title: DJ-1 links muscle ROS production with metabolic reprogramming and systemic energy homeostasis in mice.
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.
authors.affiliation: 1] Toronto General Research Institute, University Health Network, MaRS Centre, TMDT, 101 College Street, 10th floor, Room 10-363, Toronto, Ontario M5G 1L7, Canada [2] Institute of Medical Science, University of Toronto, Toronto, Ontario M5G 2M9, Canada.
authors.forename: Sally Yu
authors.initials: SY
authors.lastname: Shi
authors.affiliation: Toronto General Research Institute, University Health Network, MaRS Centre, TMDT, 101 College Street, 10th floor, Room 10-363, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Shun-Yan
authors.initials: SY
authors.lastname: Lu
authors.affiliation: 1] Toronto General Research Institute, University Health Network, MaRS Centre, TMDT, 101 College Street, 10th floor, Room 10-363, Toronto, Ontario M5G 1L7, Canada [2] Institute of Medical Science, University of Toronto, Toronto, Ontario M5G 2M9, Canada.
authors.forename: Tharini
authors.initials: T
authors.lastname: Sivasubramaniyam
authors.affiliation: Toronto General Research Institute, University Health Network, MaRS Centre, TMDT, 101 College Street, 10th floor, Room 10-363, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Xavier S
authors.initials: XS
authors.lastname: Revelo
authors.affiliation: 1] Toronto General Research Institute, University Health Network, MaRS Centre, TMDT, 101 College Street, 10th floor, Room 10-363, Toronto, Ontario M5G 1L7, Canada [2] Institute of Medical Science, University of Toronto, Toronto, Ontario M5G 2M9, Canada.
authors.forename: Erica P
authors.initials: EP
authors.lastname: Cai
authors.affiliation: 1] Toronto General Research Institute, University Health Network, MaRS Centre, TMDT, 101 College Street, 10th floor, Room 10-363, Toronto, Ontario M5G 1L7, Canada [2] Institute of Medical Science, University of Toronto, Toronto, Ontario M5G 2M9, Canada.
authors.forename: Cynthia T
authors.initials: CT
authors.lastname: Luk
authors.affiliation: Toronto General Research Institute, University Health Network, MaRS Centre, TMDT, 101 College Street, 10th floor, Room 10-363, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Schroer
authors.affiliation: Toronto General Research Institute, University Health Network, MaRS Centre, TMDT, 101 College Street, 10th floor, Room 10-363, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Prital
authors.initials: P
authors.lastname: Patel
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, Ontario M5G 2C1, Canada.
authors.forename: Raymond H
authors.initials: RH
authors.lastname: Kim
authors.affiliation: Department of Kinesiology, University of Waterloo, Waterloo, Ontario N2L 3G1, Canada.
authors.forename: Eric
authors.initials: E
authors.lastname: Bombardier
authors.affiliation: Department of Kinesiology, University of Waterloo, Waterloo, Ontario N2L 3G1, Canada.
authors.forename: Joe
authors.initials: J
authors.lastname: Quadrilatero
authors.affiliation: Department of Kinesiology, University of Waterloo, Waterloo, Ontario N2L 3G1, Canada.
authors.forename: A Russell
authors.initials: AR
authors.lastname: Tupling
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, Ontario M5G 2C1, Canada.
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
authors.affiliation: Toronto General Research Institute, University Health Network, MaRS Centre, TMDT, 101 College Street, 10th floor, Room 10-363, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Winer
authors.affiliation: 1] Toronto General Research Institute, University Health Network, MaRS Centre, TMDT, 101 College Street, 10th floor, Room 10-363, Toronto, Ontario M5G 1L7, Canada [2] Institute of Medical Science, University of Toronto, Toronto, Ontario M5G 2M9, Canada [3] Division of Endocrinology and Metabolism, Department of Medicine, University Health Network, University of Toronto, Toronto, Ontario M5G 2C4, Canada.
authors.forename: Minna
authors.initials: M
authors.lastname: Woo
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002460:Cell Line; D002470:Cell Survival; D003920:Diabetes Mellitus / Q000235:genetics; D059305:Diet, High-Fat; D004734:Energy Metabolism / Q000235:genetics*; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis / Q000235:genetics; D006706:Homeostasis / Q000235:genetics; D015151:Immunoblotting; D007333:Insulin Resistance / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism*; D032448:Myoblasts, Skeletal / Q000378:metabolism*; D009765:Obesity / Q000235:genetics; D015513:Oncogene Proteins / Q000235:genetics*; D018384:Oxidative Stress; D010101:Oxygen Consumption; D054464:Peroxiredoxins / Q000235:genetics*; D000071617:Protein Deglycase DJ-1; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D015513:Oncogene Proteins; D017382:Reactive Oxygen Species; D054464:Peroxiredoxins; D055372:AMP-Activated Protein Kinases; C503466:PARK7 protein, mouse; D000071617:Protein Deglycase DJ-1; D005947:Glucose