Dataset Information

Mouse Skeletal Muscle mitochondrial bioenergetics LC-MSMS

ABSTRACT: 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.

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Skeletal Muscle

SUBMITTER: Cristina Sánchez González

LAB HEAD: Laura Formentini

PROVIDER: PXD017621 | Pride | 2020-07-06

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	180618_LFormentini_iTRAQ_F1.mgf	Mgf
	180618_LFormentini_iTRAQ_F1.raw	Raw
	180618_LFormentini_iTRAQ_F2.mgf	Mgf
	180618_LFormentini_iTRAQ_F2.raw	Raw
	180618_LFormentini_iTRAQ_F3.mgf	Mgf

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Publications

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

Sánchez-González Cristina C Nuevo-Tapioles Cristina C Herrero Martín Juan Cruz JC Pereira Marta P MP Serrano Sanz Sandra S Ramírez de Molina Ana A Cuezva José M JM Formentini Laura L

The EMBO journal 20200603 14

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 ...[more]

PMID: 32488939

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