Metabolic Control Analysis in a Cellular Model of Elevated MAO-B: Relevance to Parkinson’s Disease
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
Bogaert YE, Rosenthal RE, Fiskum G (1994) Postischemic inhibition of cerebral cortex pyruvate dehydrogenase. Free Radic Biol Med 16:811–820
Brand MD, Vallis BP, Kesseler A (1994) The sum of flux control coefficients in the electron-transport chain of mitochondria. Eur J Biochem 226:819–829
Cascante M, Boros LG, Comin-Anduix B et al (2002) Metabolic control analysis in drug discovery and disease. Nat Biotechnol 20:243–249
Cohen G, Kesler N (1999) Monoamine oxidase and mitochondrial respiration. J Neurochem 73:2310–2315
Cohen G, Farooqui R, Kesler N (1997) Parkinson disease: a new link between monoamine oxidase and mitochondrial electron flow. Proc Natl Acad Sci USA 94:4890–4894
Cornish-Bowden A (2004) Fundamentals of enzyme kinetics, 3rd edn. Portland Press, London
Davey GP, Clark JB (1996) Threshold effects and control of oxidative phosphorylation in nonsynaptic rat brain mitochondria. J Neurochem 66:1617–1624
Davey GP, Canevari L, Clark JB (1997) Threshold effects in synaptosomal and nonsynaptic mitochondria from hippocampal CA1 and paramedian neocortex brain regions. J Neurochem 69:2564–2570
Davey GP, Peuchen S, Clark JB (1998) Energy thresholds in brain mitochondria. Potential involvement in neurodegeneration. J Biol Chem 273:12753–12757
Harper ME, Monemdjou S, Ramsey JJ, Weindruch R (1998) Age-related increase in mitochondrial proton leak and decrease in ATP turnover reactions in mouse hepatocytes. Am J Physiol 275:E197–E206
Kacser H, Burns JA (1973) The control of flux. Symp Soc Exp Biol 27:65–104
Kacser H, Burns JA (1979) MOlecular democracy: who shares the controls? Biochem Soc Trans 7:1149–1160
Kumar MJ, Nicholls DG, Andersen JK (2003) 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. J Biol Chem 278:46432–46439
Kunz WS, Kuznetsov AV, Clark JF, Tracey I, Elger CE (1999) Metabolic consequences of the cytochrome c oxidase deficiency in brain of copper-deficient Mo(vbr) mice. J Neurochem 72:1580–1585
Lenaz G, Bovina C, Castelluccio C et al (1997) Mitochondrial complex I defects in aging. Mol Cell Biochem 174:329–333
Letellier T, Heinrich R, Malgat M, Mazat JP (1994) The kinetic basis of threshold effects observed in mitochondrial diseases: a systemic approach. Biochem J 302(Pt 1):171–174
Mazat JP, Rossignol R, Malgat M et al (2001) What do mitochondrial diseases teach us about normal mitochondrial functions that we already knew: threshold expression of mitochondrial defects. Biochim Biophys Acta 1504:20–30
Mizuno Y, Suzuki K, Ohta S (1990) Postmortem changes in mitochondrial respiratory enzymes in brain and a preliminary observation in Parkinson’s disease. J Neurol Sci 96:49–57
Mizuno Y, Matuda S, Yoshino H et al (1994) An immunohistochemical study on alpha-ketoglutarate dehydrogenase complex in Parkinson’s disease. Ann Neurol 35:204–210
Murphy AN, Bredesen DE, Cortopassi G, Wang E, Fiskum G (1996) Bcl-2 potentiates the maximal calcium uptake capacity of neural cell mitochondria. Proc Natl Acad Sci USA 93:9893–9898
Nulton-Persson AC, Szweda LI (2001) Modulation of mitochondrial function by hydrogen peroxide. J Biol Chem 276:23357–23361
Rossignol R, Faustin B, Rocher C et al (2003) Mitochondrial threshold effects. Biochem J 370:751–762
Samikkannu T, Chen CH, Yih LH et al (2003) Reactive oxygen species are involved in arsenic trioxide inhibition of pyruvate dehydrogenase activity. Chem Res Toxicol 16:409–414
Schapira AH (1999) Mitochondrial involvement in Parkinson’s disease, Huntington’s disease, hereditary spastic paraplegia and Friedreich’s ataxia. Biochim Biophys Acta 1410:159–170
Schapira AH, Cooper JM, Dexter D et al (1989) Mitochondrial complex I deficiency in Parkinson’s disease. Lancet 1:1269
Schapira AH, Cooper JM, Dexter D et al (1990) Mitochondrial complex I deficiency in Parkinson’s disease. J Neurochem 54:823–827
Starkov AA, Fiskum G, Chinopoulos C et al (2004) Mitochondrial alpha-ketoglutarate dehydrogenase complex generates reactive oxygen species. J Neurosci 24:7779–7788
Tabatabaie T, Potts JD, Floyd RA (1996) Reactive oxygen species-mediated inactivation of pyruvate dehydrogenase. Arch Biochem Biophys 336:290–296
Tretter L, Adam-Vizi V (2000) Inhibition of Krebs cycle enzymes by hydrogen peroxide: a key role of [alpha]-ketoglutarate dehydrogenase in limiting NADH production under oxidative stress. J Neurosci 20:8972–8979
Tretter L, Adam-Vizi V (2004) Generation of reactive oxygen species in the reaction catalyzed by alpha-ketoglutarate dehydrogenase. J Neurosci 24:7771–7778
Trounce IA, Kim YL, Jun AS, Wallace DC (1996) Assessment of mitochondrial oxidative phosphorylation in patient muscle biopsies, lymphoblasts, and transmitochondrial cell lines. Methods Enzymol 264:484–509
Villani G, Attardi G (1997) In vivo control of respiration by cytochrome c oxidase in wild-type and mitochondrial DNA mutation-carrying human cells. Proc Natl Acad Sci USA 94:1166–1171
Villani G, Greco M, Papa S, Attardi G (1998) Low reserve of cytochrome c oxidase capacity in vivo in the respiratory chain of a variety of human cell types. J Biol Chem 273:31829–31836
Vindis C, Seguelas MH, Lanier S, Parini A, Cambon C (2001) Dopamine induces ERK activation in renal epithelial cells through H2O2 produced by monoamine oxidase. Kidney Int 59:76–86