GSH transport in mitochondria: defense against TNF-induced oxidative stress and alcohol-induced defect

Abstract

Mitochondria generate reactive oxygen species (ROS) as byproducts of molecular oxygen consumption in the electron transport chain. Most cellular oxygen is consumed in the cytochrome-c oxidase complex of the respiratory chain, which does not generate reactive species. The ubiquinone pool of complex III of respiration is the major site within the respiratory chain that generates superoxide anion as a result of a single electron transfer to molecular oxygen. Superoxide anion and hydrogen peroxide, derived from the former by superoxide dismutase, are precursor of hydroxyl radical through the participation of transition metals. Glutathione (GSH) in mitochondria is the only defense available to metabolize hydrogen peroxide. A small fraction of the total cellular GSH pool is sequestered in mitochondria by the action of a carrier that transports GSH from the cytosol to the mitochondrial matrix. Mitochondria are not only one of the main cellular sources of ROS, they also are a key target of ROS. Mitochondria are subcellular targets of cytokines, especially tumor necrosis factor (TNF); depletion of GSH in this organelle renders the cell more susceptible to oxidative stress originating in mitochondria. Ceramide generated during TNF signaling leads to increased production of ROS in mitochondria. Chronic ethanol-fed hepatocytes are selectively depleted of GSH in mitochondria due to a defective operation of the carrier responsible for transport of GSH from the cytosol into the mitochondrial matrix. Under these conditions, limitation of the mitochondrial GSH pool represents a critical contributory factor that sensitizes alcoholic hepatocytes to the prooxidant effects of cytokines and prooxidants generated by oxidative metabolism of ethanol. S-adenosyl-L-methionine prevents development of the ethanol-induced defect. The mitochondrial GSH carrier has been functionally expressed in Xenopus laevis oocytes microinjected with mRNA from rat liver. This critical carrier displays functional characteristics distinct from other plasma membrane GSH carriers, such as its ATP dependency, inhibitor specificity, and the size class of mRNA that encode the corresponding carrier, suggesting that the mitochondrial carrier of GSH is a gene product distinct from the plasma membrane transporters.

Associations between reactive oxygen species, blood pressure and arterial stiffness in black South Africans: the SABPA study

“…Therefore, excessive alcohol intake depletes cells of glutathione in the mitochondria because of a faulty operation of the carrier responsible for transport of glutathione from the cytosol into the mitochondrial matrix. 23,24 In this study, the prevalence of smoking and alcohol intake were the highest in the black South African men compared with the women. This could possibly explain why the associations with ROS were more prominent in the men who had higher blood pressure levels.…”

Pro-inflammatory cytokines increase reactive oxygen species through mitochondria and NADPH oxidase in cultured RPE cells

“…In hepatocytes Fernandez-Checa et al, 1997) and RPE cells (Kannan et al, 2004), ceramide has been shown to cause an increase in ROS generation in mitochondria. In Jurkat T lymphocytes, binding of TNF-α to its receptor causes rapid activation of an acidic sphingomyelinase (ASMase), followed by sphingomyelin hydrolysis and ceramide production within 3 min (Schutze et al, 1991).…”

Mitochondrial dysfunction and oxidative stress in the pathogenesis of alcohol- and obesity-induced fatty liver diseases

“…Studies using liver mitochondria from ob/ob mice have however demonstrated increased O 2 • − compared to mitochondria from lean mice [60,61]. Possible mechanisms for enhanced mitochondrial ROS production include molecular defects within Complexes I and III, as well as increases in RLS, and TNFα mediated ceramide [22,59,62,63]. See review [64] for a detailed description of the mechanisms responsible for alcohol induced increases in mitochondrial ROS.…”