Regulation of Mitochondrial Hydrogen Peroxide Availability by Protein S-glutathionylation

Abstract

Background: 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. Scope of the Review: 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. Major conclusions: 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. General Significance: 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.

Copper drives remodeling of metabolic state and progression of clear cell renal cell carcinoma

“…It is possible that similar activities of CuCOX in Cu Hi cancer cells regulate accumulation of H 2 O 2 in a GSH-dependent manner. Glucose-derived GSH may be also used by mitochondria to maintain redox state of ETC assembly (Leary et al, 2009; Morgada et al, 2015; Zitare et al, 2015) or contribute to glutathionylation of mitochondrial dehydrogenases and subunits of complex I, preventing formation of superoxide and H 2 O 2 while maintaining increased OCR (Applegate et al, 2008; Gill et al, 2018; Mailloux et al, 2022; O’Brien et al, 2017).…”

The emerging importance of the α-keto acid dehydrogenase complexes in serving as intracellular and intercellular signaling platforms for the regulation of metabolism

“…The reversible oxidation of cysteine switches in mitochondria controls mtO 2 •- /mtH 2 O 2 generation [ 160 , 161 ]. mtO 2 •- /mtH 2 O 2 generation by complex I was first found to be suppressed by reversible glutathionylation [ 122 , 162 ], which was later suggested to play an integral role in the propagation of redox signals through the cell [ 163 ].…”

Mitochondrial complex I ROS production and redox signaling in hypoxia

“…RET ROS causes oxidative thiol-modification of several of the cysteine residues of complex I resulting in diminution of the catalytic activity of the enzyme complex [ 158 , 130 , 156 , 159 ]. Glutathionylation of complex I subunits including NDUFS1 and NDUFV1 leads to inhibition of complex I activity and ROS production [ 160 ]. Moreover, the D-form is more susceptible to oxidative thiol-modification [ 142 ].…”