Bistability in apoptosis: Roles of Bax, Bcl-2, and mitochondrial permeability transition pores
Bistability in apoptosis: Roles of Bax, Bcl-2, and mitochondrial permeability transition pores
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DOI：
10.1529/biophysj.105.068122
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发表时间：
2006-03-01
影响因子：
3.4
通讯作者：
Bahar, I
中科院分区：
文献类型：
--
作者：
Bagci, EZ;Vodovotz, Y;Bahar, I
我们提出了一个线粒体依赖性细胞凋亡的数学模型，在该模型中，凋亡体形成的动力学协同性是保证细胞双稳定性的关键因素。我们研究了Bax和Bcl2的合成和降解率以及线粒体通透性转换孔(MPTP)的数量在细胞对凋亡刺激的反应中的作用。我们的分析表明，协作性凋亡体的形成是一种诱导双稳的机制，比其他机制所诱导的机制要强得多，例如凋亡抑制因子(IAP)对caspase-3的抑制。模拟预测了一种病理状态，在该状态下，如果Bax降解率高于阈值，或者如果Bax表达速率低于阈值，则细胞将呈现单稳态细胞存活。否则，细胞的死亡或存活取决于caspase-3的初始水平。我们发现，高表达的Bcl2可以抵消Bax的作用。我们的模拟还显示，如果MPTP的数量超过阈值，则会出现单稳态(病理性)的凋亡反应。这项研究支持了我们的观点，即基于数学模型，凋亡体形成中的协同性对于确定对凋亡刺激的健康反应至关重要，并有助于消除。Bax、Bcl2和MPTP在凋亡体形成中的作用。
We propose a mathematical model for mitochondria-dependent apoptosis, in which kinetic cooperativity in formation of the apoptosome is a key element ensuring bistability. We examine the role of Bax and Bcl-2 synthesis and degradation rates, as well as the number of mitochondrial permeability transition pores (MPTPs), on the cell response to apoptotic stimuli. Our analysis suggests that cooperative apoptosome formation is a mechanism for inducing bistability, much more robust than that induced by other mechanisms, such as inhibition of caspase-3 by the inhibitor of apoptosis (IAP). Simulations predict a pathological state in which cells will exhibit a monostable cell survival if Bax degradation rate is above a threshold value, or if Bax expression rate is below a threshold value. Otherwise, cell death or survival occur depending on initial caspase-3 levels. We show that high expression rates of Bcl-2 can counteract the effects of Bax. Our simulations also demonstrate a monostable ( pathological) apoptotic response if the number of MPTPs exceeds a threshold value. This study supports our contention, based on mathematical modeling, that cooperativity in apoptosome formation is critically important for determining the healthy responses to apoptotic stimuli, and helps de. ne the roles of Bax, Bcl-2, and MPTP vis-a-vis apoptosome formation.