Tsujimoto Yoshihide, Nakagawa Takashi, Shimizu Shigeomi
Department Medical Genetics, Osaka University Medical School, SORST of Japan Science and Technology Agency, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
Biochim Biophys Acta. 2006 Sep-Oct;1757(9-10):1297-300. doi: 10.1016/j.bbabio.2006.03.017. Epub 2006 Apr 19.
Mitochondria are important organelles for energy production, Ca2+ homeostasis, and cell death. In recent years, the role of the mitochondria in both apoptotic and necrotic cell death has received much attention. In apoptotic and necrotic death, an increase of mitochondrial membrane permeability is considered to be one of the key events, although the detailed mechanism remains to be elucidated. The mitochondrial membrane permeability transition (MPT) is a Ca2+-dependent increase in the permeability of the mitochondrial membrane that leads to loss of Deltapsi, mitochondrial swelling, and rupture of the outer mitochondrial membrane. The MPT is thought to occur after the opening of a channel, which is termed the permeability transition pore (PTP) and 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). Our studies of mice lacking Cyp D have revealed that it is essential for occurrence of the MPT and that the Cyp D-dependent MPT regulates some forms of necrotic cell death, but not apoptotic death. We have also shown that two anti-apoptotic proteins, Bcl-2 and Bcl-x(L), block the MPT by directly inhibition of VDAC activity. Here we summarize a role of the MPT in cell death.
线粒体是能量产生、钙离子稳态和细胞死亡的重要细胞器。近年来，线粒体在凋亡性和坏死性细胞死亡中的作用备受关注。在凋亡性和坏死性死亡中，线粒体膜通透性增加被认为是关键事件之一，尽管其详细机制仍有待阐明。线粒体膜通透性转换（MPT）是一种依赖钙离子的线粒体膜通透性增加，导致线粒体膜电位丧失、线粒体肿胀和线粒体外膜破裂。MPT被认为发生在一个通道开放之后，该通道被称为通透性转换孔（PTP），推测由电压依赖性阴离子通道（VDAC）、腺嘌呤核苷酸转位酶（ANT）、亲环蛋白D（Cyp D：一种线粒体肽基脯氨酰顺反异构酶）和其他分子组成。我们对缺乏Cyp D的小鼠的研究表明，它对于MPT的发生至关重要，并且依赖Cyp D的MPT调节某些形式的坏死性细胞死亡，但不调节凋亡性死亡。我们还表明，两种抗凋亡蛋白Bcl-2和Bcl-x(L)通过直接抑制VDAC活性来阻断MPT。在此，我们总结MPT在细胞死亡中的作用。
