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

Comparison of simulated and experimentally determined concentrations of TCAC intermediates. Green bars indicate the concentration range of reported experimental values [21–29]. Blue bars (normal state) and red bars (50% inhibition of KGDHC) indicate variations of concentration when varying the energetic load between 33% and 100% of maximum.
© Copyright Policy - open-access
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3376505&req=5

fig3: Comparison of simulated and experimentally determined concentrations of TCAC intermediates. Green bars indicate the concentration range of reported experimental values [21–29]. Blue bars (normal state) and red bars (50% inhibition of KGDHC) indicate variations of concentration when varying the energetic load between 33% and 100% of maximum.

Mentions: First, we defined a normal reference state where the cytosolic ATP consumption rate, which is equal to the mitochondrial ATP production rate under steady-state conditions, amounts to about 30% of the maximal consumption rate and where in concordance with experimental data [30–32] 24% of the proton gradient is utilized by the proton leak of the inner mitochondrial membrane, 16% by pumping of potassium ions and 60% by the FoF1-ATPase and phosphate uptake. Next, we calibrated our model (unknown Vmax⁡ values) such that measured intramitochondrial metabolite concentrations (Figure 3, green bars) were reproduced. We then varied the ATP consumption rate up to its maximal possible value and calculated steady-state metabolite concentrations (Figure 3, blue bars).


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)

Comparison of simulated and experimentally determined concentrations of TCAC intermediates. Green bars indicate the concentration range of reported experimental values [21–29]. Blue bars (normal state) and red bars (50% inhibition of KGDHC) indicate variations of concentration when varying the energetic load between 33% and 100% of maximum.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig3: Comparison of simulated and experimentally determined concentrations of TCAC intermediates. Green bars indicate the concentration range of reported experimental values [21–29]. Blue bars (normal state) and red bars (50% inhibition of KGDHC) indicate variations of concentration when varying the energetic load between 33% and 100% of maximum.
Mentions: First, we defined a normal reference state where the cytosolic ATP consumption rate, which is equal to the mitochondrial ATP production rate under steady-state conditions, amounts to about 30% of the maximal consumption rate and where in concordance with experimental data [30–32] 24% of the proton gradient is utilized by the proton leak of the inner mitochondrial membrane, 16% by pumping of potassium ions and 60% by the FoF1-ATPase and phosphate uptake. Next, we calibrated our model (unknown Vmax⁡ values) such that measured intramitochondrial metabolite concentrations (Figure 3, green bars) were reproduced. We then varied the ATP consumption rate up to its maximal possible value and calculated steady-state metabolite concentrations (Figure 3, blue bars).

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