AUTHOR=Liaghati Ava , Pileggi Chantal A. , Parmar Gaganvir , Patten David A. , Hadzimustafic Nina , Cuillerier Alexanne , Menzies Keir J. , Burelle Yan , Harper Mary-Ellen 

TITLE=Grx2 Regulates Skeletal Muscle Mitochondrial Structure and Autophagy

JOURNAL=Frontiers in Physiology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2021.604210

DOI=10.3389/fphys.2021.604210

ISSN=1664-042X

ABSTRACT=<p>Glutathione is an important antioxidant that regulates cellular redox status and is disordered in many disease states. Glutaredoxin 2 (<italic>Grx2</italic>) 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 that <italic>Grx2</italic> may contribute to the maintenance of mitochondrial dynamics and ultrastructure. Here, we demonstrate that <italic>Grx2</italic> deletion results in decreased GSH:GSSG, with a marked increase of GSSG in primary muscle cells isolated from C57BL/6 <italic>Grx2<sup>−/−</sup></italic> mice. The altered glutathione redox was accompanied by increased mitochondrial length, consistent with a more fused mitochondrial reticulum. Electron microscopy of <italic>Grx2<sup>−/−</sup></italic> 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 in <italic>Grx2<sup>−/−</sup></italic> 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 of <italic>tibialis anterior</italic> muscle, and decreased body weight in <italic>Grx2</italic> deficient mice. Together, these are the first results to show that <italic>Grx2</italic> regulates skeletal muscle mitochondrial structure, and autophagy.</p>