Dynamic Simulation of Mitochondrial Respiration and Oxidative Phosphorylation: Comparison with Experimental Results

摘要

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 l(4):e36, 2005). This model was validated under static conditions. To evaluate its performance under dynamical situations, we implemented and simulated it (Simulink~R, 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.