Exposure to the parkinsonian neurotoxin 1-methyl-4-phenylpyridinium (MPP+) and nitric oxide simultaneously causes cyclosporin A-sensitive mitochondrial calcium efflux and depolarisation☆

Abstract The effect of the parkinsonian neurotoxin, 1-methyl-4-phenylpyridinium (MPP + ) together with nitric oxide donors on mitochondrial calcium homeostasis and membrane potential was investigated. Simultaneous exposure of calcium-loaded mitochondria to MPP + and nitric oxide donors led to Cyclosporin A-sensitive mitochondrial calcium efflux and depolarisation. When MPP + was replaced with the respiratory inhibitor rotenone, mitochondrial calcium efflux and depolarisation also occurred. As both MPP + and rotenone induce mitochondrial Superoxide formation, the possibility that calcium efflux and depolarisation were due to peroxynitrite formation from reaction of Superoxide with nitric oxide was investigated. It was shown that simultaneous exposure of mitochondrial membranes to nitric oxide donors and rotenone led to peroxynitrite formation. The possible roles of nitric oxide, peroxynitrite, mitochondrial depolarisation, and calcium efflux in MPP + toxicity are discussed.