MPP+-induced mitochondrial dysfunction is potentiated by dopamine

MPP+, the major metabolite of the Parkinsonism-inducing compound MPTP, resp onsible for the destruction of the nigrostriatal pathway in primates and ro dents, has been assayed in isolated rat liver mitochondria in the presence of physiological concentrations of dopamine or analogous concentrations of melanin-dopamine. 5 mu M MPP+ in the presence of 70 mu M dopamine or melani n-dopamine, but not alone, decreased the heat production and oxygen consump tion of a mitochondrial suspension activated with succinate and ADP. Both d opamine and oxidized dopamine plus MPP+ also decreased the mitochondrial re ductive power measured with MTT. Mitochondrial swelling was observed, assoc iated with an increase in membrane mitochondrial potential, as a synergisti c effect between low concentrations of MPP+ and dopamine. It is suggested t hat cytosolic dopamine, by itself or via its autooxidation products, may pl ay a relevant role in the mitochondrial toxicity of MPP+. A failure in the regulation of the storage/release of dopamine could aggravate a mitochondri al damage and trigger the neurodegenerative process underlying MPTP toxicit y and Parkinson's disease. (C) 2000 Academic press.