Mitochondrial glutathione, a key survival antioxidant

Abstract

Mitochondria are the primary intracellular site of oxygen consumption and the major source of reactive oxygen species (ROS), most of them originating from the mitochondrial respiratory chain. Among the arsenal of antioxidants and detoxifying enzymes existing in mitochondria, mitochondrial glutathione (mGSH) emerges as the main line of defense for the maintenance of the appropriate mitochondrial redox environment to avoid or repair oxidative modifications leading to mitochondrial dysfunction and cell death. mGSH importance is based not only on its abundance, but also on its versatility to counteract hydrogen peroxide, lipid hydroperoxides, or xenobiotics, mainly as a cofactor of enzymes such as glutathione peroxidase or glutathione-S-transferase (GST). Many death-inducing stimuli interact with mitochondria, causing oxidative stress; in addition, numerous pathologies are characterized by a consistent decrease in mGSH levels, which may sensitize to additional insults. From the evaluation of mGSH influence on different pathologic settings such as hypoxia, ischemia/reperfusion injury, aging, liver diseases, and neurologic disorders, it is becoming evident that it has an important role in the pathophysiology and biomedical strategies aimed to boost mGSH levels.

FIG. 1.

GSH synthesis and compartmentation. GSH is synthesized in the cytoplasm by the action of γ-glutamylcysteine synthetase (γ-GCS) and glutathione synthetase (GS), both enzymes requiring ATP. Once synthesized, GSH is distributed in the endoplasmic reticulum, nucleus, and mitochondria.

FIG. 2.

Mitochondrial control of oxidative stress. Scheme depicting the different reactions that take place inside the mitochondria to cope with the oxidative stress derived from the presence of anion superoxide, hydrogen peroxide, and hydroxyl radical. GSH peroxidase (Gpx); GSSG-reductase (GR); GSSG, glutaredoxin (Grx); Mn-dependent superoxide dismutase (MnSOD); thioredoxin-2 (Trx2); Trx-reductase (TrxR); peroxiredoxin III (PrxIII).

FIG. 3.

Mitochondrial GSH transport. GSH moves easily through the mitochondrial outer membrane (MOM); however, it needs carrier-mediated transport to cross the mitochondrial inner membrane (MIM). The dicarboxylate carrier (DCc) and the 2-oxoglutarate carrier (OGc) have been shown to function as GSH transporters. In addition, the presence of unidentified additional carriers cannot be discarded at present.

FIG. 4.

2-Oxoglutarate carrier dependence on membrane dynamics. A decrease in membrane fluidity in mitochondria, or an increased cholesterol/phospholipids molar ratio, such as that observed in rat liver mitochondria after chronic alcohol intake, results in impairment of the mitochondrial GSH transport through the 2-oxoglutarate carrier and, therefore, in a decrease in mGSH levels.

FIG. 5.

Apoptotic pathways. Apoptosis occurs through two main pathways: the extrinsic pathway or death-receptor pathway, and the intrinsic or mitochondrial pathway. Both pathways converge to a final common pathway involving the activation of caspase-3 that culminates in the execution of cell death. In many cell types, the extrinsic and intrinsic pathways are integrated through the cleavage of Bid by caspase-8, consequently conferring on mitochondria a central role in the control of cell death by apoptosis.

FIG. 6.

mGSH control of cardiolipin oxidation. Under normal conditions, mGSH is able to cope with the stress derived from many apoptotic stimuli. However, depletion of mGSH below a certain threshold will compromise ROS detoxification, leading to its accumulation, resulting ultimately in cardiolipin oxidation.

FIG. 7.

Dual role of cardiolipin oxidation in promoting mitochondrial membrane permeabilization (MMP). Oxidized cardiolipin exerts a dual role in TNF-induced MOM permeabilization and cell death: (a) contributes to the availability of free cytochrome c; and (b) maximizes the Bax-lipid pore formation, without affecting Bax translocation and oligomerization to the MOM.

FIG. 8.

mGSH depletion sensitizes tumor cells to hypoxia. HIF-1α stabilization and NF-κB activation participate in promoting survival of cancer cells under hypoxic conditions. However, overgeneration of mitochondrial ROS, as obtained after mGSH depletion, may sensitize tumor cells by inhibiting the NF-κB survival pathway, despite HIF stabilization.