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

ROS production at inhibition of KGDHC. Levels of fully reduced flavin ((a) and (b)), semi-ubiquinone at n-site bound to complex I ((c) and (d)) and semi-ubiquinone at p-site bound to complex III ((e) and (f)) at various inhibitions (a) of KGDHC. The levels are depicted versus the mitochondrial membrane potential ((a), (c), and (e)) and the ATP production rate ((b), (d) and (f)). Values except membrane potential are normalized to the reference state.
© Copyright Policy - open-access
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3376505&req=5

fig10: ROS production at inhibition of KGDHC. Levels of fully reduced flavin ((a) and (b)), semi-ubiquinone at n-site bound to complex I ((c) and (d)) and semi-ubiquinone at p-site bound to complex III ((e) and (f)) at various inhibitions (a) of KGDHC. The levels are depicted versus the mitochondrial membrane potential ((a), (c), and (e)) and the ATP production rate ((b), (d) and (f)). Values except membrane potential are normalized to the reference state.

Mentions: Next, we investigated the influence of KGDHC inhibition on ROS generation by the RC. To this end, we calculated the occupation state of ROS generating sites in the presence of KGDHC inhibition. Since our simulation of the normal case suggested that the flavin radical in complex I and the semiubiquinone at n-site in complex III can be discarded as major ROS generating sites, only the fully reduced flavin, the semiubiquinone bound at n-site of complex I, and the semiubiquinone bound at p-site of complex III are shown. With increasing degree of KGDHC inhibition, there was a remarkable reduction in the occupation state of the fully reduced flavin in complex I as well as SQp of complex III at all workloads (see Figure 10), while the changes of SQn of complex I were negligibly small. Above 2.5-fold increase of the energetic load corresponding to a rise of the membrane potential above −100 mV, the RC is almost completely oxidized so that additional KGDHC inhibition has only a marginal effect on the occupation state of the considered ROS generating sites.


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)

ROS production at inhibition of KGDHC. Levels of fully reduced flavin ((a) and (b)), semi-ubiquinone at n-site bound to complex I ((c) and (d)) and semi-ubiquinone at p-site bound to complex III ((e) and (f)) at various inhibitions (a) of KGDHC. The levels are depicted versus the mitochondrial membrane potential ((a), (c), and (e)) and the ATP production rate ((b), (d) and (f)). Values except membrane potential are normalized to the reference state.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig10: ROS production at inhibition of KGDHC. Levels of fully reduced flavin ((a) and (b)), semi-ubiquinone at n-site bound to complex I ((c) and (d)) and semi-ubiquinone at p-site bound to complex III ((e) and (f)) at various inhibitions (a) of KGDHC. The levels are depicted versus the mitochondrial membrane potential ((a), (c), and (e)) and the ATP production rate ((b), (d) and (f)). Values except membrane potential are normalized to the reference state.
Mentions: Next, we investigated the influence of KGDHC inhibition on ROS generation by the RC. To this end, we calculated the occupation state of ROS generating sites in the presence of KGDHC inhibition. Since our simulation of the normal case suggested that the flavin radical in complex I and the semiubiquinone at n-site in complex III can be discarded as major ROS generating sites, only the fully reduced flavin, the semiubiquinone bound at n-site of complex I, and the semiubiquinone bound at p-site of complex III are shown. With increasing degree of KGDHC inhibition, there was a remarkable reduction in the occupation state of the fully reduced flavin in complex I as well as SQp of complex III at all workloads (see Figure 10), while the changes of SQn of complex I were negligibly small. Above 2.5-fold increase of the energetic load corresponding to a rise of the membrane potential above −100 mV, the RC is almost completely oxidized so that additional KGDHC inhibition has only a marginal effect on the occupation state of the considered ROS generating sites.

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