A mechanistic view of mitochondrial death decision pores
A mechanistic view of mitochondrial death decision pores
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DOI：
10.1590/s0100-879x2006005000109
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发表时间：
2007-08-01
影响因子：
2.3
通讯作者：
Sesso, A.
中科院分区：
文献类型：
--
作者：
Belizário, J.E.;Alves, J.;Sesso, A.
线粒体响应各种外在和内在信号传导事件，增加其外膜和内膜对溶质、质子和代谢物的通透性。细胞和细胞器内离子稳态的维持，特别是 Ca2+，可以决定细胞的生存或死亡。线粒体死亡决定集中在两个过程：内膜透化，例如当 Ca2+ 达到临界阈值时跨内膜形成的线粒体通透性转换孔促进的内膜透化，以及线粒体外膜透化，其中促凋亡蛋白 BID、BAX 和 BAK 发挥积极作用。膜透化导致凋亡蛋白的释放：细胞色素 c、凋亡诱导因子、Smac/Diablo、HtrA2/Omi 和核酸内切酶 G。细胞色素 c 启动半胱天冬酶的蛋白水解激活，进而裂解数百种蛋白质，产生细胞凋亡的形态和生化变化。电压依赖性阴离子通道、亲环蛋白 D、腺嘌呤核苷酸转位酶和促凋亡蛋白 BID、BAX 和 BAK 可能是导致线粒体透化的膜孔分子组成的一部分，但这仍然是一个有待解决的核心问题。其他转运孔和通道，包括神经酰胺通道、线粒体凋亡诱导通道以及非特异性外膜破裂也可能是这些凋亡因子的潜在释放途径。在这篇综述中，我们讨论了活性氧和半胱天冬酶通过膜脂和蛋白质的结构和构象变化促进内/外膜通透的条件，随后可能导致孔打开或线粒体外膜破裂的机制模型。
Mitochondria increase their outer and inner membrane permeability to solutes, protons and metabolites in response to a variety of extrinsic and intrinsic signaling events. The maintenance of cellular and intraorganelle ionic homeostasis, particularly for Ca2+, can determine cell survival or death. Mitochondrial death decision is centered on two processes: inner membrane permeabilization, such as that promoted by the mitochondrial permeability transition pore, formed across inner membranes when Ca2+ reaches a critical threshold, and mitochondrial outer membrane permeabilization, in which the pro-apoptotic proteins BID, BAX, and BAK play active roles. Membrane permeabilization leads to the release of apoptogenic proteins: cytochrome c, apoptosis-inducing factor, Smac/Diablo, HtrA2/Omi, and endonuclease G. Cytochrome c initiates the proteolytic activation of caspases, which in turn cleave hundreds of proteins to produce the morphological and biochemical changes of apoptosis. Voltage-dependent anion channel, cyclophilin D, adenine nucleotide translocase, and the pro-apoptotic proteins BID, BAX, and BAK may be part of the molecular composition of membrane pores leading to mitochondrial permeabilization, but this remains a central question to be resolved. Other transporting pores and channels, including the ceramide channel, the mitochondrial apoptosis-induced channel, as well as a non-specific outer membrane rupture may also be potential release pathways for these apoptogenic factors. In this review, we discuss the mechanistic models by which reactive oxygen species and caspases, via structural and conformational changes of membrane lipids and proteins, promote conditions for inner/outer membrane permeabilization, which may be followed by either opening of pores or a rupture of the outer mitochondrial membrane.