Abstract
Our group recently published a study demonstrating that deleting the gene encoding the matrix thiol oxidoreductase, glutaredoxin-2 (GRX2), alters the bioenergetics of mitochondria isolated from male C57BL/6N mice. Here, we conducted a similar study, examining H2O2 production and respiration in mitochondria isolated from female mice heterozygous (GRX2+/−) or homozygous (GRX2−/−) for glutaredoxin-2. First, we observed that deleting the Grx2 gene does not alter the rate of H2O2 production in liver and muscle mitochondria oxidizing pyruvate, α-ketoglutarate, or succinate. Examination of the rates of H2O2 release from liver mitochondria isolated from male and female mice revealed that (1) sex has an impact on the rate of ROS production by liver and muscle mitochondria and (2) loss of GRX2 only altered ROS release in mitochondria collected from male mice. Assessment of the bioenergetics of these mitochondria revealed that loss of GRX2 increased proton leak-dependent and phosphorylating respiration in liver mitochondria isolated from female mice but did not alter rates of respiration in liver mitochondria from male mice. Furthermore, we found that deleting the Grx2 gene did not alter rates of respiration in muscle mitochondria collected from female mice. This contrasts with male mice where loss of GRX2 substantially augmented proton leaks and ADP-stimulated respiration. Our findings indicate that some fundamental sexual dimorphisms exist between GRX2-deficient male and female rodents.
Highlights
Protein S-glutathionylation is a ubiquitous and reversible redox-sensitive protein modification that has emerged as an important signal for the control of cell functions
No significant differences in H2 O2 production between WT, GRX2+/−, and GRX2−/− liver mitochondria at all concentrations of pyruvate, α-ketoglutarate, or succinate used in these experiments were observed (Figure 1A–C)
Taken together, eliminating the Grx2 gene has the opposite effect on muscle mitochondria from female mice. These findings suggest that muscle mitochondria from female mice may not be as reliant on using S-glutathionylation and GRX2 to control mitochondrial bioenergetics and reactive oxygen species (ROS) production, a finding that is consistent with previous studies showing that important sex dimorphisms exist in muscle fuel metabolism [28]
Summary
Protein S-glutathionylation is a ubiquitous and reversible redox-sensitive protein modification that has emerged as an important signal for the control of cell functions. Mitochondria are highly susceptible to protein S-glutathionylation due to the physical properties of the matrix. The matrix is slightly basic, promoting thiol ionization and the formation of nucleophilic thiolate anions, factors that promote. Mitochondria are enriched in GSH (~ 2 mM) and are an important source of cellular reactive oxygen species (ROS), a driving force behind S-glutathionylation reactions [2]. Glutaredoxin-2 (GRX2), a homolog of cytosolic GRX1, catalyzes the reversible S-glutathionylation of proteins in the matrix of mitochondria. Complex I in bovine heart mitochondria was the first
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