Implications of enzyme deficiencies on mitochondrial energy metabolism and reactive oxygen species formation of neurons involved in rotenone-induced Parkinson's disease: a model-based analysis.
Steadily growing experimental evidence suggests that mitochondrial dysfunction plays a key role in the age-dependent impairment of nerve cells underlying several neurodegenerative diseases. In particular, the citric acid cycle enzyme complex α-ketoglutarate dehydrogenase (KGDHC) and respiratory chain complex I of the respiratory chain often show reduced activities in the dopaminergic neurons involved in Parkinson's disease, both giving rise to an impaired mitochondrial energy metabolism as demonstrated in a number of in vitro studies with cell lines as well as isolated mitochondria. To understand the metabolic regulation underlying these experimental findings we used a detailed kinetic model of mitochondrial energy metabolism. First, we investigated the effect of complex I inhibition on energy production and formation of reactive oxygen species (ROS). Next, we applied the model to a situation where both KGDHC and complex I exhibit reduced activities. These calculations reveal synergistic effects with respect to the energy metabolism but antagonistic effects with respect to ROS formation: the drop in the ATP production capacity is more pronounced than at inhibition of either enzyme complex alone. Interestingly, however, the reduction state of the ROS-generating sites of the impaired complex I becomes significantly lowered if additionally the activity of the KGDHC is reduced. We discuss the pathophysiological consequences of these intriguing findings.
Institute of Biochemistry, University Medicine Berlin - Charité, Germany.
Nikolaus
N
Berndt
Herrmann-Georg
HG
Holzhütter
Sascha
S
Bulik
D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D004195:Disease Models, Animal; D042967:Electron Transport Complex I / Q000378:metabolism; D004734:Energy Metabolism; D007655:Ketoglutarate Dehydrogenase Complex / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D010300:Parkinson Disease / Q000201:enzymology / Q000209:etiology / Q000378:metabolism*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012402:Rotenone / Q000494:pharmacology*
D017382:Reactive Oxygen Species; D012402:Rotenone; D000255:Adenosine Triphosphate; D007655:Ketoglutarate Dehydrogenase Complex; D042967:Electron Transport Complex I
KGDHC inhibition; Parkinson's disease; ROS; complex I inhibition; kinetic model; mitochondrial energy metabolism; neuronal metabolism