Mitochondrial glutathione in toxicology and disease of the kidneys

Abstract

The tripeptide glutathione (GSH), comprised of the amino acids L-cysteine, glycine, and L-glutamate, is found in all cells of aerobic organisms and plays numerous, critical roles as an antioxidant and nucleophile in regulating cellular homeostasis and drug metabolism. GSH is synthesized exclusively in the cytoplasm of most cells by two ATP-dependent reactions. Despite this compartmentation, GSH is found in other subcellular compartments, including mitochondria. As the GSH molecule has a net negative charge at physiological pH, it cannot cross cellular membranes by diffusion. Rather, GSH is a substrate for a variety of anion and amino acid transporters. Two organic anion carriers in the inner membrane of renal mitochondria, the dicarboxylate carrier (DIC; Slc25a10) and the 2-oxoglutarate carrier (OGC; Slc25a11), are responsible for most of the transport of GSH from cytoplasm into mitochondrial matrix. Genetic manipulation of DIC and/or OGC expression in renal cell lines demonstrated the ability to produce sustained increases in mitochondrial GSH content, which then protected these cells from cytotoxicity due to several oxidants and mitochondrial toxicants. Several diseases and pathological states are associated with mitochondrial dysfunction and oxidative stress, suggesting that the mitochondrial GSH pool may be a therapeutic target. One such disease that is of particular concern for public health is diabetic nephropathy. Another chronic, pathological state that is associated with bioenergetic and redox changes is compensatory renal hypertrophy that results from reductions in functional renal mass. This review summarizes pathways of mitochondrial GSH transport and discusses studies on its manipulation in toxicological and pathological states.