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Review
. 2024 Jan 21;25(2):1314.
doi: 10.3390/ijms25021314.

Mitochondrial Glutathione in Cellular Redox Homeostasis and Disease Manifestation

Tsung-Hsien Chen  1 , Hsiang-Chen Wang  2 , Chia-Jung Chang  3 , Shih-Yu Lee  3
Affiliations
Review

Mitochondrial Glutathione in Cellular Redox Homeostasis and Disease Manifestation

Tsung-Hsien Chen et al. Int J Mol Sci. .

Abstract

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.

Keywords: GSH deficiency; GSH/GSSG; glutathione; mitochondria; oxidative phosphorylation; programmed cell death; reactive oxygen species (ROS).

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Production of reactive oxygen species via mitochondrial oxidative phosphorylation (OXPHOS) process. OXPHOS consists of five protein complexes (I, II, III, IV, and V) and two electron carriers (CoQ and cyt c). Complex I accepts electrons from NADH and transfers them to CoQ. Complex II receives electrons from succinate and transfers them to CoQ. Complex III transfers electrons from CoQ to cyt c. Complex IV transfers electrons from cyt c to molecular oxygen, thereby reducing it to water. Complexes I, III, and IV pump protons through the mitochondrial inner membrane. These electron transfers create a proton gradient that drives the protons back into the mitochondrial matrix via ATP synthase. The leakage of electrons from complexes I and III results in the partial reduction of oxygen to superoxides [14,15]. Other potential ROS production sites include mitochondrial complex II, various mitochondrial enzyme components, and respiratory chain components [16,17]. Acetyl CoA, acetyl coenzyme A; ADP, adenosine diphosphate; ATP, adenosine triphosphate; CI, complex I; CII, complex II; CIII, complex III; CIV, complex IV; CV, complex V; CoQ, coenzyme Q; cyt c, cytochrome complex; FAD, flavin adenine dinucleotide; FADH2, reduced form of flavine adenine dinucleotide; GSH, glutathione; GSSG, glutathione disulfide; IMM, inner mitochondrial membrane; IMS, inner mitochondrial space; NAD+, oxidized form of nicotinamide adenine dinucleotide; NADH, reduced form of nicotinamide adenine dinucleotide; NADP+, oxidized form of nicotinamide adenine dinucleotide phosphate; NADPH, reduced form of nicotinamide adenine dinucleotide phosphate; OMM, outer mitochondrial membrane; Trx, thioredoxin.
Figure 2
Figure 2
Excessive production of reactive oxygen species results in altered signaling, release of cytochrome c, and cell damage. While ROS play important roles in cell signaling, an imbalance of mtROS can cause lipid peroxidation and disrupt mitochondrial function. Moreover, this imbalance can result in mutations or deletions in mtDNA, affecting mitochondrial protein function and disrupting OXPHOS. Dysfunctional OXPHOS leads to an increased accumulation of ROS. When ROS levels are low, the mitophagy mechanism is activated, but when ROS levels are high, the apoptosis mechanism is triggered. ROS also induces the release of cyt c and PTP, promoting apoptosis. cyt c, cytochrome c; MOMP, mitochondrial outer membrane permeabilization; mtDNA, mitochondrial DNA; OXPHOS, oxidative phosphorylation; PTP, protein tyrosine phosphatases; ROS, reactive oxygen species.
Figure 3
Figure 3
Glutathione is a biological redox buffer. GSH is an important antioxidant in cells as it helps maintain the reduced state of proteins. In a reaction catalyzed by GSH-Px, two GSH molecules form a disulfide bond through sulfhydryl dehydrogenation, resulting in the production of GSSG. Additionally, GR oxidizes NADPH and converts GSSG back into GSH. In normal cells, GSH makes up more than 90% of the total amount of GSH. However, when the level of oxidative stress in cells increases, the content of GSSG rises, causing the ratio of GSH to GSSG to decrease. The ratio of GSH/GSSG reflects the redox capacity of the cell, which is maintained via the oxidation/reduction reactions of GSH-Px and GR. GR, glutathione reductase; GSH, glutathione; GSH-Px, glutathione peroxidase; GSSG, GSH disulfide; NADP+, phosphate oxidized form of nicotinamide adenine dinucleotide; NADPH, reduced form of NADP+.
Figure 4
Figure 4
Glutathione synthesis. GSH synthesis relies on the enzymatic activities of cysteine, glutamate, and GSH synthetase (γ-glutamylcysteine ligase). The rate-limiting GSH synthesis intermediate, γ-glutamylcysteine, is formed from glutamate and cysteine and catalyzed by the GCL holoenzyme. The addition of glycine to γ-glutamylcysteine, catalyzed by GSH synthetase, results in the formation of GSH. ATP, adenosine triphosphate; ADP, adenosine diphosphate, GSH, glutathione; GCL, GSH cysteine ligase; Pi, phosphate groups.
Figure 5
Figure 5
The synthesis of glutathione requires the expression of three genes, namely, GCLC, GCLM, and GSS, in different tissues. These genes (GCLC, GCLM, and GSS) encode the GCL holoenzyme and glutathione synthetase. An overview of the RNA expression reveals that the RNA sequencing (RNA-SEQ) data are a combination of information from the Human Protein Atlas RNA-SEQ data and an internally generated consensus data combination. These datasets were obtained from the Human Protein Atlas Project (https://www.proteinatlas.org (accessed on 6 January 2024). GCLM, glutamate–cysteine ligase regulatory subunit; GCLC, glutamate–cysteine ligase catalytic subunit; GSS, glutathione synthetase; nTPM, transcripts per million.
Figure 6
Figure 6
Mitochondrial glutathione, transported from the cytoplasm, can prevent cell damage from reactive oxygen species. GSH is synthesized in the cytosol and can be transported to the mitochondria via specific carriers in the inner mitochondrial membrane. Currently, there are three known carriers for GSH transport: the 2-ketoglutarate carrier (OGC; SLC25A11), the dicarboxylic acid carrier (DIC; SLC25A10), and SLC25A39. When intracellular levels of ROS increase, there is a mild accumulation of ROS that induces the production of reducing molecules, such as GSH, and enhances the detoxification mechanism. However, excessive accumulation of ROS leads to increased lipid peroxidation, protein misfolding, and DNA chain breakage. GSH, glutathione; GSSG, GSH disulfide; mGSH, mitochondrial glutathione; ROS, reactive oxygen species. The ↑ bar indicates an increase.
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