Dopamine modulates mitochondrial function in viable SH-SY5Y cells possibly via its interaction with complex I: relevance to dopamine pathology in schizophrenia.
Deleterious effects of dopamine (DA) involving mitochondrial dysfunction have an important role in DA-associated neuronal disorders, including schizophrenia and Parkinson's disease. DA detrimental effects have been attributed to its ability to be auto-oxidized to toxic reactive oxygen species. Since, unlike Parkinson's disease, schizophrenia does not involve neurodegenerative processes, we suggest a novel mechanism by which DA impairs mitochondrial function without affecting cell viability. DA significantly dissipated mitochondrial membrane potential (delta psi m) in SH-SY5Y cells. Bypassing complex I prevented the DA-induced depolarization. Moreover, DA inhibited complex I but not complex II activity in disrupted mitochondria, suggesting complex I participation in DA-induced mitochondrial dysfunction. We further demonstrated that intact mitochondria can accumulate DA in a saturated manner, with an apparent Km=122.1+/-28.6 nM and Vmax=1.41+/-0.15 pmol/mg protein/min, thereby enabling the interaction between DA and complex I. DA accumulation was an energy and Na+-dependent process. The pharmacological profile of mitochondrial DA uptake differed from that of other characterized DA transporters. Finally, relevance to schizophrenia is demonstrated by an abnormal interaction between DA and complex I in schizophrenic patients. These results suggest a non-lethal interaction between DA and mitochondria possibly via complex I, which can better explain DA-related pathological processes observed in non-degenerative disorders, such as schizophrenia.
Brenner-Lavie
Hanit
H
Research Lab of Psychobiology, Department of Psychiatry - Rambam Medical Center, Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel.
Klein
Ehud
E
Zuk
Rosa
R
Gazawi
Haifa
H
Ljubuncic
Predrage
P
Ben-Shachar
Dorit
D
D000328:Adult; D000368:Aged; D001792:Blood Platelets / Q000187:drug effects; D003865:Major Depressive Disorder / Q000503:physiopathology; D004298:Dopamine / Q000494:pharmacology / Q000502:physiology*; D042967:Electron Transport Complex I / Q000502:physiology*; D042963:Electron Transport Complex II / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology*; D009447:Neuroblastoma; D017382:Reactive Oxygen Species / Q000378:metabolism; D012559:Schizophrenia / Q000503:physiopathology*; D014407:Tumor Cells, Cultured
D017382:Reactive Oxygen Species; D042963:Electron Transport Complex II; D042967:Electron Transport Complex I; D004298:Dopamine