Oxidative alpha-ketoglutarate dehydrogenase inhibition via subtle elevations in monoamine oxidase B levels results in loss of spare respiratory capacity: implications for Parkinson's disease.
Age-related increases in brain monoamine oxidase B (MAO-B) and its ability to produce reactive oxygen species as a by-product of catalysis could contribute to neurodegeneration associated with Parkinson's disease. This may be via increased oxidative stress and/or mitochondrial dysfunction either on its own or through its interaction with endogenous or exogenous neurotoxic species. We have created genetically engineered dopaminergic PC12 cell lines with subtly increased levels of MAO-B mimicking those observed during normal aging. In our cells, increased MAO-B activity was found to result in increased H2O2 production. This was found to correlate with a decrease in mitochondrial complex I activity which may involve both direct oxidative damage to the complex itself as well as oxidative effects on the tricarboxylic acid cycle enzyme alpha-ketoglutarate dehydrogenase (KGDH) which provides substrate for the complex. Both complex I and KGDH activities have been reported to be decreased in the Parkinsonian brain. These in vitro events are reversible by catalase addition. Importantly, MAO-B elevation was found to abolish the spare KGDH threshold capacity, which can normally be significantly inhibited before it affects maximal mitochondrial oxygen consumption rates. Our data suggest that H2O2 production via subtle elevations in MAO-B levels can result in oxidative effects on KGDH that can compromise the ability of dopaminergic neurons to cope with increased energetic stress.
Kumar
M Jyothi
MJ
Buck Institute for Age Research, 8001 Redwood Boulevard, Novato, CA 94945, USA. jkumar@buckinstitute.org
Nicholls
David G
DG
Andersen
Julie K
JK
D000375:Aging / Q000378:metabolism; D000818:Animals; D019069:Cell Respiration; D004318:Doxycycline / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007655:Ketoglutarate Dehydrogenase Complex / Q000037:antagonists & inhibitors*; D028361:Mitochondrial Diseases / Q000209:etiology; D008995:Monoamine Oxidase / Q000378:metabolism* / Q000502:physiology; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D016716:PC12 Cells; D010300:Parkinson Disease / Q000209:etiology; D051381:Rats; D014162:Transfection
D007655:Ketoglutarate Dehydrogenase Complex; D008995:Monoamine Oxidase; D004318:Doxycycline