Glutathione metabolism and the novel role of mitochondrial gsh in retinal degeneration

Parameswaran G. Sreekumar, Deborah A. Ferrington, Ram Kannan

Research output: Contribution to journalReview articlepeer-review

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 re-quirement for its active transport across organellar membranes. The localization and distribution of 2-oxoglutarate carrier (OGC) and dicarboxylate carrier (DIC), two recently characterized mitochon-drial 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.

Original languageEnglish (US)
Article number661
JournalAntioxidants
Volume10
Issue number5
DOIs
StatePublished - May 2021

Bibliographical note

Funding Information:
Funding: This work was supported by the National Institutes of Health (grant number R01 EY30141 (RK)), the Ryan Initiative for Macular Research (RIMR), and a gift from KECK Foundation to Doheny Eye Institute. DAF was supported by the NIH (R01 EY026012 and R01 EY028554), the Elaine and Robert Larson Endowed Vision Research Chair, the Lindsay Family Foundation, and an anonymous benefactor for AMD research.

Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

  • Bioen-ergetics
  • Mitochondrial GSH
  • RPE
  • Retinal degeneration
  • SLC25A10 (DIC)
  • SLC25A11 (OGC)

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