Protein S-glutathionylation and the regulation of cellular functions

Mailloux, Ryan J.; Gill, Robert M.; Young, Adrian

doi:10.1016/b978-0-12-818606-0.00013-4

Cited by 9 publications

(16 citation statements)

References 118 publications

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“…GSH can also bind specific protein by disulfide linkages with Cys residues [ 98 ]. This process, defined as protein S-glutathionylation can be either spontaneous or enzymatically driven, depending on the redox state of intracellular glutathione pools [ 99 , 100 ]. In particular, glutathionylation of proteins is catalyzed by glutathione S-transferases and can protect or mitigate protein oxidation.…”

Section: Oxidative Stress (General Concepts)mentioning

confidence: 99%

Extracellular Vesicles under Oxidative Stress Conditions: Biological Properties and Physiological Roles

Chiaradia

Tancini

Emiliani

et al. 2021

Cells

105

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Under physio-pathological conditions, cells release membrane-surrounded structures named Extracellular Vesicles (EVs), which convey their molecular cargo to neighboring or distant cells influencing their metabolism. Besides their involvement in the intercellular communication, EVs might represent a tool used by cells to eliminate unnecessary/toxic material. Here, we revised the literature exploring the link between EVs and redox biology. The first proof of this link derives from evidence demonstrating that EVs from healthy cells protect target cells from oxidative insults through the transfer of antioxidants. Oxidative stress conditions influence the release and the molecular cargo of EVs that, in turn, modulate the redox status of target cells. Oxidative stress-related EVs exert both beneficial or harmful effects, as they can carry antioxidants or ROS-generating enzymes and oxidized molecules. As mediators of cell-to-cell communication, EVs are also implicated in the pathophysiology of oxidative stress-related diseases. The review found evidence that numerous studies speculated on the role of EVs in redox signaling and oxidative stress-related pathologies, but few of them unraveled molecular mechanisms behind this complex link. Thus, the purpose of this review is to report and discuss this evidence, highlighting that the analysis of the molecular content of oxidative stress-released EVs (reminiscent of the redox status of originating cells), is a starting point for the use of EVs as diagnostic and therapeutic tools in oxidative stress-related diseases.

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Section: Oxidative Stress (General Concepts)mentioning

confidence: 99%

Extracellular Vesicles under Oxidative Stress Conditions: Biological Properties and Physiological Roles

Chiaradia

Tancini

Emiliani

et al. 2021

Cells

105

View full text Add to dashboard Cite

show abstract

“…Alternatively, S-glutathionylation can be catalyzed by glutathione synthetase transferase π (GSTπ), which is a detoxification enzyme with a turnover time within 2–3 h following ROS/RNS-related stress [ 46 ]. Protein S-glutathionylation in general inhibits protein function and protects against both oxidative distress and irreversible oxidation [ 47 , 48 ].…”

Section: Protein Posttranslational Modifications Redox Couples and Ci...mentioning

confidence: 99%

Mitochondria Need Their Sleep: Redox, Bioenergetics, and Temperature Regulation of Circadian Rhythms and the Role of Cysteine-Mediated Redox Signaling, Uncoupling Proteins, and Substrate Cycles

Richardson

Mailloux

2023

Antioxidants

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Although circadian biorhythms of mitochondria and cells are highly conserved and crucial for the well-being of complex animals, there is a paucity of studies on the reciprocal interactions between oxidative stress, redox modifications, metabolism, thermoregulation, and other major oscillatory physiological processes. To address this limitation, we hypothesize that circadian/ultradian interaction of the redoxome, bioenergetics, and temperature signaling strongly determine the differential activities of the sleep–wake cycling of mammalians and birds. Posttranslational modifications of proteins by reversible cysteine oxoforms, S-glutathionylation and S-nitrosylation are shown to play a major role in regulating mitochondrial reactive oxygen species production, protein activity, respiration, and metabolomics. Nuclear DNA repair and cellular protein synthesis are maximized during the wake phase, whereas the redoxome is restored and mitochondrial remodeling is maximized during sleep. Hence, our analysis reveals that wakefulness is more protective and restorative to the nucleus (nucleorestorative), whereas sleep is more protective and restorative to mitochondria (mitorestorative). The “redox–bioenergetics–temperature and differential mitochondrial–nuclear regulatory hypothesis” adds to the understanding of mitochondrial respiratory uncoupling, substrate cycling control and hibernation. Similarly, this hypothesis explains how the oscillatory redox–bioenergetics–temperature–regulated sleep–wake states, when perturbed by mitochondrial interactome disturbances, influence the pathogenesis of aging, cancer, spaceflight health effects, sudden infant death syndrome, and diseases of the metabolism and nervous system.

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“…Glutathionylation reactions are ubiquitous with ~883 and >2000 proteins reported to be modified in liver and contracting muscle tissue, respectively, as well as in many other mammalian cells [ 5 , 6 , 7 , 8 ]. At the cellular level, reversible glutathionylation of proteins is required to regulate a myriad of functions ranging from chemotaxis and neutrophil extracellular trap formation to ion transport, gene expression, and metabolism [ 9 ]. In mitochondria, the glutathionylation of proteins in response to a decrease in the GSH/GSSG ratio inhibits energy metabolism, solute transport, apoptosis, and ATP production, while promoting mitochondrial fusion and protein folding [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Conditions Conducive to the Glutathionylation of Complex I Subunit NDUFS1 Augment ROS Production following the Oxidation of Ubiquinone Linked Substrates, Glycerol-3-Phosphate and Proline

et al. 2022

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Mitochondrial complex I can produce large quantities of reactive oxygen species (ROS) by reverse electron transfer (RET) from the ubiquinone (UQ) pool. Glutathionylation of complex I does induce increased mitochondrial superoxide/hydrogen peroxide (O2●−/H2O2) production, but the source of this ROS has not been identified. Here, we interrogated the glutathionylation of complex I subunit NDUFS1 and examined if its modification can result in increased ROS production during RET from the UQ pool. We also assessed glycerol-3-phosphate dehydrogenase (GPD) and proline dehydrogenase (PRODH) glutathionylation since both flavoproteins have measurable rates for ROS production as well. Induction of glutathionylation with disulfiram induced a significant increase in O2●−/H2O2 production during glycerol-3-phosphate (G3P) and proline (Pro) oxidation. Treatment of mitochondria with inhibitors for complex I (rotenone and S1QEL), complex III (myxothiazol and S3QEL), glycerol-3-phosphate dehydrogenase (iGP), and proline dehydrogenase (TFA) confirmed that the sites for this increase were complexes I and III, respectively. Treatment of liver mitochondria with disulfiram (50–1000 nM) did not induce GPD or PRODH glutathionylation, nor did it affect their activities, even though disulfiram dose-dependently increased the total number of protein glutathione mixed disulfides (PSSG). Immunocapture of complex I showed disulfiram incubations resulted in the modification of NDUFS1 subunit in complex I. Glutathionylation could be reversed by reducing agents, restoring the deglutathionylated state of NDUFS1 and the activity of the complex. Reduction of glutathionyl moieties in complex I also significantly decreased ROS production by RET from GPD and PRODH. Overall, these findings demonstrate that the modification of NDUFS1 can result in increased ROS production during RET from the UQ pool, which has implications for understanding the relationship between mitochondrial glutathionylation reactions and induction of oxidative distress in several pathologies

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Protein S-glutathionylation and the regulation of cellular functions

Cited by 9 publications

References 118 publications

Extracellular Vesicles under Oxidative Stress Conditions: Biological Properties and Physiological Roles

Extracellular Vesicles under Oxidative Stress Conditions: Biological Properties and Physiological Roles

Mitochondria Need Their Sleep: Redox, Bioenergetics, and Temperature Regulation of Circadian Rhythms and the Role of Cysteine-Mediated Redox Signaling, Uncoupling Proteins, and Substrate Cycles

Conditions Conducive to the Glutathionylation of Complex I Subunit NDUFS1 Augment ROS Production following the Oxidation of Ubiquinone Linked Substrates, Glycerol-3-Phosphate and Proline

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