Role of the mitochondrial membrane permeability transition in cell death
Role of the mitochondrial membrane permeability transition in cell death
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DOI：
10.1007/s10495-006-0525-7
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发表时间：
2007-05-01
期刊：
影响因子：
7.2
通讯作者：
Shimizu, Shigeomi
中科院分区：
文献类型：
--
作者：
Tsujimoto, Yoshihide;Shimizu, Shigeomi
近年来，线粒体在细胞凋亡和坏死性细胞死亡中的作用受到了相当大的关注。线粒体膜通透性的增加是细胞凋亡或坏死性死亡的关键事件之一，尽管所涉及的机制的细节仍有待阐明。线粒体膜渗透性转变（MPT）是线粒体膜渗透性的Ca 2+依赖性增加，其导致Δ psi损失、线粒体肿胀和线粒体外膜破裂。MPT被认为发生在被称为渗透性转换孔（PTP）的通道打开之后，该通道由电压依赖性阴离子通道（VDAC）、腺嘌呤核苷酸转运体（ANT）、亲环素D（Cyp D：线粒体肽基脯氨酰-顺式、反式异构酶）和其他分子组成。最近，在几个实验室用缺乏Cyp D的小鼠进行的研究取得了重大进展，这些研究令人信服地证明了Cyp D对MPT的发生是必不可少的，并且Cyp D依赖性MPT调节某些形式的坏死性细胞死亡，但不调节凋亡性细胞死亡。Cyp D缺陷小鼠也已被用于显示Cyp D依赖性MPT在缺血/再灌注损伤中起关键作用。抗细胞凋亡蛋白Bcl-2和Bcl-x（L）具有阻断MPT的能力，因此除了它们公认的抑制细胞凋亡的能力之外，还可以阻断MPT依赖性坏死。
In recent years, the role of the mitochondria in both apoptotic and necrotic cell death has received considerable attention. An increase of mitochondrial membrane permeability is one of the key events in apoptotic or necrotic death, although the details of the mechanism involved remain to be elucidated. The mitochondrial membrane permeability transition (MPT) is a Ca2+-dependent increase of mitochondrial membrane permeability that leads to loss of Delta psi, mitochondrial swelling, and rupture of the outer mitochondrial membrane. The MPT is thought to occur after the opening of a channel that is known as the permeability transition pore (PTP), which putatively consists of the voltage-dependent anion channel (VDAC), the adenine nucleotide translocator (ANT), cyclophilin D (Cyp D: a mitochondrial peptidyl prolyl-cis, trans-isomerase), and other molecule(s). Recently, significant progress has been made by studies performed with mice lacking Cyp D at several laboratories, which have convincingly demonstrated that Cyp D is essential for the MPT to occur and that the Cyp D-dependent MPT regulates some forms of necrotic, but not apoptotic, cell death. Cyp D-deficient mice have also been used to show that the Cyp D-dependent MPT plays a crucial role in ischemia/reperfusion injury. The anti-apoptotic proteins Bcl-2 and Bcl-x(L) have the ability to block the MPT, and can therefore block MPT-dependent necrosis in addition to their well-established ability to inhibit apoptosis.