Mitochondria deficient in complex I activity are depolarized by hydrogen peroxide in nerve terminals: relevance to Parkinson's disease.
Deficiency of complex I in the respiratory chain and oxidative stress induced by hydrogen peroxide occur simultaneously in dopaminergic neurones in Parkinson's disease. Here we demonstrate that the membrane potential of in situ mitochondria (Delta Psi m), as measured by the fluorescence change of JC-l (5,5',6,6'-tetrachloro-1,1,3,3'-tetraethylbezimidazolyl-carbocyani ne iodide), collapses when isolated nerve terminals are exposed to hydrogen peroxide (H(2)O(2), 100 and 500 microM) in combination with the inhibition of complex I by rotenone (5 nM-1 microM). H(2)O(2) reduced the activity of complex I by 17%, and the effect of H(2)O(2) and rotenone on the enzyme was found to be additive. A decrease in Delta Psi m induced by H(2)O(2) was significant when the activity of complex I was reduced to a similar extent as found in Parkinson's disease (26%). The loss of Delta Psi m observed in the combined presence of complex I deficiency and H(2)O(2) indicates that when complex I is partially inhibited, mitochondria in nerve terminals become more vulnerable to H(2)O(2)-induced oxidative stress. This mechanism could be crucial in the development of bioenergetic failure in Parkinson's disease.
Chinopoulos
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C
Department of Medical Biochemistry, Semmelweis University, Budapest, Hungary.
Adam-Vizi
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V
D000818:Animals; D002540:Cerebral Cortex / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D042967:Electron Transport Complex I; D004734:Energy Metabolism / Q000187:drug effects; D006168:Guinea Pigs; D006861:Hydrogen Peroxide / Q000378:metabolism* / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology*; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D010300:Parkinson Disease / Q000201:enzymology* / Q000209:etiology; D017729:Presynaptic Terminals / Q000187:drug effects / Q000201:enzymology*; D012402:Rotenone / Q000494:pharmacology; D013574:Synaptosomes / Q000187:drug effects / Q000201:enzymology
D012402:Rotenone; D006861:Hydrogen Peroxide; D009247:NADH, NADPH Oxidoreductases; D042967:Electron Transport Complex I