MPP(+)-induced mitochondrial dysfunction is potentiated by dopamine.
MPP(+), the major metabolite of the Parkinsonism-inducing compound MPTP, responsible for the destruction of the nigrostriatal pathway in primates and rodents, has been assayed in isolated rat liver mitochondria in the presence of physiological concentrations of dopamine or analogous concentrations of melanin-dopamine. 5 microM MPP(+) in the presence of 70 microM dopamine or melanin-dopamine, but not alone, decreased the heat production and oxygen consumption of a mitochondrial suspension activated with succinate and ADP. Both dopamine and oxidized dopamine plus MPP(+) also decreased the mitochondrial reductive power measured with MTT. Mitochondrial swelling was observed, associated with an increase in membrane mitochondrial potential, as a synergistic effect between low concentrations of MPP(+) and dopamine. It is suggested that cytosolic dopamine, by itself or via its autooxidation products, may play a relevant role in the mitochondrial toxicity of MPP(+). A failure in the regulation of the storage/release of dopamine could aggravate a mitochondrial damage and trigger the neurodegenerative process underlying MPTP toxicity and Parkinson's disease.
Boada
J
J
Unitat de Biofísica, Universitat de Barcelona, Barcelona, Spain.
Cutillas
B
B
Roig
T
T
Bermúdez
J
J
Ambrosio
S
S
D015655:1-Methyl-4-phenylpyridinium / Q000008:administration & dosage* / Q000633:toxicity*; D000818:Animals; D004298:Dopamine / Q000008:administration & dosage* / Q000378:metabolism; D004357:Drug Synergism; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism*; D008933:Mitochondrial Swelling / Q000187:drug effects; D009245:NADH Dehydrogenase / Q000378:metabolism; D009410:Nerve Degeneration / Q000209:etiology / Q000378:metabolism; D009498:Neurotoxins / Q000008:administration & dosage* / Q000633:toxicity*; D010101:Oxygen Consumption / Q000187:drug effects; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000209:etiology / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D009498:Neurotoxins; D009245:NADH Dehydrogenase; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine