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.

Mitochondrial control of cell bioenergetics in Parkinson’s disease

“…In addition, DJ-1 has been shown to transcriptionally co-activate PINK1 expression by binding to FOXOa3; accordingly, DJ-1 loss causes decreased complex I activity and increased glycolysis via regulating PINK1 [33]. Similar effects on glucose metabolism take place in DJ-1 knockout mouse skeletal muscle, where a higher energy expenditure, AMPK activation, and uncoupled mitochondrial respiration has been observed leading to a Warburg-like metabolic reprogramming [273]. In good agreement with the view that the Warburg effect may favour cell proliferation, loss of DJ-1 increases cell proliferation via regulating PINK1 [33].…”

Pigment epithelium-derived factor stimulates skeletal muscle glycolytic activity through NADPH oxidase-dependent reactive oxygen species production

“…ROS provokes glycolytic reprogramming in cancer cells [Chandel et al 1998] to generate a chemically reduced milieu to combat ROS-induced damage [Brand & Hermfisse 1997]. Treatment of C2C12 with H 2 O 2 induced a rapid increase in ECAR and such an effect was abolished by treatment with a superoxide dismutase-mimetic and the free radical scavenger tempol confirming ROS-induced glycolytic activation in peripheral metabolic tissues [Shi et al 2015]. PEDF-induced glycolytic activation was completely ablated by antioxidants such as catalase and superoxide dismutase in both C2C12 and HSMM confirming the role of ROS in PEDF-induced glycolytic reprogramming.…”

“…We next examined the effect of PEDF-induced ROS accumulation in muscle on glycolytic activity [Shi et al 2015]. Augmented muscle glycolytic activity has been reported following treatment with inflammatory cytokines such as TNFα [Remels et al 2015, Benigni et al 2000,in disorders such as endotoxemia [Spitzer et al 1989] and mouse models of cancer cachexia associated with a pro-inflammatory state [Der-Torossian et al 2013].…”

Hepatic JAK2 protects against atherosclerosis through circulating IGF-1

“…Thresholding of maximum and minimum color intensity was conducted using ImageScope version 11.0.2.716 software (Aperio Technologies) with positively stained regions expressed as an absolute value or percentage of plaque area. For ORO staining, livers were immersed in Tissue-Tek OCT compound (Sakura) and sections were stained with ORO (Sigma-Aldrich) as previously described (75).…”