TCDD decreases ATP levels and increases reactive oxygen production through changes in mitochondrial F(0)F(1)-ATP synthase and ubiquinone.
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.
Shertzer
Howard G
HG
Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati Medical Center, P.O. Box 670056 Cincinnati, OH 45267-0056, USA. shertzhg@ucmail.uc.edu
Genter
Mary Beth
MB
Shen
Dongxiao
D
Nebert
Daniel W
DW
Chen
Ying
Y
Dalton
Timothy P
TP
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D014450:Electron Transport Complex III / Q000378:metabolism; D004785:Environmental Pollutants / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000201:enzymology; D010088:Oxidoreductases / Q000378:metabolism; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D006180:Proton-Translocating ATPases / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014451:Ubiquinone / Q000378:metabolism*
D004785:Environmental Pollutants; D000072317:Polychlorinated Dibenzodioxins; D017382:Reactive Oxygen Species; D014451:Ubiquinone; D000255:Adenosine Triphosphate; D010088:Oxidoreductases; C022691:succinate oxidase; D006180:Proton-Translocating ATPases; D014450:Electron Transport Complex III