Spatial and Temporal Dynamics of Mitochondrial Membrane Permeability Waves during Apoptosis
Spatial and Temporal Dynamics of Mitochondrial Membrane Permeability Waves during Apoptosis
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DOI：
10.1016/j.bpj.2009.07.056
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发表时间：
2009-10-21
影响因子：
3.4
通讯作者：
Simon, Sanford M.
中科院分区：
文献类型：
--
作者：
Bhola, Patrick D.;Mattheyses, Alexa L.;Simon, Sanford M.
线粒体膜对蛋白质（细胞色素c和Smac）和质子的渗透性的变化是细胞凋亡中的关键步骤。虽然从诱导细胞凋亡到线粒体通透性改变的时间在数小时内是可变的，但蛋白质的释放是一种“全部或无”现象，在单个细胞中在几分钟内完成。在这里，使用单细胞荧光显微镜，我们表明，细胞色素c从一个单一的peption的释放发生在一个单一的步骤。然而，这种增加的细胞色素c的外膜渗透性在整个细胞中传播，作为一个较慢的，空间协调波。外膜对Smac的渗透性以相同的空间模式传播，但在时间上滞后。随后是内膜对质子的渗透性增加的波。只有在这之后，线粒体才会分裂。的空间依赖性的渗透波抑制毒胡萝卜素，抑制剂的内质网钙泵，但缓冲胞浆钙没有效果。这些结果表明，触发细胞凋亡是空间定位，启动在一个或只有几个线粒体之前的线粒体能量损失，和随后的时间传播的线粒体膜通透性是钙依赖性的。
Change in the permeability of the mitochondrial membrane to proteins (cytochrome c and Smac) and protons is a critical step in apoptosis. Although the time from the induction of apoptosis to the change of mitochondrial permeability is variable over a period of hours, the release of proteins is an "all or none" phenomenon that is completed in an individual cell within minutes. Here, using single-cell fluorescence microscopy, we show that the release of cytochrome c from a single mitochondrion occurs in a single step. However, this increased permeability of the outer membrane to cytochrome c propagates throughout the cell as a slower, spatially coordinated wave. The permeability of the outer membrane to Smac propagates with the same spatial pattern but lagging in time. This is followed by a wave of increased permeability of the inner membrane to protons. Only afterward do the mitochondria fission. The spatial dependence of the permeability wave was inhibited by thapsigargin, an inhibitor of the endoplasmic reticulum calcium pumps, but buffering cytosolic calcium had no effect. These results show that the trigger for apoptosis is spatially localized, initiating at one or only a few mitochondria preceding the loss of mitochondrial energetics, and the subsequent temporal propagation of mitochondrial membrane permeability is calcium-dependent.