Nitric oxide inhibits mitochondrial NADH:ubiquinone reductase activity through peroxynitrite formation

被引:220
作者
Riobó, NA
Clementi, E
Melani, M
Boveris, A
Cadenas, E
Moncada, S
Poderoso, JJ
机构
[1] Univ Buenos Aires, Univ Hosp, Lab Oxygen Metab, RA-1120 Buenos Aires, DF, Argentina
[2] Univ Calabria, Dept Pharmacobiol, I-87036 Arcavacata Di Rende, Italy
[3] UCL, Wolfson Inst Biochem Res, London W1P 9LN, England
[4] Univ Buenos Aires, Sch Pharm & Biochem, Lab Free Rad Biol, RA-1120 Buenos Aires, DF, Argentina
[5] Univ So Calif, Sch Pharm, Dept Mol Pharmacol & Toxicol, Los Angeles, CA 90089 USA
关键词
Complex I; hydrogen peroxide; superoxide anion; ubiquinol;
D O I
10.1042/0264-6021:3590139
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
This study was aimed at assessing the effects of long-term exposure to NO of respiratory activities in mitochondria from different tissues (with different ubiquinol contents), under conditions that either promote or prevent the formation of peroxynitrite. Mitochondria and submitochondrial particles isolated from rat heart, liver and brain were exposed either to a steady-state concentration or to a bolus addition of NO. NO induced the mitochondrial production of superoxide anions, hydrogen peroxide and peroxynitrite. the latter shown by nitration of mitochondrial proteins. Long-term incubation of mitochondrial membranes with NO resulted in a persistent inhibition of NADH: cytochrome c reductase activity, interpreted as inhibition of NADH: ubiquinone reductase (Complex I) activity, whereas succinate:cytochrome c reductase activity, including Complex II and Complex III electron transfer, remained unaffected. This selective effect of NO and derived species was partially prevented by superoxide dismutase and uric acid. In addition, peroxynitrite mimicked the effect of NO, including tyrosine nitration of some Complex I proteins. These results seem to indicate that the inhibition of NADH: ubiquinone reductase (Complex I) activity depends on the NO-induced generation of superoxide radical and peroxynitrite and that Complex I is selectively sensitive to peroxynitrite. Inhibition of Complex I activity by peroxynitrite may have critical implications for energy supply in tissues such as the brain, whose mitochondrial function depends largely on the channelling of reducing equivalents through Complex I.
引用
收藏
页码:139 / 145
页数:7
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