Regulation of Mitochondrial Hydrogen Peroxide Availability by Protein S-glutathionylation

It has been four decades since protein S-glutathionylation was proposed to serve as a regulator of cell metabolism. Since then, this redox-sensitive covalent modification has been identified as a cell-wide signaling platform required for embryonic development and regulation of many physiological functions.

Mitochondria use hydrogen peroxide (H₂O₂) as a second messenger, but its availability must be controlled to prevent oxidative distress and promote changes in cell behavior in response to stimuli. Experimental data favor the function of protein S-glutathionylation as a feedback loop for the inhibition of mitochondrial H₂O₂ production.

The glutathione pool redox state is linked to the availability of H₂O₂, making glutathionylation an ideal mechanism for preventing oxidative distress whilst playing a part in desensitizing mitochondrial redox signals.

The biological significance of glutathionylation is rooted in redox status communication. The present review critically evaluates the experimental evidence supporting its role in negating mitochondrial H₂O₂ production for cell signaling and prevention of electrophilic stress.