Mitochondria as the focus of apoptosis research
Mitochondria as the focus of apoptosis research
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线粒体作为细胞凋亡研究的焦点
DOI：
10.1038/sj.cdd.4400272
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发表时间：
1997
影响因子：
12.4
通讯作者：
B. Zhivotovsky
中科院分区：
文献类型：
--
作者：
S. Orrenius;D. H. Burgess;M. Hampton;B. Zhivotovsky
随着近年来对细胞凋亡研究的增加，研究的重点从细胞核转移到细胞质，最近又转移到线粒体。直到几年前，人们的注意力都集中在细胞核上，寻找死亡基因和核酸内切酶，它们可能与细胞凋亡过程中染色质浓缩和断裂的特征模式有关。半胱天冬酶的发现及其在细胞死亡中的作用使研究的焦点转向细胞质，许多研究者开始认为细胞凋亡中的核事件是细胞凋亡过程中的“晚期和非必需”事件。这一观点得到了去核细胞质实验的支持。最近，试图了解大量的凋亡诱导剂如何激活半胱天冬酶并启动死亡过程，导致了对共同介质或执行剂的搜索。这一探索将细胞凋亡研究的重点放在了线粒体上。保存形态完整的线粒体被认为是凋亡性细胞死亡的标志。然而，自从发现Bcl-2蛋白定位于线粒体外膜（Hockenbery等人，1990年）。Newmeyer及其同事（1994）表明，非洲爪蟾卵母细胞提取物介导细胞凋亡，需要富含线粒体的致密细胞器组分。与此相关，据报道，其他无细胞系统中的核凋亡依赖于ATP的存在（Lazebnik等人，1993; Kass等人，1996年）。在经历放线菌素D诱导的凋亡性细胞死亡的HeLa细胞中发现了对细胞内ATP的类似需求（Chou等人，1995).虽然这些发现表明细胞凋亡中需要ATP，但其他研究表明，几种细胞凋亡诱导剂可以触发电子传递与ATP产生的解偶联，导致线粒体膜电位降低和相应的活性氧物质产生（Zamzami et al.，1995年）。这使得Kroemer提出细胞凋亡中的关键的、常见的步骤是通过所谓的渗透性转换（PT）打开线粒体巨通道（Kroemer等人，1995年）。尽管线粒体渗透性转变与蛋白水解级联的激活之间的联系是未知的，但最近的报道已经表明线粒体含有分子量约为50 kDa的可溶性蛋白质，即凋亡诱导因子（AIF），其在PT后释放并且足以引起核凋亡（Zamzami等人，1996年）。Bcl-2的过表达阻止线粒体PT和AIF的释放，但不影响线粒体内AIF的基础水平。
Coincident with the recent increase in research on apoptosis, there has been a shift in the focus of this research from the cell nucleus to the cytoplasm, and most recently, to the mitochondria. Until a few years ago the attention was directed at the nucleus, with a search fordeath genes' and endonuclease (s) that could be linked to the characteristic pattern of chromatin condensation and fragmentation during apoptosis. The discovery of the caspases and their role in cell death directed the research focus to the cytoplasm, and many investigators began to regard the nuclear events in apoptosis aslate'andnon-essential'for the apoptotic process. This view received support from experiments with enucleated cytoplasts. More recently, attempts to understand how a large variety of inducers of apoptosis can activate the caspases and initiate the death process have led to a search for a common mediator orexecutioner'. This search has placed the focus of apoptosis research on the mitochondria. Preservation of morphologically intact mitochondria has been considered a hallmark of apoptotic cell death. However, mitochondria have been implicated in apoptosis ever since the discovery that the Bcl-2 protein localizes to the outer mitochondrial membrane (Hockenbery et al., 1990). Newmeyer and colleagues (1994) showed that a Xenopus oocyte extract, which mediated apoptosis, required a dense organelle fraction enriched in mitochondria. In relation to this, nuclear apoptosis in other cell-free systems was reported to depend on the presence of ATP (Lazebnik et al., 1993; Kass et al., 1996). A similar requirement for intracellular ATP was found in HeLa cells undergoing actinomycin D-induced apoptotic cell death (Chou et al., 1995).While these findings suggest a requirement for ATP in apoptosis, other studies indicate that several apoptosisinducing agents can trigger the uncoupling of electron transport from ATP production, leading to a decrease in mitochondrial membrane potential and a corresponding production of reactive oxygen species (Zamzami et al., 1995). This led Kroemer to suggest that a crucial, common step in apoptosis is the opening of mitochondrial megachannels by so-called permeability transitions (PT)(Kroemer et al., 1995). Although the link between the mitochondrial permeability transition and the activation of a proteolytic cascade is unknown, recent reports have indicated that mitochondria contain a soluble protein, apoptosis-inducing factor (AIF) with a molecular weight of approximately 50kDa, that is released after PT and is sufficient to cause nuclear apoptosis (Zamzami et al., 1996). Overexpression of Bcl-2 prevented mitochondrial PT and the release of AIF, but did not affect the basal levels of AIF within the mitochondria.