Parkinson disease: a new link between monoamine oxidase and mitochondrial electron flow.
Two factors that contribute to the progression of Parkinson disease are a brain defect in mitochondrial respiration and the generation of hydrogen peroxide (H2O2) by monoamine oxidase (MAO). Here we show that the two are linked. Metabolism of the neurotransmitter dopamine, or other monoamines (benzylamine, tyramine), by intact rat brain mitochondria suppresses pyruvate- and succinate-dependent electron transport. MAO inhibitors prevent this action. Mitochondrial damage is also reversed during electron flow. A probable explanation is that MAO-generated H2O2 oxidizes glutathione to glutathione disulfide (GSSG), which undergoes thiol-disulfide interchange to form protein mixed disulfides, thereby interfering reversibly with thiol-dependent enzymatic function. In agreement with this premise, direct addition of GSSG to mitochondria resulted in similar reversible inhibition of electron transport. In addition, the monoamines induced an elevation in protein mixed disulfides within mitochondria. These observations imply that (i) heightened activity and metabolism of neurotransmitter by monoamine neurons may affect neuronal function, and (ii) apparent defects in mitochondrial respiration associated with Parkinson disease may reflect, in part, an established increase in dopamine turnover. The experimental results also target mitochondrial repair mechanisms for further investigation and may, in time, lead to newer forms of therapy.
Cohen
G
G
Department of Neurology and Fishberg Center for Neurobiology, Mount Sinai School of Medicine, New York, NY 10029, USA.
Farooqui
R
R
Kesler
N
N
D000818:Animals; D001596:Benzylamines / Q000494:pharmacology; D001921:Brain / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism / Q000494:pharmacology*; D004579:Electron Transport / Q000187:drug effects; D005978:Glutathione / Q000031:analogs & derivatives / Q000378:metabolism; D019803:Glutathione Disulfide; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D008959:Models, Neurological; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D009474:Neurons / Q000502:physiology; D010101:Oxygen Consumption; D010300:Parkinson Disease / Q000378:metabolism* / Q000503:physiopathology; D011773:Pyruvates / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013386:Succinates / Q000378:metabolism; D014439:Tyramine / Q000494:pharmacology
D001596:Benzylamines; D008996:Monoamine Oxidase Inhibitors; D011773:Pyruvates; D013386:Succinates; C030796:benzylamine; D006861:Hydrogen Peroxide; D008995:Monoamine Oxidase; D005978:Glutathione; D019803:Glutathione Disulfide; D004298:Dopamine; D014439:Tyramine