Alterations in bioenergetic function induced by Parkinson's disease mimetic compounds: lack of correlation with superoxide generation.
In vitro and in vivo models of Parkinson's disease (PD) suggest that increased oxidant production leads to mitochondrial dysfunction in dopaminergic neurons and subsequent cell death. However, it remains unclear if cell death in these models is caused by inhibition of mitochondrial function or oxidant production. The objective of this study was to determine the relationship between mitochondrial dysfunction and oxidant production in response to multiple PD neurotoxicant mimetics. MPP(+) caused a dose-dependent decrease in the basal oxygen consumption rate in dopaminergic N27 cells, indicating a loss of mitochondrial function. In parallel, we found that MPP(+) only modestly increased oxidation of hydroethidine as a diagnostic marker of superoxide production in these cells. Similar results were found using rotenone as a mitochondrial inhibitor, or 6-hydroxydopamine (6-OHDA) as a mechanistically distinct PD neurotoxicant, but not with exposure to paraquat. In addition, the extracellular acidification rate, used as a marker of glycolysis, was stimulated to compensate for oxygen consumption rate inhibition after exposure to MPP(+), rotenone, or 6-OHDA, but not paraquat. Together these data indicate that MPP(+), rotenone, and 6-OHDA dramatically shift bioenergetic function away from the mitochondria and towards glycolysis in N27 cells.
Department of Biophysics and Free Radical Research Center, Medical College of Wisconsin, Milwaukee, WI, USA.
Brian P
BP
Dranka
Jacek
J
Zielonka
Anumantha G
AG
Kanthasamy
Balaraman
B
Kalyanaraman
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000378:metabolism; D018663:Adrenergic Agents / Q000494:pharmacology; D000818:Animals; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / Q000494:pharmacology; D002461:Cell Line, Transformed; D015259:Dopamine Agents / Q000494:pharmacology; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004734:Energy Metabolism / Q000187:drug effects*; D006540:Herbicides / Q000494:pharmacology; D007306:Insecticides / Q000494:pharmacology; D009498:Neurotoxins / Q000494:pharmacology*; D009840:Oligomycins / Q000494:pharmacology; D016627:Oxidopamine / Q000494:pharmacology; D010101:Oxygen Consumption / Q000187:drug effects; D010269:Paraquat / Q000494:pharmacology; D061209:Proton Ionophores / Q000494:pharmacology; D051381:Rats; D012402:Rotenone / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism*; D013997:Time Factors
D018663:Adrenergic Agents; D015259:Dopamine Agents; D006540:Herbicides; D007306:Insecticides; D009498:Neurotoxins; D009840:Oligomycins; D061209:Proton Ionophores; D012402:Rotenone; D013481:Superoxides; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; C042075:oligomycin C; D016627:Oxidopamine; D000255:Adenosine Triphosphate; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D010269:Paraquat