Bax-induced caspase activation and apoptosis via cytochrome c release from mitochondria is inhibitable by Bcl-xL
Bax-induced caspase activation and apoptosis via cytochrome c release from mitochondria is inhibitable by Bcl-xL
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DOI：
10.1074/jbc.274.4.2225
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发表时间：
1999-01-22
影响因子：
4.8
通讯作者：
Green, DR
中科院分区：
文献类型：
--
作者：
Finucane, DM;Bossy-Wetzel, E;Green, DR
越来越多的证据支持线粒体和线粒体衍生因子在细胞死亡过程中的作用。特别是，许多注意力集中在细胞色素c，电子传递链的关键组成部分，已被报道从线粒体易位到细胞质中经历细胞凋亡的细胞。这种释放的机制目前尚不清楚。在这里，我们报告，异位表达的Bax诱导细胞凋亡细胞色素c的早期释放之前，许多凋亡相关的形态学改变，以及半胱天冬酶激活和随后的底物蛋白水解，线粒体跨膜电位的损失，在体内检测到，虽然没有线粒体肿胀或跨膜电位的损失，观察到在离体线粒体与Bax处理在体外。半胱天冬酶抑制剂，如内源性XIAP和合成肽苄氧基羰基-Val-Ala-Asp-氟甲基酮（zVAD-fatomic ketone），虽然能够改变细胞死亡的动力学和可能的模式，但对这种释放没有影响，这表明如果细胞色素c在半胱天冬酶激活中起作用，则它必须先于凋亡过程中的这一步骤。线粒体渗透性转变也被半胱天冬酶抑制显著阻止，表明细胞色素c从线粒体到胞质溶胶的易位不是需要线粒体膜去极化的事件的结果。相反，Bcl-xL能够阻止细胞色素c释放，同时也显著抑制细胞死亡。因此，线粒体释放细胞色素c等因子似乎是细胞死亡的关键步骤，这种释放不依赖于渗透性转换和半胱天冬酶激活，但受到Bcl-xL的抑制。
A growing body of evidence supports a role for mitochondria and mitochondria-derived factors in the cell death process. In particular, much attention has focused on cytochrome c, a key component of the electron transport chain, that has been reported to translocate from the mitochondria to the cytosol in cells undergoing apoptosis. The mechanism for this release is, as yet, unknown. Here we report that ectopic expression of Bax induces apoptosis with an early release of cytochrome c preceding many apoptosis-associated morphological alterations as well as caspase activation and subsequent substrate proteolysis, A loss of mitochondrial transmembrane potential was detected in vivo, although no mitochondrial swelling or loss of transmembrane potential was observed in isolated mitochondria treated with Bax in vitro. Caspase inhibitors, such as endogenous XIAP and synthetic peptide benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone (zVAD-fmk), although capable of altering the kinetics and perhaps mode of cell death, had no influence on this release, suggesting that if cytochrome c plays a role in caspase activation it must precede this step in the apoptotic process. Mitochondrial permeability transition was also shown to be significantly prevented by caspase inhibition, indicating that the translocation of cytochrome c from mitochondria to cytosol is not a consequence of events requiring mitochondrial membrane depolarization, In contrast, Bcl-xL was capable of preventing cytochrome c release while also significantly inhibiting cell death. It would therefore appear that the mitochondrial release of factors such as cytochrome c represents a critical step in committing a cell to death, and this release is independent of permeability transition and caspase activation but is inhibited by Bcl-xL.