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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

Abstract:

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.

23937586

Projects: A1.1: Central liver metabolism and its regulation under nutritional chal..., A1.2: Detoxification in hepatocytes challenged by steatotic conditions

FEBS J.
FEBS J. 280(20): 5080-93
12th Sep 2013

Nikolaus Berndt, Herrmann-Georg Holzhütter, Sascha Bulik

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[Nikolaus Berndt] [Hermann-Georg Holzhütter] [Sascha Bulik]

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Views: 1584
  • Created: 20th Jan 2014 at 10:41

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