Limits...
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

System characteristics under energetic challenge. Energetic demand was varied and behaviour of system variables determined. (a) mitochondrial membrane potential; (b) blue NADH to NAD ratio, red oxygen consumption rate; (c) share of created proton gradient used for ATP synthesis; (d) blue: ubiquinon at p-site, green: ubiquinol at n-site, red: ubiquinon at n-site, black: ubiquinol at p-site. ATP production and oxygen consumption are normalized to the reference state of the system.
© Copyright Policy - open-access
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3376505&req=5

fig4: System characteristics under energetic challenge. Energetic demand was varied and behaviour of system variables determined. (a) mitochondrial membrane potential; (b) blue NADH to NAD ratio, red oxygen consumption rate; (c) share of created proton gradient used for ATP synthesis; (d) blue: ubiquinon at p-site, green: ubiquinol at n-site, red: ubiquinon at n-site, black: ubiquinol at p-site. ATP production and oxygen consumption are normalized to the reference state of the system.

Mentions: To check the reliability of our model, we compared load-dependent changes of further model parameters with experimental observation reported for various tissues (Figure 4). The membrane potential is remarkably stable between −150 mV and −120 mV over a wide range of ATP consumption rates [33]. However, beyond a 2.5-fold increase of the ATP consumption rate, a small further increase in the ATP consumption rate was accompanied by a large drop in the membrane potential, hinting to metabolic failure. The mitochondrial redox potential (expressed through the NADH/NAD ratio) showed a quasilinear decline from 0.3 to 0.1 for ATP consumption rates up to the 2.5-fold of the normal. Concurrently, the oxygen consumption rate doubled. The fact that oxygen consumption only doubled at threefold increased ATP consumption is accounted for by increased efficiency of ATP production, that is, the share of ATP generation in the utilization of the proton gradient increases from initially 60% to over 90% (Figure 4(c)). The total ubiquinol to ubiquinon ratio (at n-site + p-site) varied between 1.5 and about 0.5, in agreement with experimental data [29]. At the mitochondrial p-site, this ratio dropped from about 1 to zero at maximal indicating that ubiquinol diffusion becomes rate limiting at high ATP consumption rates [34].


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)

System characteristics under energetic challenge. Energetic demand was varied and behaviour of system variables determined. (a) mitochondrial membrane potential; (b) blue NADH to NAD ratio, red oxygen consumption rate; (c) share of created proton gradient used for ATP synthesis; (d) blue: ubiquinon at p-site, green: ubiquinol at n-site, red: ubiquinon at n-site, black: ubiquinol at p-site. ATP production and oxygen consumption are normalized to the reference state of the system.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig4: System characteristics under energetic challenge. Energetic demand was varied and behaviour of system variables determined. (a) mitochondrial membrane potential; (b) blue NADH to NAD ratio, red oxygen consumption rate; (c) share of created proton gradient used for ATP synthesis; (d) blue: ubiquinon at p-site, green: ubiquinol at n-site, red: ubiquinon at n-site, black: ubiquinol at p-site. ATP production and oxygen consumption are normalized to the reference state of the system.
Mentions: To check the reliability of our model, we compared load-dependent changes of further model parameters with experimental observation reported for various tissues (Figure 4). The membrane potential is remarkably stable between −150 mV and −120 mV over a wide range of ATP consumption rates [33]. However, beyond a 2.5-fold increase of the ATP consumption rate, a small further increase in the ATP consumption rate was accompanied by a large drop in the membrane potential, hinting to metabolic failure. The mitochondrial redox potential (expressed through the NADH/NAD ratio) showed a quasilinear decline from 0.3 to 0.1 for ATP consumption rates up to the 2.5-fold of the normal. Concurrently, the oxygen consumption rate doubled. The fact that oxygen consumption only doubled at threefold increased ATP consumption is accounted for by increased efficiency of ATP production, that is, the share of ATP generation in the utilization of the proton gradient increases from initially 60% to over 90% (Figure 4(c)). The total ubiquinol to ubiquinon ratio (at n-site + p-site) varied between 1.5 and about 0.5, in agreement with experimental data [29]. At the mitochondrial p-site, this ratio dropped from about 1 to zero at maximal indicating that ubiquinol diffusion becomes rate limiting at high ATP consumption rates [34].

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