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

Berndt N, Bulik S, Holzhütter HG - Int J Cell Biol (2012)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Biochemistry, University Medicine-Charité, 13347 Berlin, Germany.

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.

No MeSH data available.


Related in: MedlinePlus

NADH level comparison experiment and simulation. Experimental determined NADH level as black points with error bars at different inhibition levels of KGDHC and aconitase (data from [15]). Different coloured curves vary in the basal ATP demand of the system from low (blue) to increased (black). Green curves are for the ATP demand of the reference state. NADH levels are normalized to the NADH level without enzyme inhibition respective to the ATP demand.
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fig9: NADH level comparison experiment and simulation. Experimental determined NADH level as black points with error bars at different inhibition levels of KGDHC and aconitase (data from [15]). Different coloured curves vary in the basal ATP demand of the system from low (blue) to increased (black). Green curves are for the ATP demand of the reference state. NADH levels are normalized to the NADH level without enzyme inhibition respective to the ATP demand.

Mentions: The redox state of the RC and thus the residual energetic capacity of the mitochondrion is common level. Figure 8 shows the combined impact of KGDHC inhibition and energetic load on the mitochondrial NADH level. Generally, progressive inhibition of the KGDHC is equivalent to progressive increase of energetic load. For example, relative inhibition of about 40% has the same effect as a 1.5-fold increase of the energetic load by the mitochondrial NADH. The effect of KGDHC and aconitase inhibition on mitochondrial NADH content has been determined experimentally [15]. Figure 9 demonstrates that our simulations are in good concordance with these experimental data. Inhibition of the KGDHC has a much stronger effect on the NADH content than inhibition of the aconitase. Whereas half-reduction of the NADH level is already achieved with about 40% inhibition of the KGDHC, the same effect requires about 95% inhibition of the aconitase.


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

Berndt N, Bulik S, Holzhütter HG - Int J Cell Biol (2012)

NADH level comparison experiment and simulation. Experimental determined NADH level as black points with error bars at different inhibition levels of KGDHC and aconitase (data from [15]). Different coloured curves vary in the basal ATP demand of the system from low (blue) to increased (black). Green curves are for the ATP demand of the reference state. NADH levels are normalized to the NADH level without enzyme inhibition respective to the ATP demand.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3376505&req=5

fig9: NADH level comparison experiment and simulation. Experimental determined NADH level as black points with error bars at different inhibition levels of KGDHC and aconitase (data from [15]). Different coloured curves vary in the basal ATP demand of the system from low (blue) to increased (black). Green curves are for the ATP demand of the reference state. NADH levels are normalized to the NADH level without enzyme inhibition respective to the ATP demand.
Mentions: The redox state of the RC and thus the residual energetic capacity of the mitochondrion is common level. Figure 8 shows the combined impact of KGDHC inhibition and energetic load on the mitochondrial NADH level. Generally, progressive inhibition of the KGDHC is equivalent to progressive increase of energetic load. For example, relative inhibition of about 40% has the same effect as a 1.5-fold increase of the energetic load by the mitochondrial NADH. The effect of KGDHC and aconitase inhibition on mitochondrial NADH content has been determined experimentally [15]. Figure 9 demonstrates that our simulations are in good concordance with these experimental data. Inhibition of the KGDHC has a much stronger effect on the NADH content than inhibition of the aconitase. Whereas half-reduction of the NADH level is already achieved with about 40% inhibition of the KGDHC, the same effect requires about 95% inhibition of the aconitase.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Biochemistry, University Medicine-Charité, 13347 Berlin, Germany.

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.

No MeSH data available.


Related in: MedlinePlus