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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

System characteristics under KGDHC inhibition. ATP production rate (red), NADH level (green), mitochondrial membrane potential (magenta, right scale), and reduced cytochrome c level (black) at normal ATP demand versus increased inhibition of KGDHC, maximal ATP production capacity in blue. Values except membrane potential normalized to reference state without inhibition.
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fig6: System characteristics under KGDHC inhibition. ATP production rate (red), NADH level (green), mitochondrial membrane potential (magenta, right scale), and reduced cytochrome c level (black) at normal ATP demand versus increased inhibition of KGDHC, maximal ATP production capacity in blue. Values except membrane potential normalized to reference state without inhibition.

Mentions: Next, we investigated the effects of KGDHC and aconitase inhibition on the energy metabolism. Simulations were performed with increasing degree of inhibition of the KGDHC from 0 to 70% (see Figure 6). The maximal ATP production capacity decreased very slowly until about 50% inhibition of the enzyme. Higher inhibition resulted at first in an approximately linear decrease of the maximal ATP production capacity and finally also in a linear reduction of the ATP production rate in the reference state, that is, the energy demand of the normal load state can be satisfied until about 60% inhibition. At an inhibition of about 70%, the system is close to collapse as can be seen by the highly depolarized membrane potential. Successive depletion of NADH (green curve) caused depletion of reduced cytochrome c (black curve) in a nonlinear manner which is ultimately responsible for the metabolic failure seen at high inhibition states. Notably, as long as reduced cytochrome c is not fully exhausted, the membrane potential can be kept close to the reference value. Caution must be used at interpreting the curves in regimes with strongly depolarized mitochondrial membrane (>−80 mV), since mechanisms not modeled (like initiation of apoptotic pathway/transition pore opening) are likely to dominate the cellular behavior.


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 KGDHC inhibition. ATP production rate (red), NADH level (green), mitochondrial membrane potential (magenta, right scale), and reduced cytochrome c level (black) at normal ATP demand versus increased inhibition of KGDHC, maximal ATP production capacity in blue. Values except membrane potential normalized to reference state without inhibition.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig6: System characteristics under KGDHC inhibition. ATP production rate (red), NADH level (green), mitochondrial membrane potential (magenta, right scale), and reduced cytochrome c level (black) at normal ATP demand versus increased inhibition of KGDHC, maximal ATP production capacity in blue. Values except membrane potential normalized to reference state without inhibition.
Mentions: Next, we investigated the effects of KGDHC and aconitase inhibition on the energy metabolism. Simulations were performed with increasing degree of inhibition of the KGDHC from 0 to 70% (see Figure 6). The maximal ATP production capacity decreased very slowly until about 50% inhibition of the enzyme. Higher inhibition resulted at first in an approximately linear decrease of the maximal ATP production capacity and finally also in a linear reduction of the ATP production rate in the reference state, that is, the energy demand of the normal load state can be satisfied until about 60% inhibition. At an inhibition of about 70%, the system is close to collapse as can be seen by the highly depolarized membrane potential. Successive depletion of NADH (green curve) caused depletion of reduced cytochrome c (black curve) in a nonlinear manner which is ultimately responsible for the metabolic failure seen at high inhibition states. Notably, as long as reduced cytochrome c is not fully exhausted, the membrane potential can be kept close to the reference value. Caution must be used at interpreting the curves in regimes with strongly depolarized mitochondrial membrane (>−80 mV), since mechanisms not modeled (like initiation of apoptotic pathway/transition pore opening) are likely to dominate the cellular behavior.

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