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Modeling of the Role of a Bax-Activation Switch in the Mitochondrial Apoptosis Decision

State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, People's Republic of China

Correspondence: Address reprint requests to Pingping Shen, E-mail: ppshen{at}nju.edu.cn.

We performed in silico modeling of the regulatory network of mitochondrial apoptosis through which we examined the role of a Bax-activation switch in governing the mitochondrial apoptosis decision. Two distinct modeling methods were used in this article. One is continuous and deterministic, comprised of a set of ordinary differential equations. The other, carried out in a discrete manner, is based on a cellular automaton, which takes stochastic fluctuations into consideration. We focused on dynamic properties of the mitochondrial apoptosis regulatory network. The roles of Bcl-2 family proteins in cellular responses to apoptotic stimuli were examined. In our simulations, a self-amplification process of Bax-activation is indicated. Further analysis suggests that the core module of Bax-activation is bistable in both deterministic and stochastic models, and this feature is robust to noise and wide ranges of parameter variation. When coupling with Bax-polymerization, it forms a one-way-switch, which governs irreversible behaviors of Bax-activation even with attenuation of apoptotic stimulus. Together with the growing biochemical evidence, we propose a novel molecular switch mechanism embedded in the mitochondrial apoptosis regulatory network and give a plausible explanation for the all-or-none, irreversible character of mitochondrial apoptosis.