Mitochondria deficient in complex I activity are depolarized by hydrogen peroxide in nerve terminals: relevance to Parkinson's disease

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Abstract
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 (ΔΨm), as measured by the fluorescence change of JC‐l (5,5′,6,6′‐tetrachloro‐1,1,3,3′‐tetraethylbenzimidazolyl‐carbocyanine iodide), collapses when isolated nerve terminals are exposed to hydrogen peroxide (H2O2,100 and 500 µm) in combination with the inhibition of complex I by rotenone (5 nm−1 µm). H2O2 reduced the activity of complex I by 17%, and the effect of H2O2 and rotenone on the enzyme was found to be additive. A decrease in ΔΨm induced by H2O2 was significant when the activity of complex I was reduced to a similar extent as found in Parkinson's disease (26%). The loss of ΔΨm 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 oxidative stress. This mechanism could be crucial in the development of bioenergetic failure in Parkinson's disease.