Age-related loss of mitochondrial glutathione exacerbates menadione-induced inhibition of Complex I

Thomas, Nicholas O.; Shay, Kate Petersen; Hagen, Tory M.

doi:10.1016/j.redox.2019.101155

Cited by 6 publications

(5 citation statements)

References 69 publications

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“…GSH is also a redox regulator of electron transport chain (ETC) proteins that perform oxidative phosphorylation, a process involving the sequential transfer of electrons between the five ETC protein complexes embedded in the inner mitochondrial membrane (IMM) [ 78 , 79 ]. Regulation of these ETC proteins suggest a possible link between mitochondrial metabolism and redox homeostasis through mGSH status [ 80 ]. mGSH depletion significantly decreased mitochondrial basal respiration and ATP production, and the reserve capacity in human RPE cells suggests an oxidative stress-dependent mechanism [ 81 ].…”

Section: Mitochondrial Gsh and Its Critical Rolementioning

confidence: 99%

“…Treatment of RPE cells with phenyl succinate (PS—an inhibitor of OGC) or butylmalonate (BM—an inhibitor of DIC) caused a disruption of complex II. It has been demonstrated that acute oxidative stress to the mitochondria caused significant vulnerability to complex I in rat hepatocytes [ 80 ]. However, no significant change was noticed in the respiratory chain complex V.…”

Section: Mitochondrial Gsh and Its Critical Rolementioning

confidence: 99%

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

2021

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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.

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Section: Mitochondrial Gsh and Its Critical Rolementioning

confidence: 99%

Section: Mitochondrial Gsh and Its Critical Rolementioning

confidence: 99%

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

2021

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“…Our results on the expression pattern of complex I have to be interpreted with caution because of the close proximity of complex I and IV bands in WB analysis under non-reducing conditions. It was reported under acute redox cycling challenge to mitochondria that the complex I protein is more vulnerable [59]. However, a complex V segment of the respiratory chain was less impacted.…”

Section: Discussionmentioning

confidence: 97%

Transporter-Mediated Mitochondrial GSH Depletion Leading to Mitochondrial Dysfunction and Rescue with αB Crystallin Peptide in RPE Cells

et al. 2020

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Mitochondrial glutathione (mGSH) is critical for cell survival. We recently reported the localization of OGC (SLC25A11) and DIC (SLC25A10) in hRPE. Herein, we investigated the suppression of OGC and DIC and the effect of αB crystallin chaperone peptide co-treatment on RPE cell death and mitochondrial function. Non-polarized and polarized human RPE were co-treated for 24 h with phenyl succinic acid (PS, 5 mM) or butyl malonic acid (BM, 5 mM) with or without αB cry peptide (75 µg/mL). mGSH levels, mitochondrial bioenergetics, and ETC proteins were analyzed. The effect of mGSH depletion on cell death and barrier function was determined in polarized RPE co-treated with PS, OGC siRNA or BM and αB cry peptide. Inhibition of OGC and DIC resulted in a significant decrease in mGSH and increased apoptosis. mGSH depletion significantly decreased mitochondrial respiration, ATP production, and altered ETC protein expression. αB cry peptide restored mGSH, attenuated apoptosis, upregulated ETC proteins, and improved mitochondrial bioenergetics and biogenesis. mGSH transporters exhibited differential polarized localization: DIC (apical) and OGC (apical and basal). Inhibition of mGSH transport compromised barrier function which was partially restored by αB cry peptide. Our findings suggest mGSH augmentation by its transporters may be a valuable approach in AMD therapy.

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“…Additionally, mGSH also plays a critical role in supporting redox signaling and the biosynthesis of iron-sulfur (Fe-S) cluster cofactors within the mitochondrial matrix. The regulation of OXPHOS proteins suggests a possible link between mitochondrial metabolism and redox homeostasis, potentially via mGSH status [13].…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial Glutathione in Cellular Redox Homeostasis and Disease Manifestation

Chen,

Wang,

Chang

et al. 2024

IJMS

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Mitochondria are critical for providing energy to maintain cell viability. Oxidative phosphorylation involves the transfer of electrons from energy substrates to oxygen to produce adenosine triphosphate. Mitochondria also regulate cell proliferation, metastasis, and deterioration. The flow of electrons in the mitochondrial respiratory chain generates reactive oxygen species (ROS), which are harmful to cells at high levels. Oxidative stress caused by ROS accumulation has been associated with an increased risk of cancer, and cardiovascular and liver diseases. Glutathione (GSH) is an abundant cellular antioxidant that is primarily synthesized in the cytoplasm and delivered to the mitochondria. Mitochondrial glutathione (mGSH) metabolizes hydrogen peroxide within the mitochondria. A long-term imbalance in the ratio of mitochondrial ROS to mGSH can cause cell dysfunction, apoptosis, necroptosis, and ferroptosis, which may lead to disease. This study aimed to review the physiological functions, anabolism, variations in organ tissue accumulation, and delivery of GSH to the mitochondria and the relationships between mGSH levels, the GSH/GSH disulfide (GSSG) ratio, programmed cell death, and ferroptosis. We also discuss diseases caused by mGSH deficiency and related therapeutics.

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Age-related loss of mitochondrial glutathione exacerbates menadione-induced inhibition of Complex I

Cited by 6 publications

References 69 publications

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

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

Transporter-Mediated Mitochondrial GSH Depletion Leading to Mitochondrial Dysfunction and Rescue with αB Crystallin Peptide in RPE Cells

Mitochondrial Glutathione in Cellular Redox Homeostasis and Disease Manifestation

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