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A more recent version of this article appeared on July 8, 2005
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M500095200v1
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Papers In Press, published online ahead of print May 9, 2005
J. Biol. Chem, 10.1074/jbc.M500095200
Submitted on January 4, 2005
Accepted on May 9, 2005

Glutahione redox state regulates mitochondrial reactive oxygen production

Dongxiao Shen, Timothy P. Dalton, Daniel W. Nebert, and Howard G. Shertzer

Department of Environmental Health, University of Cincinnati Medical Center, Cincinnati, OH 45267-0056

Corresponding Author: shertzhg{at}ucmail.uc.edu

Oxidative stress induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; dioxin) is poorly understood. Following one dose of TCDD (5 µg/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 decrease 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 increase in GSSG/2GSH reduction potential. Comparing Ahr(-/-) knockout 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 4-fold increase in formamidopyrimidine DNA N-glycosylase (FPG)-sensitive cleavage sites in mitochondrial DNA, compared with a 2-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.


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