Propagation of the apoptotic signal by mitochondrial waves
Propagation of the apoptotic signal by mitochondrial waves
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DOI：
10.1093/emboj/20.15.4107
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发表时间：
2001-08-01
期刊：
影响因子：
11.4
通讯作者：
Hajnóczky, G
中科院分区：
文献类型：
--
作者：
Pacher, P;Hajnóczky, G
线粒体信号的产生被认为在细胞凋亡的承诺中是重要的，但是协调单个线粒体输出的机制仍然难以捉摸。我们发现，在心脏肌管暴露于凋亡剂，Ca 2+尖峰启动去极化的线粒体在离散的亚细胞区域，这些线粒体启动慢波的去极化和Ca 2+释放传播通过细胞。Bcl-X-L阻止线粒体行波，涉及渗透性转换孔（PTP）开放，并产生细胞色素c释放，半胱天冬酶激活和核凋亡。线粒体Ca 2+摄取对于波的传播是至关重要的，并且在波的起源处的线粒体特别有效地摄取Ca 2+，提供了可能是选择起始位点的基础的机制。因此，凋亡剂通过使PTP对Ca 2+敏感而将线粒体转化为可兴奋状态。通过线粒体波传播通过整个细胞的局部激发的扩展可以在大细胞中的凋亡机制的激活中特别重要。
Generation of mitochondrial signals is believed to be important in the commitment to apoptosis, but the mechanisms coordinating the output of individual mitochondria remain elusive. We show that in cardiac myotubes exposed to apoptotic agents, Ca2+ spikes initiate depolarization of mitochondria in discrete subcellular regions, and these mitochondria initiate slow waves of depolarization and Ca2+ release propagating through the cell. Traveling mitochondrial waves are prevented by Bcl-X-L, involve permeability transition pore (PTP) opening, and yield cytochrome c release, caspase activation and nuclear apoptosis. Mitochondrial Ca2+ uptake is critical for wave propagation, and mitochondria at the origin of waves take up Ca2+ particularly effectively, providing a mechanism that may underlie selection of the initiation sites. Thus, apoptotic agents transform the mitochondria into an excitable state by sensitizing PTP to Ca2+. Expansion of the local excitation by mitochondrial waves propagating through the whole cell can be especially important in activation of the apoptotic machinery in large cells.