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DJ-1 links muscle ROS production with metabolic reprogramming and systemic energy homeostasis in mice.

Nature communications (2015-06-17)
Sally Yu Shi, Shun-Yan Lu, Tharini Sivasubramaniyam, Xavier S Revelo, Erica P Cai, Cynthia T Luk, Stephanie A Schroer, Prital Patel, Raymond H Kim, Eric Bombardier, Joe Quadrilatero, A Russell Tupling, Tak W Mak, Daniel A Winer, Minna Woo
ABSTRACT

Reactive oxygen species (ROS) have been linked to a wide variety of pathologies, including obesity and diabetes, but ROS also act as endogenous signalling molecules, regulating numerous biological processes. DJ-1 is one of the most evolutionarily conserved proteins across species, and mutations in DJ-1 have been linked to some cases of Parkinson's disease. Here we show that DJ-1 maintains cellular metabolic homeostasis via modulating ROS levels in murine skeletal muscles, revealing a role of DJ-1 in maintaining efficient fuel utilization. We demonstrate that, in the absence of DJ-1, ROS uncouple mitochondrial respiration and activate AMP-activated protein kinase, which triggers Warburg-like metabolic reprogramming in muscle cells. Accordingly, DJ-1 knockout mice exhibit higher energy expenditure and are protected from obesity, insulin resistance and diabetes in the setting of fuel surplus. Our data suggest that promoting mitochondrial uncoupling may be a potential strategy for the treatment of obesity-associated metabolic disorders.

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