Apoptosis and Mitochondria
Apoptosis and Mitochondria
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DOI：
10.1007/978-3-642-00150-5_29
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发表时间：
2010-01-01
期刊：
影响因子：
--
通讯作者：
Garcia-Ruiz, Carmen
中科院分区：
文献类型：
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作者：
Fernandez-Checa, Jose C.;Garcia-Ruiz, Carmen
在包括坏死和自噬的各种公认的细胞死亡形式中，细胞凋亡或程序性细胞死亡在进化上是保守的、高度组织化的，并且特征在于独特的核变化、染色质收缩、DNA片段化、膜起泡和包含垂死细胞组分的凋亡小体的形成。细胞凋亡是生命的一个重要组成部分，它消除了不需要的细胞，对胚胎发育、体内平衡和免疫防御至关重要。细胞凋亡的失调是许多病理生理状态和疾病的基础。凋亡性细胞死亡的关键介质是半胱氨酸蛋白酶，称为半胱天冬酶，其以协调级联方式工作以切割关键底物并拆除细胞[1]。半胱天冬酶级联反应涉及“启动子”半胱天冬酶和“执行子”半胱天冬酶，它们可以通过不同的凋亡刺激以不同的方式被激活。虽然细胞核的变化是凋亡性细胞死亡的特征，但也涉及其他亚细胞器，如内质网，溶酶体，特别是线粒体。此外，虽然半胱天冬酶是至关重要的凋亡，类似的形态学变化可以产生一个半胱天冬酶独立的方式。在脊椎动物中，半胱天冬酶依赖性细胞凋亡通过两个主要途径发生，即外源性途径和内源性途径（图29.1）。外源性途径在细胞外配体与TNF超家族的跨膜死亡受体结合后启动（见下文），这导致死亡诱导信号复合物（DISC）的组装。然后DISC激活引发剂半胱天冬酶，其触发导致凋亡性死亡的酶级联反应。内源性途径，也称为线粒体途径，通过导致线粒体外膜（OMM）透化和随后从线粒体膜间隙（IMS）释放蛋白质的刺激来激活，所述蛋白质启动或调节半胱天冬酶激活，例如细胞色素c。细胞色素c通常位于线粒体内膜（IMM）的嵴内，并被狭窄的嵴连接处有效地隔离。在IMM内，细胞色素c参与线粒体电子传递链，使用其血红素基团作为氧化还原中间体在复合物III和复合物IV之间穿梭电子。然而，当细胞检测到凋亡刺激，如DNA损伤或代谢应激时，内在凋亡途径被触发，线粒体细胞色素c被释放到胞质溶胶中。该过程被认为分两个阶段发生，首先是细胞色素c的动员，然后是其通过透化的OMM的易位。除了细胞色素c，其他IMS蛋白被动员并释放到胞质溶胶中，在那里它们参与促进或抵消半胱天冬酶激活并因此细胞死亡的战略性战斗。
Among the various recognized forms of cell death that include necrosis and autophagy, apoptosis or programmed cell death is evolutionarily conserved, highly organized, and characterized by unique nuclear changes, chromatin shrinkage, DNA fragmentation, membrane blebbing, and formation of apoptotic bodies that contain components of the dying cell. Apoptosis is a crucial component of life that eliminates unwanted cells and is vital for embryonic development, homeostasis, and immune defense. Dysregulation of apoptosis underlies many pathophysiological states and diseases. The key mediators of apoptotic cell death are cysteine proteases, called caspases, that work in a coordinated cascade to cleave key substrates and dismantle the cell [1]. The caspase cascade involves “initiator” caspases and “executioner” caspases that can be activated in different ways by different apoptotic stimuli. While changes in nuclei are characteristic in apoptotic cell death, other subcellular organelles are also involved such as endoplasmic reticulum, lysosomes, and, particularly, mitochondria. Moreover, although caspases are crucial in apoptosis, similar morphologic changes can be produced in a caspase-independent fashion. In vertebrates, caspase-dependent apoptosis occurs through two main pathways, the extrinsic pathway and the intrinsic pathway (Fig. 29.1). The extrinsic pathway is initiated upon the binding of an extracellular ligand to transmembrane death receptors of the TNF superfamily (see below), which leads to the assembly of the death-inducing signaling complex (DISC). The DISC then activates an initiator caspase, which triggers the enzymatic cascade that leads to apoptotic death. The intrinsic pathway, also known as the mitochondrial pathway, is activated by stimuli that lead to the permeabilization of the outer mitochondrial membrane (OMM) and the subsequent release of proteins from the mitochondrial intermembrane space (IMS), which initiate or regulate caspase activation, such as cytochrome c. Cytochrome c normally resides within the cristae of the inner mitochondrial membrane (IMM) and is effectively sequestered by narrow cristae junctions. Within the IMM, cytochrome c participates in the mitochondrial electron-transport chain, using its heme group as a redox intermediate to shuttle electrons between complex III and complex IV. However, when the cell detects an apoptotic stimulus, such as DNA damage, or metabolic stress, the intrinsic apoptotic pathway is triggered and mitochondrial cytochrome c is released into the cytosol. This process is thought to occur in two phases, first the mobilization of cytochrome c and then its translocation through permeabilized OMM. In addition to cytochrome c, other IMS proteins are mobilized and released into the cytosol where they are engaged in a strategic battle to promote or counteract caspase activation and hence cell death.