Mitochondrial Aidoptosis-Induced Channel (MAC) Function Triggers a Bax/Bak-Dependent Bystander Effect
Mitochondrial Aidoptosis-Induced Channel (MAC) Function Triggers a Bax/Bak-Dependent Bystander Effect
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DOI：
10.1016/j.ajpath.2010.11.014
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发表时间：
2011-01-01
影响因子：
6
通讯作者：
Kinnally, Kathleen W.
中科院分区：
文献类型：
--
作者：
Peixoto, Pablo M.;Lue, Jennifer K.;Kinnally, Kathleen W.
细胞凋亡向附近细胞的附带扩散被称为旁观者效应，这是组织稳态不可或缺的过程，也是抗癌治疗的挑战。在许多系统中，细胞凋亡依赖于线粒体外膜对细胞色素c和Smac/DIABLO等因子的透化。这种透化发生通过形成的线粒体凋亡诱导的通道（MAC），并在这里模仿单细胞显微注射细胞色素c到非洲爪蟾胚胎。在体内观察到从注射到邻近细胞的凋亡波。这一发现表明，细胞色素c释放下游产生的死亡信号扩散到邻近细胞，最终杀死了动物。然后在表达或不表达其主要成分Bax和/或巴克的小鼠胚胎成纤维细胞中评估MAC在旁观者效应中的作用。外源性表达的绿色荧光蛋白-Bax触发的外膜的透化和这些细胞的凋亡。延时录像显示，邻近细胞也经历了凋亡，但Bax和/或巴克的表达是必不可少的这种效果，因为没有旁观者观察到在细胞缺乏这两个MAC组件。这些结果可能指导开发新的治疗策略，以选择性地消除肿瘤或最小化退行性或创伤性细胞死亡中组织损伤的大小。(Am J Pathol 2011，178：48-54; DOI：10.1016/j.ajpath.2010.11.014）
Collateral spread of apoptosis to nearby cells is referred to as the bystander effect, a process that is integral to tissue homeostasis and a challenge to anticancer therapies. In many systems, apoptosis relies on permeabilization of the mitochondrial outer membrane to factors such as cytochrome c and Smac/DIABLO. This permeabilization occurs via formation of a mitochondrial apoptosis-induced channel (MAC) and was mimicked here by single-cell microinjection of cytochrome c into Xenopus laevis embryos. Waves of apoptosis were observed in vivo from the injected to the neighboring cells. This finding indicates that a death signal generated downstream of cytochrome c release diffused to neighboring cells and ultimately killed the animals. The role of MAC in bystander effects was then assessed in mouse embryonic fibroblasts that did or did not express its main components, Bax and/or Bak. Exogenous expression of green fluorescent protein-Bax triggered permeabilization of the outer membrane and apoptosis in these cells. Time-lapse videos showed that neighboring cells also underwent apoptosis, but expression of Bax and/or Bak was essential to this effect, because no bystanders were observed in cells lacking both of these MAC components. These results may guide development of novel therapeutic strategies to selectively eliminate tumors or minimize the size of tissue injury in degenerative or traumatic cell death. (Am J Pathol 2011, 178:48-54; DOI: 10.1016/j.ajpath.2010.11.014)