Glutathione Metabolism and the Novel Role of Mitochondrial GSH in Retinal Degeneration

Abstract

Glutathione (GSH) is present ubiquitously, and its role as a crucial cellular antioxidant in tissues, including the retina, is well established. GSH’s antioxidant function arises from its ability to scavenge reactive oxygen species or to serve as an essential cofactor for GSH S-transferases and peroxidases. This review summarizes the general functions, retinal distribution, disorders linked to GSH deficiency, and the emerging role for mitochondrial GSH (mGSH) in retinal function. Though synthesized only in the cytosol, the presence of GSH in multiple cell organelles suggests the requirement for its active transport across organellar membranes. The localization and distribution of 2-oxoglutarate carrier (OGC) and dicarboxylate carrier (DIC), two recently characterized mitochondrial carrier proteins in RPE and retina, show that these transporters are highly expressed in human retinal pigment epithelium (RPE) cells and retinal layers, and their expression increases with RPE polarity in cultured cells. Depletion of mGSH levels via inhibition of the two transporters resulted in reduced mitochondrial bioenergetic parameters (basal respiration, ATP production, maximal respiration, and spare respiratory capacity) and increased RPE cell death. These results begin to reveal a critical role for mGSH in maintaining RPE bioenergetics and cell health. Thus, augmentation of mGSH pool under GSH-deficient conditions may be a valuable tool in treating retinal disorders, such as age-related macular degeneration and optic neuropathies, whose pathologies have been associated with mitochondrial dysfunction.

Dysregulated Tear Film Proteins in Macular Edema Due to the Neovascular Age-Related Macular Degeneration Are Involved in the Regulation of Protein Clearance, Inflammation, and Neovascularization

“…One of the most striking findings was the downregulation of glutathione S-transferase P. Glutathione (GSH) is one of the most important, ubiquitous antioxidant agents, whose role in the retinal anti-OS defense is well-established. It works by scavenging the reactive oxygen species and is a cofactor for GSH S-transferase P [ 9 , 10 ]. Its lowered concentration in the tear film of AMD patients may suggest the impaired cell-detoxification mechanisms.…”

“…Tear film is produced by lacrimal and accessory glands, as well as by meibomian glands and goblet cells [5]. Since tear film is readily accessible, it has been analyzed in many clinical studies on dry eye syndrome, diabetes, Parkinson's disease, multiple sclerosis, and cancer [6][7][8][9][10][11][12].…”

The state of pro- and antioxidant systems in rats with DMH-induced colon carcinogenesis on the background of extracorporeal detoxification

“…including protecting proteins during an oxidative stress through the reversible glutathionylation of active thiols and maintaining of the reduced form of multiple antioxidant enzymes through the process of redox cycling, which involves repeated reduction-oxidation (SH to SS) reactions (Sreekumar et al 2021). We found that the content of GSH in the blood serum of rats with DMH-induced colon carcinogenesis progressively decreased starting from the fourth month of the experiment.…”

Vitamin A aldehyde-taurine adducts function in photoreceptor cells

“…This finding suggests that taurine scavenges these dicarbonyls ( Fig. S5 ) and that like glutathione [ 71 ] taurine may be bifunctional in photoreceptor cells. Scavenging activity such as this is also consistent with high taurine concentrations in retina [ 2 ].…”