Huber Heinrich J, Laussmann Maike A, Prehn Jochen H M, Rehm Markus
Sytems Biology Group, Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
BMC Syst Biol. 2010 Feb 4;4:9. doi: 10.1186/1752-0509-4-9.
Apoptosis is an essential cell death process throughout the entire life span of all metazoans and its deregulation in humans has been implicated in many proliferative and degenerative diseases. Mitochondrial outer membrane permeabilisation (MOMP) and activation of effector caspases are key processes during apoptosis signalling. MOMP can be subject to spatial coordination in human cancer cells, resulting in intracellular waves of cytochrome-c release. To investigate the consequences of these spatial anisotropies in mitochondrial permeabilisation on subsequent effector caspase activation, we devised a mathematical reaction-diffusion model building on a set of partial differential equations.
Reaction-diffusion modelling suggested that even if strong spatial anisotropies existed during mitochondrial cytochrome c release, these would be eliminated by free diffusion of the cytosolic proteins that instantiate the apoptosis execution network. Experimentally, rapid sampling of mitochondrial permeabilisation and effector caspase activity in individual HeLa cervical cancer cells confirmed predictions of the reaction-diffusion model and demonstrated that the signalling network of apoptosis execution could efficiently translate spatial anisotropies in mitochondrial permeabilisation into a homogeneous effector caspase response throughout the cytosol. Further systems modelling suggested that a more than 10,000-fold impaired diffusivity would be required to maintain spatial anisotropies as observed during mitochondrial permeabilisation until the time effector caspases become activated.
Multi-protein diffusion efficiently contributes to eliminating spatial asynchronies which are present during the initiation of apoptosis execution and thereby ensures homogeneous apoptosis execution throughout the entire cell body. For previously reported biological scenarios in which effector caspase activity was shown to be targeted selectively to specific subcellular regions additional mechanisms must exist that limit or spatially coordinate caspase activation and/or protect diffusing soluble caspase substrates from unwanted proteolysis.
细胞凋亡是所有后生动物整个生命周期中必不可少的细胞死亡过程，其在人类中的失调与许多增殖性和退行性疾病有关。线粒体外膜通透性改变（MOMP）和效应半胱天冬酶的激活是细胞凋亡信号传导过程中的关键步骤。在人类癌细胞中，MOMP可能受到空间协调，导致细胞色素c释放的细胞内波。为了研究线粒体通透性这些空间各向异性对随后效应半胱天冬酶激活的影响，我们基于一组偏微分方程设计了一个数学反应扩散模型。
反应扩散模型表明，即使在线粒体细胞色素c释放过程中存在强烈的空间各向异性，这些也会通过构成细胞凋亡执行网络的胞质蛋白的自由扩散而消除。在实验中，对单个HeLa宫颈癌细胞中线粒体通透性和效应半胱天冬酶活性的快速采样证实了反应扩散模型的预测，并表明细胞凋亡执行信号网络可以有效地将线粒体通透性的空间各向异性转化为整个细胞质中均匀的效应半胱天冬酶反应。进一步的系统模型表明，在效应半胱天冬酶激活之前，需要超过10000倍的扩散率受损才能维持线粒体通透性过程中观察到的空间各向异性。
多蛋白扩散有效地有助于消除细胞凋亡执行起始过程中存在的空间异步性，从而确保整个细胞体均匀的细胞凋亡执行。对于先前报道的效应半胱天冬酶活性被显示选择性靶向特定亚细胞区域的生物学场景，必须存在其他机制来限制或在空间上协调半胱天冬酶激活和/或保护扩散的可溶性半胱天冬酶底物免受不必要的蛋白水解。
