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

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 and Minna Woo ()
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Sally Yu Shi: Toronto General Research Institute, University Health Network
Shun-Yan Lu: Toronto General Research Institute, University Health Network
Tharini Sivasubramaniyam: Toronto General Research Institute, University Health Network
Xavier S. Revelo: Toronto General Research Institute, University Health Network
Erica P. Cai: Toronto General Research Institute, University Health Network
Cynthia T. Luk: Toronto General Research Institute, University Health Network
Stephanie A. Schroer: Toronto General Research Institute, University Health Network
Prital Patel: Toronto General Research Institute, University Health Network
Raymond H. Kim: The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network
Eric Bombardier: University of Waterloo
Joe Quadrilatero: University of Waterloo
A. Russell Tupling: University of Waterloo
Tak W. Mak: The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network
Daniel A. Winer: Toronto General Research Institute, University Health Network
Minna Woo: Toronto General Research Institute, University Health Network

Nature Communications, 2015, vol. 6, issue 1, 1-12

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms8415

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