S-glutathionylation: relevance in diabetes and potential role as a biomarker

Abstract

Glutathione is considered the main regulator of redox balance in the cellular milieu due to its capacity for detoxifying deleterious molecules. The oxidative stress induced as a result of a variety of stimuli promotes protein oxidation, usually at cysteine residues, leading to changes in their activity. Mild oxidative stress, which may take place in physiological conditions, induces the reversible oxidation of cysteines to sulfenic acid form, while pathological conditions are associated with higher rates of reactive oxygen species production, inducing the irreversible oxidation of cysteines. Among these, neurodegenerative disorders, cardiovascular diseases and diabetes have been proposed to be pathogenetically linked to this state. In diabetes-associated vascular complications, lower levels of glutathione and increased oxidative stress have been reported. S-glutathionylation has been proposed as a posttranslational modification able to protect proteins from over-oxidizing environments. S-glutathionylation has been identified in proteins involved in diabetic models both in vitro and in vivo. In all of them, S-glutathionylation represents a mechanism that regulates the response to diabetic conditions, and has been described to occur in erythrocytes and neutrophils from diabetic patients. However, additional studies are necessary to discern whether this modification represents a biomarker for the early onset of diabetic vascular complications.

Redox regulation of mitochondrial function with emphasis on cysteine oxidation reactions

“…The generation of O 2 − from the highly reduced Q, and from Complex III in general, is believed to be the primary source of mitochondrial dysfunction during diabetes. Two recent reviews have addressed the role of redox signaling and S-glutathionylation in glucose-stimulated insulin release and how deregulated redox signaling could potentially be related to development of diabetes [175]. However, very few studies have actually addressed the role of redox signaling in modulation mitochondrial function in pancreatic β-cells.…”

Targeting of Gamma-Glutamyl-Cysteine Ligase by miR-433 Reduces Glutathione Biosynthesis and Promotes TGF-β-Dependent Fibrogenesis

“…4B, left panel). Decreased 2GSH/GSSG ratio is associated with potentially increased S-glutathionylation (48,56). To verify this, HUVEC were labeled with biotinylated glutathione ethyl ester (BIOGEE) in the presence or absence of S-nitrosoglutathione (GSNO), an inductor of S-thiolation (23).…”

“…G lutathione (GSH) is considered the quintessential endogenous antioxidant largely due to its relatively high intracellular concentrations (0.5-10 mM) (40). While ubiquitous, it is preferentially synthesized in the liver as a tripeptide (c-glutamyl-L-cysteinyl-glycine) and it pairs with the disulfide form (GSSG) in a relatively constant molar ratio (2GSH/GSSG) of 100-300:1 corresponding to redox potentials from -220 to -240 mV (56), although this relationship has been recently challenged (42). GSH contributes to detoxify deleterious metabolites, regulating the cell cycle and, above all, maintaining redox homeostasis by preserving nucleophilic tone, redox potential and facilitating redox signaling [see Ref.…”

Glyoxalase 1 expression is downregulated in preimplantation blastocysts of diabetic rabbits

“…Nitrosylation and glutathionylation, in contrast, seem to have an inhibitory effect on GLO1 activity (Birkenmeier et al, 2010;Mitsumoto et al, 1999Mitsumoto et al, , 2000. This post-translational modification can act as a very sensitive redox and dicarbonyl stress sensor to regulate elevated glucose metabolites (Sánchez-Gómez, Espinosa-Díez, Dubey, Dikshit, & Lamas, 2013;Wadham, Parker, Wang, & Xia, 2007).…”