Metabolic control analysis in a cellular model of elevated MAO-B: relevance to Parkinson's disease

Neurotox Res. 2009 Oct;16(3):186-93. doi: 10.1007/s12640-009-9032-2. Epub 2009 Mar 5.

Abstract

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 H(2)O(2) 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 H(2)O(2) generation, and could be instrumental in determining the fate of mitochondrial metabolism in this cellular PD model system.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aconitate Hydratase / metabolism
  • Animals
  • Cell Respiration / drug effects
  • Cell Respiration / physiology
  • Doxycycline / pharmacology
  • Electron Transport Complex I / metabolism
  • Gene Expression Regulation, Enzymologic / drug effects
  • Gene Expression Regulation, Enzymologic / physiology*
  • Hydrogen Peroxide / pharmacology
  • Insecticides / pharmacology
  • Ketoglutarate Dehydrogenase Complex / metabolism
  • Ketone Oxidoreductases / metabolism
  • Mitochondria / drug effects
  • Mitochondria / enzymology*
  • Monoamine Oxidase / metabolism*
  • NADH, NADPH Oxidoreductases / metabolism
  • Oxidants / pharmacology
  • Oxygen Consumption / drug effects
  • Oxygen Consumption / physiology
  • PC12 Cells / drug effects
  • PC12 Cells / enzymology
  • Quinone Reductases
  • Rats
  • Rotenone / pharmacology
  • Succinate Dehydrogenase / metabolism

Substances

  • Insecticides
  • Oxidants
  • Rotenone
  • Hydrogen Peroxide
  • Ketone Oxidoreductases
  • pyruvate dehydrogenase (NADP+)
  • Ketoglutarate Dehydrogenase Complex
  • Succinate Dehydrogenase
  • Monoamine Oxidase
  • NADH, NADPH Oxidoreductases
  • Quinone Reductases
  • dichlorophenolindophenol reductase
  • Aconitate Hydratase
  • Electron Transport Complex I
  • Doxycycline