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

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.

Effects of selenoprotein extracts from Cardamine hupingshanensis on growth, selenium metabolism, antioxidant capacity, immunity and intestinal health in largemouth bass Micropterus salmoides

“…As a dimeric disulfide oxidoreductase, GR can catalyze the reduction of GSH disulfide (GSSG) to GSH for resisting oxidative stress. This process helps maintain the redox environment in human and animal cells ( 66 ). Consistent with previous findings in various fish species ( 46 ), our study demonstrates higher GR activities and GSH levels in fish fed with adequate SePCH, indicating that sufficient SePCH can enhance cellular redox homeostasis and increase antioxidant capacities by boosting GSH synthesis in the liver and intestine of largemouth bass.…”

Role of Antioxidant Molecules in the Oxidative Stress Response Networks in the Tangerine Pathotype of Alternaria alternata

“…Interestingly, this study found significant influence of key genes involved in glutathione metabolism, attributed to the inactivation of AaBemA, AaNoxB, AaTrr1, AaGlr1, AaYap1, and A. alternata wildtype under ROS stress. Glutathione, an important metabolite in eukaryotes, plays a key role in protecting cells from oxidative damage through direct scavenging of various oxidants [59,60]. We also found that significant impacts of inactivation of AaBemA, AaNoxB, AaTrr1, and AaGlr1 on the expression of genes enriched in various crucial molecular functions and pathways such as oxidoreductase activity, transmembrane transporter activity, and multiple metabolic pathways related to the regulation of ROS tolerance, providing insights into ROS detoxification and NADPH oxidase-mediated responses.…”

Morroniside Protects C2C12 Myoblasts from Oxidative Damage Caused by ROS-Mediated Mitochondrial Damage and Induction of Endoplasmic Reticulum Stress

“…GSH, a ubiquitous cellular thiol compound involved in ROS scavenging and antioxidant defense against electrophiles, serves as a key regulator of redox status within cells. Since GSH is oxidized to GSSG when reacting with ROS or electrophiles, the GSH/GSSG ratio reflects the oxidation state, and a decrease in this ratio is related to the accumulation of excessive ROS ( Hanko et al ., 2019 ; Chai and Mieyal, 2023 ). It stands to reason therefore that increasing GSH levels may be an effective strategy to protect cells from oxidative damage.…”