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.

Glutathione Levels and Susceptibility to Chemically Induced Injury in Two Human Prostate Cancer Cell Lines

“…Renal mitochondria [22], like hepatic mitochondria [23], do not appear to synthesize GSH de novo but must transport GSH from the cytoplasm into the mitochondrial matrix. The transport is mediated by either the dicarboxylate carrier (DCC; Slc25a10 ) or 2-oxoglutarate carrier (OGC; Slc25a11 ) [24,25]. Again, in what would appear to be a compensatory response, expression of both the DCC and OGC was much higher in LNCaP cells than in PC-3 cells (4.5- and 2.1-fold higher, respectively, adjusted for expression of the voltage-dependent anion channel [VDAC]).…”

Mitochondrial Glutathione in Diabetic Nephropathy

“…The critical importance of mitochondrial energetics in determining both mitochondrial and overall cellular GSH status is apparent from the integration of transport pathways with the citric acid cycle and ATP generation. The figure is based on one published in reference [ 25 ] with slight modifications. Abbreviations: BBM, brush-border membrane; BLM, basolateral membrane; DIC, dicarboxylate carrier; Mrp2/4, multidrug resistance proteins 2/4; NaC3, sodium-dicarboxylate carrier 3; OA, organic anion; Oat1/3, organic anion transporter 1/3; Oatp1a1; organic anion transporting polypeptide 1a1; 2-OG, 2-oxoglutarate; OGC, oxoglutarate carrier; P i 2 − , inorganic phosphate.…”

“…The history of biochemical and toxicological studies on the mtGSH pool in liver and kidney were summarized in several review articles over the past decade [ 21 , 22 , 23 , 24 , 25 ] and will not be extensively discussed here. The main point is that there has been significant interest in mtGSH for understanding mechanisms of cellular function and response to toxicants for more than 50 years.…”

“…Abbreviations: GFR, glomerular filtration rate; GSH, glutathione; RBF, renal blood flow; ROS, reactive oxygen species. The scheme is based on one published in reference [ 25 ] with some modifications.…”

Diverse Roles of Mitochondria in Renal Injury from Environmental Toxicants and Therapeutic Drugs

“…The reader is referred to earlier reviews of renal mtGSH transport for more background and details on the identification of specific carriers involved in the transport process [34][35][36]. The primary rationale for determining the derivation and regulation of mtGSH was based on the realizations that renal GSH synthesis appears to exclusively occur in the cytoplasm [37], that renal mitochondria contain a distinct pool of GSH with concentrations in the millimolar range [38], and that the GSH molecule has a net negative charge at physiological pH.…”