP synthase upon acidification of the mitochondrial matrix [19,25], IF1 is found bound to tetramers of heart ATP synthase under physiological conditions [26,27], suggesting that IF1 regulates the activity of the enzyme under phosphorylating conditions.…”

“…The contribution of IF1 to human diseases such as cancer and diabetes has been recently outlined [ 14 , 15 , 21 , 29 ], but its physiological relevance in the tissues where it is expressed is not well understood [ 30 ]. That is the case of human and mouse neurons, where IF1 levels exceed those of the ATP synthase [ 30 ].…”