The role of glutaredoxin-2 in the modulation of fat metabolism and ROS production in skeletal muscle mitochondria

Abstract

Protein S-glutathionylation (PGLU) reactions in mitochondria, catalyzed by glutaredoxin-2 (Grx2), have been shown to regulate carbon catabolism, oxidative phosphorylation and reactive oxygen species (ROS) production in response to changes in redox balance. In addition, deletion of the Grx2 gene increases phosphorylating respiration and proton leaks in muscle tissue which correlates with decreased fat mass and body weight. However, whether or not manipulation of Grx2 levels protects from diet-induced obesity (DIO) has never been investigated. Our objective was to examine the potential anti-obesity effect associated with the absence of the Grx2 gene in C57BL/6N mice. Here, we demonstrate that Grx2⁺/⁻ mice were protected from diet-induced weight gain and obesity-related disorders associated with increases in mitochondrial respiration attributed, in part, to increased leaks through uncoupling protein-3. Collectively, our results demonstrate that S-glutathionylation reactions are integral for regulating muscle metabolism and fat combustion and reveal that manipulation of Grx2 signaling may serve as an exercise mimetic that can be employed to treat/prevent DIO.