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Title: TCDD decreases ATP levels and increases reactive oxygen production through changes in mitochondrial F F{sub 1}-ATP synthase and ubiquinone

Abstract

Mitochondria generate ATP and participate in signal transduction and cellular pathology and/or cell death. TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) decreases hepatic ATP levels and generates mitochondrial oxidative DNA damage, which is exacerbated by increasing mitochondrial glutathione redox state and by inner membrane hyperpolarization. This study identifies mitochondrial targets of TCDD that initiate and sustain reactive oxygen production and decreased ATP levels. One week after treating mice with TCDD, liver ubiquinone (Q) levels were significantly decreased, while rates of succinoxidase and Q-cytochrome c oxidoreductase activities were increased. However, the expected increase in Q reduction state following TCDD treatment did not occur; instead, Q was more oxidized. These results could be explained by an ATP synthase defect, a premise supported by the unusual finding that TCDD lowers ATP/O ratios without concomitant changes in respiratory control ratios. Such results suggest either a futile cycle in ATP synthesis, or hydrolysis of newly synthesized ATP prior to release. The TCDD-mediated decrease in Q, concomitant with an increase in respiration, increases complex 3 redox cycling. This acts in concert with glutathione to increase membrane potential and reactive oxygen production. The proposed defect in ATP synthase explains both the greater respiratory rates and the lower tissue ATP levels.

Authors:
 [1];  [2];  [2];  [2];  [2];  [2]
  1. Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati Medical Center, P.O. Box 670056 Cincinnati, OH 45267-0056 (United States). E-mail: shertzhg@ucmail.uc.edu
  2. Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati Medical Center, P.O. Box 670056 Cincinnati, OH 45267-0056 (United States)
Publication Date:
OSTI Identifier:
20850510
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 217; Journal Issue: 3; Other Information: DOI: 10.1016/j.taap.2006.09.014; PII: S0041-008X(06)00343-7; Copyright (c) 2006 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; APOPTOSIS; ATP; BIOLOGICAL STRESS; CARBON MONOXIDE; DIOXIN; DNA DAMAGES; GLUCOSE; GLUTATHIONE; HYDROLYSIS; IRON; LIVER; MITOCHONDRIA; OXIDASES; OXYGEN; PATHOLOGY; PH VALUE; POTASSIUM CHLORIDES; POTASSIUM PHOSPHATES; RESPIRATION; UBIQUINONE

Citation Formats

Shertzer, Howard G., Genter, Mary Beth, Shen, Dongxiao, Nebert, Daniel W., Chen, Ying, and Dalton, Timothy P. TCDD decreases ATP levels and increases reactive oxygen production through changes in mitochondrial F F{sub 1}-ATP synthase and ubiquinone. United States: N. p., 2006. Web. doi:10.1016/j.taap.2006.09.014.
Shertzer, Howard G., Genter, Mary Beth, Shen, Dongxiao, Nebert, Daniel W., Chen, Ying, & Dalton, Timothy P. TCDD decreases ATP levels and increases reactive oxygen production through changes in mitochondrial F F{sub 1}-ATP synthase and ubiquinone. United States. doi:10.1016/j.taap.2006.09.014.
Shertzer, Howard G., Genter, Mary Beth, Shen, Dongxiao, Nebert, Daniel W., Chen, Ying, and Dalton, Timothy P. Fri . "TCDD decreases ATP levels and increases reactive oxygen production through changes in mitochondrial F F{sub 1}-ATP synthase and ubiquinone". United States. doi:10.1016/j.taap.2006.09.014.
@article{osti_20850510,
title = {TCDD decreases ATP levels and increases reactive oxygen production through changes in mitochondrial F F{sub 1}-ATP synthase and ubiquinone},
author = {Shertzer, Howard G. and Genter, Mary Beth and Shen, Dongxiao and Nebert, Daniel W. and Chen, Ying and Dalton, Timothy P.},
abstractNote = {Mitochondria generate ATP and participate in signal transduction and cellular pathology and/or cell death. TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) decreases hepatic ATP levels and generates mitochondrial oxidative DNA damage, which is exacerbated by increasing mitochondrial glutathione redox state and by inner membrane hyperpolarization. This study identifies mitochondrial targets of TCDD that initiate and sustain reactive oxygen production and decreased ATP levels. One week after treating mice with TCDD, liver ubiquinone (Q) levels were significantly decreased, while rates of succinoxidase and Q-cytochrome c oxidoreductase activities were increased. However, the expected increase in Q reduction state following TCDD treatment did not occur; instead, Q was more oxidized. These results could be explained by an ATP synthase defect, a premise supported by the unusual finding that TCDD lowers ATP/O ratios without concomitant changes in respiratory control ratios. Such results suggest either a futile cycle in ATP synthesis, or hydrolysis of newly synthesized ATP prior to release. The TCDD-mediated decrease in Q, concomitant with an increase in respiration, increases complex 3 redox cycling. This acts in concert with glutathione to increase membrane potential and reactive oxygen production. The proposed defect in ATP synthase explains both the greater respiratory rates and the lower tissue ATP levels.},
doi = {10.1016/j.taap.2006.09.014},
journal = {Toxicology and Applied Pharmacology},
number = 3,
volume = 217,
place = {United States},
year = {Fri Dec 15 00:00:00 EST 2006},
month = {Fri Dec 15 00:00:00 EST 2006}
}
  • Studies were carried out to determine whether a simple electron-dense heavy atom like iodine could be introduced selectively into one or more of the subunits of the mitochondrial ATP synthase complex of rat liver. Surprisingly, very low amounts of iodine are incorporated into the isolated F/sub 1/ moiety of this complex under conditions which result in a marked loss of catalytic activity. ATPase activity is inactivated in a concentration-dependent manner at pH 7.5 with half-maximal inactivation occurring at about 40 ..mu..M iodine. A maximum of only 10 atoms of iodine are incorporated per F/sub 1/ molecule under conditions where inhibitionmore » of ATPase activity is linearly related to iodine incorporation. The molecular size of F/sub 1/ after iodination is unchanged, indicating that inactivation is due to modification of essential amino acid residues rather than subunit dissociation. Treatment of F/sub 1/ with 20-50 ..mu..M (/sup 125/I)iodine followed sequentially by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and autoradiography showed that the ..beta.. subunit is preferentially labeled. Significantly, about two atoms of iodine per ..beta.. subunit are incorporated. Nucleotide binding to F/sub 1/ is unaltered by iodine, and neither phosphate, MgADP, nor MgATP protects F/sub 1/ against inhibition by this agent. Rather, loss of ATPase activity upon iodination appears to be associated with one or more pH-sensitive groups. These studies represent the first attempt to introduce a heavy atom into an F/sub 1/-ATPase preparation in a selective manner. The results show that at low concentrations iodine does react preferentially with ..beta.. subunits of the rat liver enzyme while inactivating the catalytic capacity of the intact complex. These findings may prove useful in future studies directed at understanding structural-functional relationships within ATP synthase complexes.« less
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