Bid-induced mitochondrial membrane permeabilization waves propagated by local reactive oxygen species (ROS) signaling
Bid-induced mitochondrial membrane permeabilization waves propagated by local reactive oxygen species (ROS) signaling
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DOI：
10.1073/pnas.1118244109
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发表时间：
2012-03-20
影响因子：
11.1
通讯作者：
Hajnoczky, Gyoergy
中科院分区：
文献类型：
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作者：
Garcia-Perez, Cecilia;Roy, Soumya Sinha;Hajnoczky, Gyoergy
bid诱导的线粒体膜透化和细胞色素c释放是细胞凋亡的核心。微量的Bid如何同步大量离散细胞器的功能仍然是一个谜，特别是在富含维生素A的细胞中。观察细胞群体，Bid诱导的透化的速率和滞后时间是剂量依赖性的，但即使是非常低的剂量也最终导致细胞色素c完全释放。相比之下，单个线粒体显示相对快速和均匀的动力学，表明群体中观察到的剂量依赖性是由于个体事件在时间上的传播。我们报告说，投标诱导的透化和细胞色素c的释放经常表现出波浪状的图案，通过一个细胞以恒定的速度传播，没有耗散。这种波不依赖于半胱天冬酶激活或渗透性转换孔开放。然而，活性氧（ROS）清除剂抑制细胞色素c释放的协调，也抑制了BID诱导的细胞死亡，而超氧化物和过氧化氢敏化线粒体BID诱导的透化。因此，Bid参与了ROS依赖性的局部线粒体增强机制，该机制将凋亡信号放大为波。
Bid-induced mitochondrial membrane permeabilization and cytochrome c release are central to apoptosis. It remains a mystery how tiny amounts of Bid synchronize the function of a large number of discrete organelles, particularly in mitochondria-rich cells. Looking at cell populations, the rate and lag time of the Bid-induced permeabilization are dose-dependent, but even very low doses lead eventually to complete cytochrome c release. By contrast, individual mitochondria display relatively rapid and uniform kinetics, indicating that the dose dependence seen in populations is due to a spreading of individual events in time. We report that Bid-induced permeabilization and cytochrome c release regularly demonstrate a wave-like pattern, propagating through a cell at a constant velocity without dissipation. Such waves do not depend on caspase activation or permeability transition pore opening. However, reactive oxygen species (ROS) scavengers suppressed the coordination of cytochrome c release and also inhibited Bid-induced cell death, whereas both superoxide and hydrogen peroxide sensitized mitochondria to Bid-induced permeabilization. Thus, Bid engages a ROS-dependent, local intermitochondrial potentiation mechanism that amplifies the apoptotic signal as a wave.