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.
Bibliographical noteFunding Information:
We thank Val A. Fajardo (University of Waterloo, Waterloo, ON, Canada) for assistance with muscle fiber type distribution analysis, and Dr Tianru Jin (Toronto General Research Institute, Toronto, ON, Canada) for providing the INS-1 cells. This work was supported by the Canadian Institute of Health Research (CIHR) operating grants MOP-81148 and MOP-93707, and by a Canadian Diabetes Association (CDA) Grant-in-aid to M.W. M.W. is supported by the Canada Research Chair in Signal Transduction in Diabetes Pathogenesis. S.Y.S. and T.S. are supported by the CIHR Doctoral Research Award, the CDA Doctoral Student Research Award and the Canadian Liver Foundation Graduate Studentship. X.S.R. is supported by a Banting and Best Diabetes Centre (BBDC) Fellowship in Diabetes Care (Eli Lilly Canada). E.P.C. is supported by the CDA Doctoral Student Research Award. C.T.L. is supported by the Eliot Phillipson Clinician Scientist Training Program, the CDA Postdoctoral Fellowship, the Canadian Society of Endocrinology and Metabolism Dr Fernand Labrie Fellowship Research Award and the BBDC postdoctoral fellowship.