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 induc ed by hydrogen peroxide occur simultaneously in dopaminergic neurones in Pa rkinson's disease. Here we demonstrate that the membrane potential of in si f(I mitochondria (Delta Psim), as measured by the fluorescence change of JC -I (5,5',6,6'-tetrachloro-1,1,3,3'-tetraethylbenzimidazolylcarbocyanine iod ide), collapses when isolated nerve terminals are exposed to hydrogen perox ide (H2O2,100 and 500 muM) in combination with the inhibition of complex I by rotenone (5 nM-1 muM). H2O2 reduced the activity of complex I by 17%, an d the effect of H2O2 and rotenone on the enzyme was found to be additive. A decrease in Delta Psim induced by H2O2 was significant when the activity o f complex I was reduced to a similar extent as found in Parkinson's disease (26%). The loss of Delta Psim observed in the combined presence of complex I deficiency and H2O2 indicates that when complex I is partially inhibited , mitochondria in nerve terminals become more vulnerable to H2O2-induced ox idative stress. This mechanism could be crucial in the development of bioen ergetic failure in Parkinson's disease.