Grx2 Regulates Skeletal Muscle Mitochondrial Structure and Autophagy

Abstract

Glutathione is an important antioxidant that regulates cellular redox status and is disordered in many disease states. Glutaredoxin 2 (Grx2) is a glutathione-dependent oxidoreductase that plays a pivotal role in redox control by catalyzing reversible protein deglutathionylation. As oxidized glutathione (GSSG) can stimulate mitochondrial fusion, we hypothesized thatGrx2may contribute to the maintenance of mitochondrial dynamics and ultrastructure. Here, we demonstrate thatGrx2deletion results in decreased GSH:GSSG, with a marked increase of GSSG in primary muscle cells isolated from C57BL/6Grx2−/−mice. The altered glutathione redox was accompanied by increased mitochondrial length, consistent with a more fused mitochondrial reticulum. Electron microscopy ofGrx2−/−skeletal muscle fibers revealed decreased mitochondrial surface area, profoundly disordered ultrastructure, and the appearance of multi-lamellar structures. Immunoblot analysis revealed that autophagic flux was augmented inGrx2−/−muscle as demonstrated by an increase in the ratio of LC3II/I expression. These molecular changes resulted in impaired complex I respiration and complex IV activity, a smaller diameter oftibialis anteriormuscle, and decreased body weight inGrx2deficient mice. Together, these are the first results to show thatGrx2regulates skeletal muscle mitochondrial structure, and autophagy.