Abstract
Hypoxia hampers ATP production and threatens cell survival. Since cellular energetics tightly controls cell responses and fate, ATP levels and dynamics are of utmost importance. An integrated mathematical model of ATP synthesis by the mitochondrial oxidative phosphorylation/electron transfer chain system has been recently published (Beard, PLoS Comput Biol 1(4):e36, 2005). This model was validated under static conditions. To evaluate its performance under dynamical situations, we implemented and simulated it (Simulink®, The Mathworks). Inner membrane potential (ΔΨ) and [NADH] (feeding the electron transfer chain) were used as indicators of mitochondrial function. Root mean squared error (rmse) was used to compare simulations and experiments (isolated cardiac mitochondria, Bose et al. J Biol Chem 278(40):39155–39165, 2003). Steady-state experimental data were reproduced within 2–6%. Model dynamics were evaluated under: (i) baseline, (ii) activation of NADH production, (iii) addition of ADP, (iv) addition of inorganic phosphate, (v) oxygen exhaustion. In all phases, except the last one, ΔΨ and [NADH] as well as oxygen consumption, were reproduced (within 10, 7 and 12%, respectively). Under anoxia, simulated ΔΨ markedly depolarized (no change in experiments). In conclusion, the model reproduces dynamic data as long as oxygen is present. Anticipated improvement by the inclusion of ATP consumption and explicit Krebs cycle are under evaluation.
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Abbreviations
- ATP:
-
Adenosine-5′-triphosphate, the energetic currency of the cell
- ADP:
-
Adenosine-5′-diphosphate (ADP and Pi are the substrates for the ATP-synthase)
- AMP:
-
Adenosine-5′-monophosphate
- Complex I:
-
NADH dehydrogenase, EC 1.6.5.3, or NADH:(ubi)quinone oxidoreductase, first respiratory complex of the electron transfer chain, catalyzes the transfer of NADH electrons to (oxidized) ubiquinone and translocates four protons to the mitochondrial intermembrane space
- Complex III:
-
(ubi)quinone:cytochrome c oxidoreductase, EC 1.10.2.2, third complex of the electron transport chain, transfers electrons from (reduced) ubiquinol to (oxidized)cytochrome c (two protons translocated in the process)
- Complex IV:
-
Cytochrome c oxidase, EC 1.9.3.1, the last “respiratory complex”, catalyzes the transfer of electrons (four) from cytochrome c to molecular oxygen, producing two molecules of wate (translocating four protons)
- Cytochrome c :
-
Cyt c is a small, soluble protein, loosely associated with the (outer aspect of the) mitochondrial inner membrane; its redox couple plays an essential role in the electron transfer chain (between complex III and complex IV)
- ΔΨ:
-
Transmembrane electrical potential difference across the mitochondrial inner membrane
- EC:
-
Enzyme Commission number (see url http://www.chem.qmul.ac.uk/iubmb/enzyme/)
- Pi:
-
Inorganic phosphate
- NADH (+H+):
-
Nicotinamide adenine dinucleotide coenzyme (reduced form)
- ODE:
-
Ordinary differential equations
- Ubiquinone:
-
The oxidized form of the ubiquinone/ubiquinol couple, involved as a redox cofactor in the electron transfer chain.
- url:
-
Universal resource locator
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Acknowledgements
We wish to thank Dr Dan Beard, from the Biotechnology and Bioengineering Centre (Medical College of Wisconsin, Milwaukee, USA) for helpful comments and precisions about his model. We thank Pr Jean-Pierre Mazat (Inserm U688, Université de Bordeaux, France) for experimental data. This work was supported by the CNRS (PH), the INSERM, and the Faculty of Medicine and Pharmacy (University of Poitiers).
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Guillaud, F., Hannaert, P. Dynamic Simulation of Mitochondrial Respiration and Oxidative Phosphorylation: Comparison with Experimental Results. Acta Biotheor 56, 157–172 (2008). https://doi.org/10.1007/s10441-008-9035-z
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DOI: https://doi.org/10.1007/s10441-008-9035-z