Dopamine toxicity involves mitochondrial complex I inhibition: implications to dopamine-related neuropsychiatric disorders.
Dopamine, which is suggested as a prominent etiological factor in several neuropsychiatric disorders such as Parkinson's disease and schizophrenia, demonstrates neurotoxic properties. In such dopamine-related diseases mitochondrial dysfunction has been reported. Dopamine oxidized metabolites were shown to inhibit the mitochondrial respiratory system both in vivo and in vitro. In the present study, we suggest an additional mechanism for dopamine toxicity, which involves mitochondrial complex I inhibition by dopamine. In human neuroblastoma SH-SY5Y cells dopamine induced a reduction in ATP concentrations, which was negatively correlated to intracellular dopamine levels (r = - 0.96, P = 0.012), and was already evident at non-toxic dopamine doses. In disrupted mitochondria dopamine inhibited complex I activity with IC50 = 11.87 +/- 1.45 microm or 8.12 +/- 0.75 microM in the presence of CoQ or ferricyanide, respectively, with no effect on complexes IV and V activities. The catechol moiety, but not the amine group, of dopamine is essential for complex I inhibition, as is indicated by comparing the inhibitory potential of functionally and structurally dopamine-related compounds. In line with the latter is the finding that chelatable FeCl2 prevented dopamine-induced inhibition of complex I. Monoamine oxidase A and B inhibitors, as well as the antioxidant butylated hydroxytoluene (BHT), did not prevent dopamine-induced inhibition, suggesting that dopamine oxidation was not involved in this process. The present study suggests that dopamine toxicity involves, or is initiated by, its interaction with the mitochondrial oxidative phosphorylation system. We further hypothesize that this interaction between dopamine and mitochondria is associated with mitochondrial dysfunction observed in dopamine-related neuropsychiatric disorders, such as schizophrenia and Parkinson's disease.
Ben-Shachar
D
D
Research Lab of Psychobiology, Department of Psychiatry, Bruce Rappaport Faculty of Medicine, Rambam Medical Center, Technion ITT, P.O. Box 9649, Haifa, Israel. shachar@tx.technion.ac.il
Zuk
R
R
Gazawi
H
H
Ljubuncic
P
P
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D004298:Dopamine / Q000633:toxicity*; D003576:Electron Transport Complex IV / Q000378:metabolism; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology; D025261:Mitochondrial Proton-Translocating ATPases / Q000378:metabolism; D009245:NADH Dehydrogenase / Q000187:drug effects / Q000378:metabolism*; D009247:NADH, NADPH Oxidoreductases / Q000187:drug effects / Q000378:metabolism*; D010300:Parkinson Disease / Q000209:etiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012559:Schizophrenia / Q000139:chemically induced; D014407:Tumor Cells, Cultured
D000255:Adenosine Triphosphate; D009247:NADH, NADPH Oxidoreductases; C014227:ferricyanide reductase; D009245:NADH Dehydrogenase; D003576:Electron Transport Complex IV; D000251:Adenosine Triphosphatases; D025261:Mitochondrial Proton-Translocating ATPases; D004298:Dopamine