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

Nat Commun. 2015 Jun 16:6:7415. doi: 10.1038/ncomms8415.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / metabolism
  • Adipose Tissue / metabolism
  • Adipose Tissue / pathology
  • Animals
  • Cell Line
  • Cell Survival
  • Diabetes Mellitus / genetics
  • Diet, High-Fat
  • Energy Metabolism / genetics*
  • Glucose / metabolism
  • Glycolysis / genetics
  • Homeostasis / genetics
  • Immunoblotting
  • Insulin Resistance / genetics
  • Mice
  • Mice, Knockout
  • Mitochondria / metabolism*
  • Muscle Fibers, Skeletal / metabolism
  • Muscle, Skeletal / metabolism*
  • Myoblasts, Skeletal / metabolism*
  • Obesity / genetics
  • Oncogene Proteins / genetics*
  • Oxidative Stress
  • Oxygen Consumption
  • Peroxiredoxins / genetics*
  • Protein Deglycase DJ-1
  • Reactive Oxygen Species / metabolism*

Substances

  • Oncogene Proteins
  • Reactive Oxygen Species
  • Peroxiredoxins
  • AMP-Activated Protein Kinases
  • PARK7 protein, mouse
  • Protein Deglycase DJ-1
  • Glucose

Associated data

  • GEO/GSE63051