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Glutaredoxin and Glutathione

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A special issue of Antioxidants (ISSN 2076-3921). This special issue belongs to the section "Antioxidant Enzyme Systems".

Deadline for manuscript submissions: closed (15 February 2023) | Viewed by 24391

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Dr. Yuh-Cherng Chai

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Guest Editor

Department of Chemistry, John Carroll University, University Heights, OH 44118, USA
Interests: redox biochemistry; protein S-glutathionylation; redox mechanism regulating the activation of cellular caspase 3 in apoptosis

Prof. Dr. John J. Mieyal

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Guest Editor

Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
Interests: redox regulation and signal transduction in health and disease; glutaredoxin enzyme system; mechanisms of redox dysregulation in Parkinson’s disease and cardiovascular diseases

Special Issue Information

Dear Colleagues,

The tripeptide glutathione (GSH), the most abundant non-enzymatic antioxidant molecule, and its oxidized form glutathione disulfide (GSSG) constitute a crucial redox buffer in cells. Besides various metabolic reactions involving GSH/GSSG, one particular aspect that has drawn extensive interest in the redox field over the last decade is S-glutathionylation, the formation of mixed disulfides between glutathione and reactive protein thiols. Protein S-glutathionylation is a reversible post-translational modification that can act as a switch between active and inactive forms of proteins engaged in cell signaling and redox homeostasis. The dysregulation of protein S-glutathionylation has been linked to a range of pathological conditions involving oxidative stress. Within this context, glutaredoxins (Grx) have been characterized a class of GSH-dependent cytosolic oxidoreductase enzymes that specifically catalyze reversible protein S-glutathionylation, serving to protect protein thiols from irreversible oxidation and/or to regulate redox signal transduction. The diverse regulatory roles of Grx have been implicated in cardiovascular, neurological and pulmonary diseases, as well as viral infections. Alternative isoforms of Grx (e.g., Grx2) have been implicated in redox regulation within the mitochondria, and in control of iron homeostasis.

This Special Issue of Antioxidants aims to collect review articles and original research studies focused on advancing the current understanding of unique roles of the GSH/Grx system in cellular homeostasis and disease processes.

Dr. Yuh-Cherng Chai
Prof. Dr. John Mieyal
Guest Editors

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Keywords

glutathione
glutaredoxin
glutathionylation
redox homeostasis
redox signaling
oxidative stress

Published Papers (10 papers)

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Research

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18 pages, 2407 KiB

Open AccessArticle

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

by Kevin Wang, Jonathan Hirschenson, Amanda Moore and Ryan J. Mailloux

Antioxidants 2022, 11(10), 2043; https://doi.org/10.3390/antiox11102043 - 17 Oct 2022

Cited by 8 | Viewed by 2222

Abstract

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 Full article

(This article belongs to the Special Issue Glutaredoxin and Glutathione)

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11 pages, 1400 KiB

Open AccessArticle

Introduction of a More Glutaredoxin-like Active Site to PDI Results in Competition between Protein Substrate and Glutathione Binding

by Mirva J. Saaranen, Heli I. Alanen, Kirsi E. H. Salo, Emmanuel Nji, Pekka Kärkkäinen, Constanze Schmotz and Lloyd W. Ruddock

Antioxidants 2022, 11(10), 1920; https://doi.org/10.3390/antiox11101920 - 28 Sep 2022

Cited by 4 | Viewed by 1450

Abstract

Proteins in the thioredoxin superfamily share a similar fold, contain a -CXXC- active site, and catalyze oxidoreductase reactions by dithiol-disulfide exchange mechanisms. Protein disulfide isomerase (PDI) has two -CGHC- active sites. For in vitro studies, oxidation/reduction of PDI during the catalytic cycle is accomplished with glutathione. Glutathione may act as electron donor/acceptor for PDI also in vivo, but at least for oxidation reactions, GSSG probably is not the major electron acceptor and PDI may not have evolved to react with glutathione with high affinity, but merely having adequate affinity for both glutathione and folding proteins/peptides. Glutaredoxins, on the other hand, have a high affinity for glutathione. They commonly have -CXFC- or -CXYC- active site, where the tyrosine residue forms part of the GSH binding groove. Mutating the active site of PDI to a more glutaredoxin-like motif increased its reactivity with glutathione. All such variants showed an increased rate in GSH-dependent reduction or GSSG-dependent oxidation of the active site, as well as a decreased rate of the native disulfide bond formation, with the magnitude of the effect increasing with glutathione concentration. This suggests that these variants lead to competition in binding between glutathione and folding protein substrates. Full article

(This article belongs to the Special Issue Glutaredoxin and Glutathione)

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16 pages, 3994 KiB

Open AccessArticle

Administration of Glutaredoxin-1 Attenuates Liver Fibrosis Caused by Aging and Non-Alcoholic Steatohepatitis

by Yuko Tsukahara, Beatriz Ferran, Erika T. Minetti, Brian S. H. Chong, Adam C. Gower, Markus M. Bachschmid and Reiko Matsui

Antioxidants 2022, 11(5), 867; https://doi.org/10.3390/antiox11050867 - 28 Apr 2022

Cited by 6 | Viewed by 2566

Abstract

Liver fibrosis is a sign of non-alcoholic fatty liver disease progression towards steatohepatitis (NASH) and cirrhosis and is accelerated by aging. Glutaredoxin-1 (Glrx) controls redox signaling by reversing protein S-glutathionylation, induced by oxidative stress, and its deletion causes fatty liver in mice. Although Glrx regulates various pathways, including metabolism and apoptosis, the impact of Glrx on liver fibrosis has not been studied. Therefore, we evaluated the role of Glrx in liver fibrosis induced by aging or by a high-fat, high-fructose diet. We found that: (1) upregulation of Glrx expression level inhibits age-induced hepatic apoptosis and liver fibrosis. In vitro studies indicate that Glrx regulates Fas-induced apoptosis in hepatocytes; (2) diet-induced NASH leads to reduced expression of Glrx and higher levels of S-glutathionylated proteins in the liver. In the NASH model, hepatocyte-specific adeno-associated virus-mediated Glrx overexpression (AAV-Hep-Glrx) suppresses fibrosis and apoptosis and improves liver function; (3) AAV-Hep-Glrx significantly inhibits transcription of Zbtb16 and negatively regulates immune pathways in the NASH liver. In conclusion, the upregulation of Glrx is a potential therapeutic for the reversal of NASH progression by attenuating inflammatory and fibrotic processes. Full article

(This article belongs to the Special Issue Glutaredoxin and Glutathione)

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Review

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15 pages, 1316 KiB

Open AccessReview

Glutathione and Glutaredoxin—Key Players in Cellular Redox Homeostasis and Signaling

by Yuh-Cherng Chai and John J. Mieyal

Antioxidants 2023, 12(8), 1553; https://doi.org/10.3390/antiox12081553 - 3 Aug 2023

Cited by 13 | Viewed by 2809

Abstract

This Special Issue of Antioxidants on Glutathione (GSH) and Glutaredoxin (Grx) was designed to collect review articles and original research studies focused on advancing the current understanding of the roles of the GSH/Grx system in cellular homeostasis and disease processes. The tripeptide glutathione (GSH) is the most abundant non-enzymatic antioxidant/nucleophilic molecule in cells. In addition to various metabolic reactions involving GSH and its oxidized counterpart GSSG, oxidative post-translational modification (PTM) of proteins has been a focal point of keen interest in the redox field over the last few decades. In particular, the S-glutathionylation of proteins (protein-SSG formation), i.e., mixed disulfides between GSH and protein thiols, has been studied extensively. This reversible PTM can act as a regulatory switch to interconvert inactive and active forms of proteins, thereby mediating cell signaling and redox homeostasis. The unique architecture of the GSH molecule enhances its relative abundance in cells and contributes to the glutathionyl specificity of the primary catalytic activity of the glutaredoxin enzymes, which play central roles in redox homeostasis and signaling, and in iron metabolism in eukaryotes and prokaryotes under physiological and pathophysiological conditions. The class-1 glutaredoxins are characterized as cytosolic GSH-dependent oxidoreductases that catalyze reversible protein S-glutathionylation specifically, thereby contributing to the regulation of redox signal transduction and/or the protection of protein thiols from irreversible oxidation. This Special Issue includes nine other articles: three original studies and six review papers. Together, these ten articles support the central theme that GSH/Grx is a unique system for regulating thiol-redox hemostasis and redox-signal transduction, and the dysregulation of the GSH/Grx system is implicated in the onset and progression of various diseases involving oxidative stress. Within this context, it is important to appreciate the complementary functions of the GSH/Grx and thioredoxin systems not only in thiol-disulfide regulation but also in reversible S-nitrosylation. Several potential clinical applications have emerged from a thorough understanding of the GSH/Grx redox regulatory system at the molecular level, and in various cell types in vitro and in vivo, including, among others, the concept that elevating Grx content/activity could serve as an anti-fibrotic intervention; and discovering small molecules that mimic the inhibitory effects of S-glutathionylation on dimer association could identify novel anti-viral agents that impact the key protease activities of the HIV and SARS-CoV-2 viruses. Thus, this Special Issue on Glutathione and Glutaredoxin has focused attention and advanced understanding of an important aspect of redox biology, as well as spawning questions worthy of future study. Full article

(This article belongs to the Special Issue Glutaredoxin and Glutathione)

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19 pages, 2386 KiB

Open AccessReview

Protein Glutathionylation and Glutaredoxin: Role in Neurodegenerative Diseases

by Haseena P. A., Latha Diwakar and Vijayalakshmi Ravindranath

Antioxidants 2022, 11(12), 2334; https://doi.org/10.3390/antiox11122334 - 25 Nov 2022

Cited by 6 | Viewed by 2196

Abstract

Oxidative stress has been implicated in the pathogenesis and progression of many neurodegenerative disorders including Parkinson’s disease and Alzheimer’s disease. One of the major enzyme systems involved in the defense against reactive oxygen species are the tripeptide glutathione and oxidoreductase glutaredoxin. Glutathione and glutaredoxin system are very important in the brain because of the oxidative modification of protein thiols to protein glutathione mixed disulfides with the concomitant formation of oxidized glutathione during oxidative stress. Formation of Pr-SSG acts as a sink in the brain and is reduced back to protein thiols during recovery, thus restoring protein functions. This is unlike in the liver, which has a high turnover of glutathione, and formation of Pr-SSG is very minimal as liver is able to quickly quench the prooxidant species. Given the important role glutathione and glutaredoxin play in the brain, both in normal and pathologic states, it is necessary to study ways to augment the system to help maintain the protein thiol status. This review details the importance of glutathione and glutaredoxin systems in several neurodegenerative disorders and emphasizes the potential augmentation of this system as a target to effectively protect the brain during aging. Full article

(This article belongs to the Special Issue Glutaredoxin and Glutathione)

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18 pages, 1881 KiB

Open AccessReview

Defining the S-Glutathionylation Proteome by Biochemical and Mass Spectrometric Approaches

by Xiaolu Li, Tong Zhang, Nicholas J. Day, Song Feng, Matthew J. Gaffrey and Wei-Jun Qian

Antioxidants 2022, 11(11), 2272; https://doi.org/10.3390/antiox11112272 - 17 Nov 2022

Cited by 7 | Viewed by 2735

Abstract

Protein S-glutathionylation (SSG) is a reversible post-translational modification (PTM) featuring the conjugation of glutathione to a protein cysteine thiol. SSG can alter protein structure, activity, subcellular localization, and interaction with small molecules and other proteins. Thus, it plays a critical role in redox signaling and regulation in various physiological activities and pathological events. In this review, we summarize current biochemical and analytical approaches for characterizing SSG at both the proteome level and at individual protein levels. To illustrate the mechanism underlying SSG-mediated redox regulation, we highlight recent examples of functional and structural consequences of SSG modifications. Finally, we discuss the analytical challenges in characterizing SSG and the thiol PTM landscape, future directions for understanding of the role of SSG in redox signaling and regulation and its interplay with other PTMs, and the potential role of computational approaches to accelerate functional discovery. Full article

(This article belongs to the Special Issue Glutaredoxin and Glutathione)

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11 pages, 1299 KiB

Open AccessReview

Regulation of Retroviral and SARS-CoV-2 Protease Dimerization and Activity through Reversible Oxidation

by David A. Davis, Haydar Bulut, Prabha Shrestha, Hiroaki Mitsuya and Robert Yarchoan

Antioxidants 2022, 11(10), 2054; https://doi.org/10.3390/antiox11102054 - 18 Oct 2022

Cited by 2 | Viewed by 1796

Abstract

Most viruses encode their own proteases to carry out viral maturation and these often require dimerization for activity. Studies on human immunodeficiency virus type 1 (HIV-1), type 2 (HIV-2) and human T-cell leukemia virus (HTLV-1) proteases have shown that the activity of these proteases can be reversibly regulated by cysteine (Cys) glutathionylation and/or methionine oxidation (for HIV-2). These modifications lead to inhibition of protease dimerization and therefore loss of activity. These changes are reversible with the cellular enzymes, glutaredoxin or methionine sulfoxide reductase. Perhaps more importantly, as a result, the maturation of retroviral particles can also be regulated through reversible oxidation and this has been demonstrated for HIV-1, HIV-2, Mason-Pfizer monkey virus (M-PMV) and murine leukemia virus (MLV). More recently, our group has learned that SARS-CoV-2 main protease (M^pro) dimerization and activity can also be regulated through reversible glutathionylation of Cys300. Overall, these studies reveal a conserved way for viruses to regulate viral polyprotein processing particularly during oxidative stress and reveal novel targets for the development of inhibitors of dimerization and activity of these important viral enzyme targets. Full article

(This article belongs to the Special Issue Glutaredoxin and Glutathione)

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30 pages, 6357 KiB

Open AccessReview

Glutathione and Glutaredoxin in Redox Regulation and Cell Signaling of the Lens

by Marjorie F. Lou

Antioxidants 2022, 11(10), 1973; https://doi.org/10.3390/antiox11101973 - 1 Oct 2022

Cited by 23 | Viewed by 2506

Abstract

The ocular lens has a very high content of the antioxidant glutathione (GSH) and the enzymes that can recycle its oxidized form, glutathione disulfide (GSSG), for further use. It can be synthesized in the lens and, in part, transported from the neighboring anterior aqueous humor and posterior vitreous body. GSH is known to protect the thiols of the structural lens crystallin proteins from oxidation by reactive oxygen species (ROS) so the lens can maintain its transparency for proper visual function. Age-related lens opacity or senile cataract is the major visual impairment in the general population, and its cause is closely associated with aging and a constant exposure to environmental oxidative stress, such as ultraviolet light and the metabolic end product, H₂O₂. The mechanism for senile cataractogenesis has been hypothesized as the results of oxidation-induced protein-thiol mixed disulfide formation, such as protein-S-S-glutathione and protein-S-S-cysteine mixed disulfides, which if not reduced in time, can change the protein conformation to allow cascading modifications of various kinds leading to protein–protein aggregation and insolubilization. The consequence of such changes in lens structural proteins is lens opacity. Besides GSH, the lens has several antioxidation defense enzymes that can repair oxidation damage. One of the specific redox regulating enzymes that has been recently identified is thioltransferase (glutaredoxin 1), which works in concert with GSH, to reduce the oxidative stress as well as to regulate thiol/disulfide redox balance by preventing protein-thiol mixed disulfide accumulation in the lens. This oxidation-resistant and inducible enzyme has multiple physiological functions. In addition to protecting structural proteins and metabolic enzymes, it is able to regulate the redox signaling of the cells during growth factor-stimulated cell proliferation and other cellular functions. This review article focuses on describing the redox regulating functions of GSH and the thioltransferase enzyme in the ocular lens. Full article

(This article belongs to the Special Issue Glutaredoxin and Glutathione)

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31 pages, 2034 KiB

Open AccessReview

S-Denitrosylation: A Crosstalk between Glutathione and Redoxin Systems

by Surupa Chakraborty, Esha Sircar, Camelia Bhattacharyya, Ankita Choudhuri, Akansha Mishra, Sreejita Dutta, Sneha Bhatta, Kumar Sachin and Rajib Sengupta

Antioxidants 2022, 11(10), 1921; https://doi.org/10.3390/antiox11101921 - 28 Sep 2022

Cited by 9 | Viewed by 3165

Abstract

S-nitrosylation of proteins occurs as a consequence of the derivatization of cysteine thiols with nitric oxide (NO) and is often associated with diseases and protein malfunction. Aberrant S-nitrosylation, in addition to other genetic and epigenetic factors, has gained rapid importance as a prime cause of various metabolic, respiratory, and cardiac disorders, with a major emphasis on cancer and neurodegeneration. The S-nitrosoproteome, a term used to collectively refer to the diverse and dynamic repertoire of S-nitrosylated proteins, is relatively less explored in the field of redox biochemistry, in contrast to other covalently modified versions of the same set of proteins. Advancing research is gradually unveiling the enormous clinical importance of S-nitrosylation in the etiology of diseases and is opening up new avenues of prompt diagnosis that harness this phenomenon. Ever since the discovery of the two robust and highly conserved S-nitrosoglutathione reductase and thioredoxin systems as candidate denitrosylases, years of rampant speculation centered around the identification of specific substrates and other candidate denitrosylases, subcellular localization of both substrates and denitrosylases, the position of susceptible thiols, mechanisms of S-denitrosylation under basal and stimulus-dependent conditions, impact on protein conformation and function, and extrapolating these findings towards the understanding of diseases, aging and the development of novel therapeutic strategies. However, newer insights in the ever-expanding field of redox biology reveal distinct gaps in exploring the crucial crosstalk between the redoxins/major denitrosylase systems. Clarifying the importance of the functional overlap of the glutaredoxin, glutathione, and thioredoxin systems and examining their complementary functions as denitrosylases and antioxidant enzymatic defense systems are essential prerequisites for devising a rationale that could aid in predicting the extent of cell survival under high oxidative/nitrosative stress while taking into account the existence of the alternative and compensatory regulatory mechanisms. This review thus attempts to highlight major gaps in our understanding of the robust cellular redox regulation system, which is upheld by the concerted efforts of various denitrosylases and antioxidants. Full article

(This article belongs to the Special Issue Glutaredoxin and Glutathione)

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13 pages, 1346 KiB

Open AccessReview

S-Glutathionylation-Controlled Apoptosis of Lung Epithelial Cells; Potential Implications for Lung Fibrosis

by Elizabeth Corteselli, Reem Aboushousha and Yvonne Janssen-Heininger

Antioxidants 2022, 11(9), 1789; https://doi.org/10.3390/antiox11091789 - 10 Sep 2022

Cited by 6 | Viewed by 1912

Abstract

Glutathione (GSH), a major antioxidant in mammalian cells, regulates several vital cellular processes, such as nutrient metabolism, protein synthesis, and immune responses. In addition to its role in antioxidant defense, GSH controls biological processes through its conjugation to reactive protein cysteines in a post-translational modification known as protein S-glutathionylation (PSSG). PSSG has recently been implicated in the pathogenesis of multiple diseases including idiopathic pulmonary fibrosis (IPF). Hallmarks of IPF include repeated injury to the alveolar epithelium with aberrant tissue repair, epithelial cell apoptosis and fibroblast resistance to apoptosis, and the accumulation of extracellular matrix and distortion of normal lung architecture. Several studies have linked oxidative stress and PSSG to the development and progression of IPF. Additionally, it has been suggested that the loss of epithelial cell homeostasis and increased apoptosis, accompanied by the release of various metabolites, creates a vicious cycle that aggravates disease progression. In this short review, we highlight some recent studies that link PSSG to epithelial cell apoptosis and highlight the potential implication of metabolites secreted by apoptotic cells. Full article

(This article belongs to the Special Issue Glutaredoxin and Glutathione)

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