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

Schematic of the respiratory chain. The respiratory chain: in complex I, NADH is oxidized to NAD, while four protons are pumped from the mitochondrial matrix into the intermembrane space/cytosol. Concomitantly ubiquinon (Q), residing in the inner membranous space, is reduced to ubiquinol (QH2) along with the uptake of two matrix protons. In Complex II, succinate is oxidized to fumarate while ubiquinon is reduced to ubiquinol. In this reduction two protons are taken up from the matrix space, but no protons are pumped across the mitochondrial membrane. In complex III, innermembranous ubiquinol is oxidized to ubiquinon. Via the q-cycle mechanism, two protons are taken up from the matrix space, and four protons are released into the inter membrane space/cytosol. The two electrons are consecutively transferred via Fe-S cluster to cytochrome c1 and reduce two molecules of cytochrome c. In complex IV, two molecules of reduced cytochrome c are oxidized, and oxygen is reduced to water along with the transduction of two protons from the matrix space into the inter membrane space/cytosol. With either NADH or succinate as substrates, the respiratory chain pumps ten and six protons, respectively, from the matrix space to the inter membrane space/cytosol, and one molecule of water is formed.
© Copyright Policy - open-access
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3376505&req=5

fig2: Schematic of the respiratory chain. The respiratory chain: in complex I, NADH is oxidized to NAD, while four protons are pumped from the mitochondrial matrix into the intermembrane space/cytosol. Concomitantly ubiquinon (Q), residing in the inner membranous space, is reduced to ubiquinol (QH2) along with the uptake of two matrix protons. In Complex II, succinate is oxidized to fumarate while ubiquinon is reduced to ubiquinol. In this reduction two protons are taken up from the matrix space, but no protons are pumped across the mitochondrial membrane. In complex III, innermembranous ubiquinol is oxidized to ubiquinon. Via the q-cycle mechanism, two protons are taken up from the matrix space, and four protons are released into the inter membrane space/cytosol. The two electrons are consecutively transferred via Fe-S cluster to cytochrome c1 and reduce two molecules of cytochrome c. In complex IV, two molecules of reduced cytochrome c are oxidized, and oxygen is reduced to water along with the transduction of two protons from the matrix space into the inter membrane space/cytosol. With either NADH or succinate as substrates, the respiratory chain pumps ten and six protons, respectively, from the matrix space to the inter membrane space/cytosol, and one molecule of water is formed.

Mentions: In order to include the potential formation of ROS in our model, we developed a detailed submodel of the respiratory chain that takes into account the substructure of complexes I and III composed of several prosthetic groups and iron sulfur clusters (see Figure 2).


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)

Schematic of the respiratory chain. The respiratory chain: in complex I, NADH is oxidized to NAD, while four protons are pumped from the mitochondrial matrix into the intermembrane space/cytosol. Concomitantly ubiquinon (Q), residing in the inner membranous space, is reduced to ubiquinol (QH2) along with the uptake of two matrix protons. In Complex II, succinate is oxidized to fumarate while ubiquinon is reduced to ubiquinol. In this reduction two protons are taken up from the matrix space, but no protons are pumped across the mitochondrial membrane. In complex III, innermembranous ubiquinol is oxidized to ubiquinon. Via the q-cycle mechanism, two protons are taken up from the matrix space, and four protons are released into the inter membrane space/cytosol. The two electrons are consecutively transferred via Fe-S cluster to cytochrome c1 and reduce two molecules of cytochrome c. In complex IV, two molecules of reduced cytochrome c are oxidized, and oxygen is reduced to water along with the transduction of two protons from the matrix space into the inter membrane space/cytosol. With either NADH or succinate as substrates, the respiratory chain pumps ten and six protons, respectively, from the matrix space to the inter membrane space/cytosol, and one molecule of water is formed.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig2: Schematic of the respiratory chain. The respiratory chain: in complex I, NADH is oxidized to NAD, while four protons are pumped from the mitochondrial matrix into the intermembrane space/cytosol. Concomitantly ubiquinon (Q), residing in the inner membranous space, is reduced to ubiquinol (QH2) along with the uptake of two matrix protons. In Complex II, succinate is oxidized to fumarate while ubiquinon is reduced to ubiquinol. In this reduction two protons are taken up from the matrix space, but no protons are pumped across the mitochondrial membrane. In complex III, innermembranous ubiquinol is oxidized to ubiquinon. Via the q-cycle mechanism, two protons are taken up from the matrix space, and four protons are released into the inter membrane space/cytosol. The two electrons are consecutively transferred via Fe-S cluster to cytochrome c1 and reduce two molecules of cytochrome c. In complex IV, two molecules of reduced cytochrome c are oxidized, and oxygen is reduced to water along with the transduction of two protons from the matrix space into the inter membrane space/cytosol. With either NADH or succinate as substrates, the respiratory chain pumps ten and six protons, respectively, from the matrix space to the inter membrane space/cytosol, and one molecule of water is formed.
Mentions: In order to include the potential formation of ROS in our model, we developed a detailed submodel of the respiratory chain that takes into account the substructure of complexes I and III composed of several prosthetic groups and iron sulfur clusters (see Figure 2).

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