The expanding role of mitochondria in apoptosis.
The expanding role of mitochondria in apoptosis.
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作者：
X. Wang
对细胞凋亡或程序性细胞死亡的遗传基础的初步认识，是从对秀丽隐杆线虫的巧妙研究中获得的（回顾，见Horvitz 1999）。这些研究揭示了一个线性途径，即指定为Ced-3和ced -4的两个基因的产物是必要的，并且足以触发131个预定细胞在发育过程中完美定时和精心安排的死亡。这一途径与高等动物的相关性是通过发现这些基因的明显哺乳动物同源物，以及证明哺乳动物ced -3相关基因编码蛋白酶（称为半胱天冬酶），其活性负责细胞凋亡的形态学变化特征（回顾，见Hengartner 2000）而建立的。随着Bcl-2基因的发现，凋亡程序的复杂性开始增加，Bcl-2基因的产物在淋巴细胞中引起细胞凋亡抵抗（Vaux et al. 1988; McDonnell et al. 1989）。Bcl-2被证明可以部分纠正秀丽隐杆线虫中Ced-9突变的表型，Ced-9是在Ced-4和Ced-3上游起作用的细胞存活基因（Vaux et al. 1992）。这一发现表明秀丽隐杆线虫和哺乳动物抗凋亡途径之间存在明显的一对一的相关性。然而，这种相关性并不能解释在哺乳动物细胞中观察到的两个现象。首先，在线虫的线粒体膜上发现了Bcl-2蛋白，与线虫的凋亡无关；其次，非洲爪蟾卵母细胞提取物只有在富含线粒体的膜组分存在时才会产生凋亡变化（Hockenberry et al. 1990; Newmeyer et al. 1994）。当生化研究发现几种能够直接激活细胞凋亡程序的线粒体蛋白时，线粒体在哺乳动物细胞凋亡中的复杂作用成为人们关注的焦点（Liu et al. 1996; Susin et al. 1999; Du et al. 2000; Verhagen et al. 2000; Li et al. 2001）。正常情况下，这些蛋白质存在于线粒体的膜间空间。作为对各种凋亡刺激的反应，它们被释放到细胞质和/或细胞核中。它们通过激活半胱天冬酶和核酸酶或中和这一过程的胞质抑制剂来促进细胞凋亡。线粒体和细胞质促凋亡蛋白与抗凋亡蛋白相互作用，每个细胞的生死悬于平衡之中，这是一幅复杂的图景。本文综述了线粒体在细胞凋亡中广泛而复杂的作用。
The initial insight into the genetic basis of apoptosis, or programmed cell death, was gained from ingenious studies of the roundworm Caenorhabditis elegans (for review, see Horvitz 1999). These studies revealed a linear pathway whereby the products of two genes, designated Ced-3 andCed-4, were necessary and sufficient to trigger the perfectly timed and orchestrated death of 131 preordained cells during development. The relevance of this pathway to higher animals was established by the discovery of apparent mammalian orthologs of these genes and the demonstration that the mammalian Ced-3-related genes encode proteases (designated caspases) whose activities are responsible for the morphological changes characteristic of apoptosis (for review, see Hengartner 2000). The complexity of the apoptotic program began to increase with the discovery of Bcl-2, a gene whose product causes resistance to apoptosis in lymphocytes (Vaux et al. 1988; McDonnell et al. 1989). Bcl-2 was shown to correct partially the phenotype of a C. elegans mutation in Ced-9, a cell survival gene that functions upstream of Ced-4 and Ced-3 (Vaux et al. 1992). This finding suggested an apparent one-for-one correlation between the C. elegans and mammalian proand antiapoptotic pathways. However, this correlation did not explain two observations made in mammalian cells. First, the Bcl-2 protein was found on the membrane of mitochondria, which were not implicated in C. elegans apoptosis; and second, apoptotic changes could be produced in Xenopus laevis oocyte extracts only when a membrane fraction enriched in mitochondria was present (Hockenberry et al. 1990; Newmeyer et al. 1994). The complex role of mitochondria in mammalian cell apoptosis came into focus when biochemical studies identified several mitochondrial proteins that are able to activate cellular apoptotic programs directly (Liu et al. 1996; Susin et al. 1999; Du et al. 2000; Verhagen et al. 2000; Li et al. 2001). Normally, these proteins reside in the intermembrane space of mitochondria. In response to a variety of apoptotic stimuli, they are released to the cytosol and/or the nucleus. They promote apoptosis either by activating caspases and nucleases or by neutralizing cytosolic inhibitors of this process. A complex picture has emerged in which mitochondrial and cytosolic proapoptotic proteins interact with antiapoptotic proteins with each cell’s life or death hanging in the balance. This review summarizes the recent data on the expanding and complex role of mitochondria in apoptosis.