Computational Modeling Analysis of Acute and Chronic Ethanol-Induced Oxidative Stress

N. I. Markevich ; J. B. Hoek

Matematičeskaâ biologiâ i bioinformatika, Tome 9 (2014) no. 1, pp. 63-88.

Résumé

The main goal of this work is to develop a computational model of reactive oxygen species (ROS) production by the mitochondrial respiratory chain and analyze the control of oxidative stress that is enhanced by acute and excessive chronic ethanol treatment, resulting in ethanol-induced injury. The computational model consists of a system of 35 ordinary differential equations and describes the oxidized and reduced states of different electron carriers and the electron flow through Complexes I, II, III and IV as well as the rates of superoxide and $\mathrm{H_2O_2}$ production and degradation in the control and upon ethanol-related alterations in different segments of the respiratory chain and glutathione peroxidase and glutathione reductase reactions. The effect of acute ethanol metabolism on ROS production was simulated in the computational model by an increase in the mitochondrial NADH/NAD ratio and a closure of voltage dependent anionic channel (VDAC) in the outer mitochondrial membrane. Excessive chronic ethanol consumption was modeled in accord with experimental observations available in the literature through inhibition of the activity of different segments of the respiratory chain and glutathione peroxidase as well as activation of glutathione reductase and changes in the total mitochondrial glutathione levels. Computational analysis of $\Delta\Psi$ dependencies of ROS production upon chronic ethanol consumption during oxidation of different respiratory substrates was carried out. Computational results show that chronic ethanol increases the concentration of superoxide and $\mathrm{H_2O_2}$ in the mitochondrial matrix over the entire range of the membrane potential of $0\Delta\Psi180$ mV during oxidation of NADH alone and NADH + succinate. Ethanol-induced changes in the concentration of superoxide in the intermembrane space (IMS) are non-monotonic and depend on the membrane potential under this condition due to non-monotonic alterations in the rate of superoxide generation by the unstable semiquinone of Complex III. Ethanol-induced alterations in the concentration of both superoxide and $\mathrm{H_2O_2}$ in the mitochondrial matrix and IMS are also non-monotonic and depend on $\Delta\Psi$ during oxidation of succinate alone. Computational results are very compatible with available experimental observations of ROS production under control condition and acute and chronic ethanol treatment and predict that the effect of ethanol on ROS production depends on the membrane potential, i.e. metabolic state of mitochondria.

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