Kinetic Modeling of the Mitochondrial Energy Metabolism of Neuronal Cells: The Impact of Reduced -Ketoglutarate Dehydrogenase Activities on ATP Production and Generation of Reactive Oxygen SpeciesReport as inadecuate




Kinetic Modeling of the Mitochondrial Energy Metabolism of Neuronal Cells: The Impact of Reduced -Ketoglutarate Dehydrogenase Activities on ATP Production and Generation of Reactive Oxygen Species - Download this document for free, or read online. Document in PDF available to download.

International Journal of Cell BiologyVolume 2012 2012, Article ID 757594, 11 pages

Research ArticleInstitute of Biochemistry, University Medicine-Charité, 13347 Berlin, Germany

Received 9 March 2012; Accepted 11 April 2012

Academic Editor: Giuseppe Filomeni

Copyright © 2012 Nikolaus Berndt et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Reduced activity of brain α-ketoglutarate dehydrogenase complex KGDHC occurs in a number of neurodegenerative diseases like Parkinson-s disease and Alzheimer-s disease. In order to quantify the relation between diminished KGDHC activity and the mitochondrial ATP generation, redox state, transmembrane potential, and generation of reactive oxygen species ROS by the respiratory chain RC, we developed a detailed kinetic model. Model simulations revealed a threshold-like decline of the ATP production rate at about 60% inhibition of KGDHC accompanied by a significant increase of the mitochondrial membrane potential. By contrast, progressive inhibition of the enzyme aconitase had only little impact on these mitochondrial parameters. As KGDHC is susceptible to ROS-dependent inactivation, we also investigated the reduction state of those sites of the RC proposed to be involved in ROS production. The reduction state of all sites except one decreased with increasing degree of KGDHC inhibition suggesting an ROS-reducing effect of KGDHC inhibition. Our model underpins the important role of reduced KGDHC activity in the energetic breakdown of neuronal cells during development of neurodegenerative diseases.





Author: Nikolaus Berndt, Sascha Bulik, and Hermann-Georg Holzhütter

Source: https://www.hindawi.com/



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