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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

Potential ROS producing states in the RC. ROS producing states of complex I ((a) and (b)) and complex III ((c) and (d)) are depicted versus the mitochondrial membrane potential ((a) and (c)) or the ATP production rate. Red: fully reduced flavin, green: flavin radical, blue: semi-ubiquinon at n-site bound to the respective complex, black: semi-ubiquinon at p-site bound to complex III. ATP production and occupation of ROS producing states are normalized to the reference state of the system.
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fig5: Potential ROS producing states in the RC. ROS producing states of complex I ((a) and (b)) and complex III ((c) and (d)) are depicted versus the mitochondrial membrane potential ((a) and (c)) or the ATP production rate. Red: fully reduced flavin, green: flavin radical, blue: semi-ubiquinon at n-site bound to the respective complex, black: semi-ubiquinon at p-site bound to complex III. ATP production and occupation of ROS producing states are normalized to the reference state of the system.

Mentions: Since multiple sites for mitochondrial ROS production in complex I and complex III have been suggested in the literature, we monitored the occupation states of the disputed ROS producing sites at varying ATP consumption rate (see Figure 5). From our model simulations, we concluded that the fully reduced flavin, the semi-ubiquinone bound at n-site in complex I, and the semiubiquinone bound a t p-site in complex III are in agreement with expected dependencies on the membrane potential, while the flavin radical and the semiubiquinone at p-site can be ruled out as main ROS producers.


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)

Potential ROS producing states in the RC. ROS producing states of complex I ((a) and (b)) and complex III ((c) and (d)) are depicted versus the mitochondrial membrane potential ((a) and (c)) or the ATP production rate. Red: fully reduced flavin, green: flavin radical, blue: semi-ubiquinon at n-site bound to the respective complex, black: semi-ubiquinon at p-site bound to complex III. ATP production and occupation of ROS producing states are normalized to the reference state of the system.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig5: Potential ROS producing states in the RC. ROS producing states of complex I ((a) and (b)) and complex III ((c) and (d)) are depicted versus the mitochondrial membrane potential ((a) and (c)) or the ATP production rate. Red: fully reduced flavin, green: flavin radical, blue: semi-ubiquinon at n-site bound to the respective complex, black: semi-ubiquinon at p-site bound to complex III. ATP production and occupation of ROS producing states are normalized to the reference state of the system.
Mentions: Since multiple sites for mitochondrial ROS production in complex I and complex III have been suggested in the literature, we monitored the occupation states of the disputed ROS producing sites at varying ATP consumption rate (see Figure 5). From our model simulations, we concluded that the fully reduced flavin, the semi-ubiquinone bound at n-site in complex I, and the semiubiquinone bound a t p-site in complex III are in agreement with expected dependencies on the membrane potential, while the flavin radical and the semiubiquinone at p-site can be ruled out as main ROS producers.

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