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 that Grx2 may contribute to the maintenance of mitochondrial dynamics and ultrastructure. Here, we demonstrate that Grx2 deletion results in decreased GSH:GSSG, with a marked increase of GSSG in primary muscle cells isolated from C57BL/6 Grx2−/− mice. The altered glutathione redox was accompanied by increased mitochondrial length, consistent with a more fused mitochondrial reticulum. Electron microscopy of Grx2−/− 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 Grx2−/− 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 tibialis anterior muscle, and decreased body weight in Grx2 deficient mice. Together, these are the first results to show that Grx2 regulates skeletal muscle mitochondrial structure, and autophagy.
Highlights
Disordered mitochondrial glutathione reduction-oxidation reactions are associated with many disease states, such as type 2 diabetes, aging-associated neurodegenerative diseases, and rare genetic mitochondrial diseases (McMurray et al, 2016; Calabrese et al, 2017; Stockwell et al, 2017; Hoffmann and Griffiths, 2018; Kanaan et al, 2018)
We examined the cross-sectional area of Hematoxylin and eosin (H&E) stained skeletal muscle sections to determine if differences in skeletal muscle size were contributing to the decrease in lean body mass in Glutaredoxin 2 (Grx2)−/− mice
The present study examined the impact of Grx2 deficiency on skeletal muscle mitochondrial ultrastructure and dynamics, as well as on bioenergetics in ex vivo muscle fibers
Summary
Disordered mitochondrial glutathione reduction-oxidation reactions (redox) are associated with many disease states, such as type 2 diabetes, aging-associated neurodegenerative diseases, and rare genetic mitochondrial diseases (McMurray et al, 2016; Calabrese et al, 2017; Stockwell et al, 2017; Hoffmann and Griffiths, 2018; Kanaan et al, 2018). As a major non-protein antioxidant in cells, glutathione buffers elevations in hydrogen peroxide (H2O2), a form of reactive oxygen species (ROS) that contributes directly to the pathophysiology of these diseases (Houstis et al, 2006). Protein glutathionylation is a rapid and reversible post-translational modification, which functions to protect vulnerable sulfhydryl groups from irreversible oxidation/damage in response to fluctuations in the redox environment (Nikolaienko et al, 2018; Figlia et al, 2020; Mailloux, 2020). Grx is the primary mitochondria-specific Grx isoform whose function varies in response to fluctuations in the reduced glutathione (GSH); oxidized glutathione (GSSG) ratio; a high GSH:GSSG ratio promotes protein deglutathionylation, and a low GSH:GSSG ratio promotes Grx glutathionylation of target proteins (Beer et al, 2004; Hurd et al, 2008). Glutathionylation reactions can alter protein activity thereby rendering the targets active or inactive (Adachi et al, 2004; Pimentel et al, 2006), and are abundant in mitochondrial proteins rich in cysteine thiols (Mailloux, 2020)
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