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

Mitochondrial membrane potential characteristics at inhibition of KGDHC. Mitochondrial membrane potential versus the ATP production rate at different inhibition levels of KGDHC. Dotted line: −80 mV membrane potential level.
© Copyright Policy - open-access
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3376505&req=5

fig7: Mitochondrial membrane potential characteristics at inhibition of KGDHC. Mitochondrial membrane potential versus the ATP production rate at different inhibition levels of KGDHC. Dotted line: −80 mV membrane potential level.

Mentions: The dependence of the mitochondrial membrane potential on the ATP consumption rate at different inhibitions of the KGDHC is shown in Figure 7. At moderate inhibition of the KGDHC <30%, the increase of the membrane potential was only 20 mV up to 2.5-fold elevated energetic load, that is, a significant rise of the membrane potential occurred only at very high energetic load. At KGDHC inhibition of about 60%, the membrane potential was already elevated at normal ATP consumption rate, and the membrane depolarized at much smaller increase of the ATP demand. Given pathological states of mitochondria to occur at values of the membrane potential above −80 mV (dotted line in Figure 7), increasing KGDHC inhibition of the membrane potential resulted in a dramatic reduction of the tolerable maximal energetic load and successive membrane depolarization at normal energy demand.


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)

Mitochondrial membrane potential characteristics at inhibition of KGDHC. Mitochondrial membrane potential versus the ATP production rate at different inhibition levels of KGDHC. Dotted line: −80 mV membrane potential level.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig7: Mitochondrial membrane potential characteristics at inhibition of KGDHC. Mitochondrial membrane potential versus the ATP production rate at different inhibition levels of KGDHC. Dotted line: −80 mV membrane potential level.
Mentions: The dependence of the mitochondrial membrane potential on the ATP consumption rate at different inhibitions of the KGDHC is shown in Figure 7. At moderate inhibition of the KGDHC <30%, the increase of the membrane potential was only 20 mV up to 2.5-fold elevated energetic load, that is, a significant rise of the membrane potential occurred only at very high energetic load. At KGDHC inhibition of about 60%, the membrane potential was already elevated at normal ATP consumption rate, and the membrane depolarized at much smaller increase of the ATP demand. Given pathological states of mitochondria to occur at values of the membrane potential above −80 mV (dotted line in Figure 7), increasing KGDHC inhibition of the membrane potential resulted in a dramatic reduction of the tolerable maximal energetic load and successive membrane depolarization at normal energy demand.

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