Title: Glutathione redox state regulates mitochondrial reactive oxygen production.

Authors: Shen, Dongxiao; Dalton, Timothy P; Nebert, Daniel W; Shertzer, Howard G

Published In J Biol Chem, (2005 Jul 08)

Abstract: Oxidative stress induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; dioxin) is poorly understood. Following one dose of TCDD (5 microg/kg body weight), mitochondrial succinate-dependent production of superoxide and H2O2 in mouse liver doubled at 7-28 days, then subsided by day 56; concomitantly, levels of GSH and GSSG increased in both cytosol and mitochondria. Cytosol displayed a typical oxidative stress response, consisting of diminished GSH relative to GSSG, decreased potential to reduce protein-SSG mixed disulfide bonds (type 1 thiol redox switch) or protein-SS-protein disulfide bonds (type 2 thiol redox switch), and a +10 mV change in GSSG/2GSH reduction potential. In contrast, mitochondria showed a rise in reduction state, consisting of increased GSH relative to GSSG, increases in type 1 and type 2 thiol redox switches, and a -25 mV change in GSSG/2GSH reduction potential. Comparing Ahr(-/-) knock-out and wild-type mice, we found that TCDD-induced thiol changes in both cytosol and mitochondria were dependent on the aromatic hydrocarbon receptor (AHR). GSH was rapidly taken up by mitochondria and stimulated succinate-dependent H2O2 production. A linear dependence of H2O2 production on the reduction potential for GSSG/2GSH exists between -150 and -300 mV. The TCDD-stimulated increase in succinate-dependent and thiol-stimulated production of reactive oxygen paralleled a four-fold increase in formamidopyrimidine DNA N-glycosylase (FPG)-sensitive cleavage sites in mitochondrial DNA, compared with a two-fold increase in nuclear DNA. These results suggest that TCDD produces an AHR-dependent oxidative stress in mitochondria, with concomitant mitochondrial DNA damage mediated, at least in part, by an increase in the mitochondrial thiol reduction state.

PubMed ID: 15883162

MeSH Terms: Animals; Basic Helix-Loop-Helix Transcription Factors; Cell Nucleus/drug effects; Cell Nucleus/metabolism; Cytosol/metabolism; Glutathione Disulfide/metabolism; Glutathione/metabolism*; Hydrogen Peroxide/metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondria/drug effects; Mitochondria/metabolism*; Oxidation-Reduction; Polychlorinated Dibenzodioxins/pharmacology; Reactive Oxygen Species/metabolism*; Receptors, Aryl Hydrocarbon/genetics; Teratogens/pharmacology