Glutaredoxin-2 Is Required to Control Oxidative Phosphorylation in Cardiac Muscle by Mediating Deglutathionylation Reactions

Abstract

Background: Mitochondrial proteins are controlled by glutaredoxin-2 (Grx2)-mediated deglutathionylation reactions. Results: Grx2 deficiency compromises cardiac mitochondrial functions leading to hypertrophy and fibrosis in male mice. This is associated with deregulated glutathionylation reactions and mitochondrial dysfunction. Conclusion: Through deglutathionylation, Grx2 controls mitochondrial oxidative phosphorylation in cardiac muscle. Significance: Deregulated glutathionylation in heart can have pathological consequences.

Reactive Metabolite-induced Protein Glutathionylation: A Potentially Novel Mechanism Underlying Acetaminophen Hepatotoxicity

“…In parallel with these observations, complexes I-III and the ATP synthase F 0 complex subunit B1 was found to be glutathionylated by 30 mM APAP in our study, and complexes I, II and ATP synthase F 1 subunit α are known to be inhibited by glutathionylation (38,45,46). Collectively, glutathionylation of the electron transport chain and ATP synthase accounts for the profound decrease in ATP levels observed with APAP.…”

Protective effects of dietary avocado oil on impaired electron transport chain function and exacerbated oxidative stress in liver mitochondria from diabetic rats

“…Thus, the mechanism underlying the beneficial effects of avocado oil in mitochondria from diabetic rats might consist in the maintenance of a more reduced GSH/GSSG ratio similar to that observed in control mitochondria (4.1 ± 0.4 vs 3.5 ± 0.3, respectively), which would prevent and/or revert complex I inhibition as high GSH/GSSG ratio enables Grx2-mediated deglutathionylation (Ribas et al 2014). Despite this mechanism is merely speculative because we have not measured complex I gluthationylation, there is increasingly evidence supporting the pathologic importance of complex I inhibition by glutahionylation, as demonstrated in a recent report where complex I inhibition due to homozygotic Grx2 deletion caused cardiac impairment and hypertension and this was prevented by restoration of mitochondrial redox environment (Mailloux et al 2014).…”

Thiol switches in mitochondria: operation and physiological relevance

“…In contrast, Grx2 deficient mice present more specific defects affecting lens epithelial cells (Wu et al, 2011), as well as cardiac tissue and skeletal muscle. These effects are probably a consequence of increased proton leakage and perturbed oxidative phosphorylation caused by dysregulation of glutathionylation and de-glutathionylation events in the electron transport chain complexes (Mailloux et al, 2013(Mailloux et al, , 2014. For enzymes of the IMS, it appears to be more challenging to unequivocally assign distinct functions for redox enzymes in the control of ROS levels in the IMS as some of these, including SOD1, Grx1, TXNRD1, Gpx1 and Gpx4, are known to dually localize to the cytosol, IMS and other compartments of the cell (Table 1).…”