Metabolic Control Analysis in a Cellular Model of Elevated MAO-B: Relevance to Parkinson’s Disease

Neurotoxicity Research - Tập 16 - Trang 186-193 - 2009
Jyothi K. Mallajosyula1, Shankar J. Chinta1, Subramanian Rajagopalan1, David G. Nicholls1, Julie K. Andersen1
1Buck Institute for Age Research, Novato, USA

Tóm tắt

We previously demonstrated that spare respiratory capacity of the TCA cycle enzyme alpha-ketoglutarate dehydrogenase (KGDH) was completely abolished upon increasing levels of MAO-B activity in a dopaminergic cell model system (Kumar et al., J Biol Chem 278:46432–46439, 2003). MAO-B mediated increases in H2O2 also appeared to result in direct oxidative inhibition of both mitochondrial complex I and aconitase. In order to elucidate the contribution that each of these components exerts over metabolic respiratory control as well as the impact of MAO-B elevation on their spare respiratory capacities, we performed metabolic respiratory control analysis. In addition to KGDH, we assessed the activities and substrate-mediated respiration of complex I, pyruvate dehydrogenase (PDH), succinate dehydrogenase (SDH), and mitochondrial aconitase in the absence and presence of complex-specific inhibitors in specific and mixed substrate conditions in mitochondria from our MAO-B elevated cells versus controls. Data from this study indicates that Complex I and KGDH are the most sensitive to inhibition by MAO-B mediated H2O2 generation, and could be instrumental in determining the fate of mitochondrial metabolism in this cellular PD model system.

Tài liệu tham khảo

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