Inhibiting Drp1-mediated mitochondrial fission selectively prevents the release of cytochrome c during apoptosis
Inhibiting Drp1-mediated mitochondrial fission selectively prevents the release of cytochrome c during apoptosis
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DOI：
10.1038/sj.cdd.4402107
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发表时间：
2007-06-01
影响因子：
12.4
通讯作者：
Arnoult, D.
中科院分区：
文献类型：
--
作者：
Estaquier, J.;Arnoult, D.
大多数细胞死亡刺激触发细胞色素c和其他辅因子的线粒体释放，诱导半胱天冬酶激活和随后的凋亡。细胞凋亡也与大量线粒体碎片和嵴重塑有关。动力蛋白相关蛋白1（Dynamin-related protein 1，Drp 1）是线粒体分裂机制中的一种蛋白质，参与细胞凋亡过程中的线粒体断裂。已经提出了几种解释细胞色素c释放机制的理论。一种认为它依赖于Drp 1介导的线粒体分裂的激活。在这里，我们报告说，Drp 1的下调抑制线粒体网络的碎片化，并部分阻止细胞色素c的释放，但未能阻止释放其他线粒体因子，如第二个caspase/直接IAP-结合蛋白与低pI，Omi/HtrA 2，腺苷酸激酶2和耳聋肌张力障碍肽/TIMM 8a。通过我们的观察，抑制Drp 1介导的线粒体分裂防止了可溶性OPA 1的线粒体释放，该可溶性OPA 1被提出来调节细胞凋亡过程中的嵴重塑和完整的细胞色素c释放，从而提供了对细胞色素c释放的预防的解释。最后，我们观察到Drp 1的下调延迟但不抑制细胞凋亡，这表明线粒体片段化不是细胞凋亡的先决条件。
Most cell death stimuli trigger the mitochondrial release of cytochrome c and other cofactors that induce caspase activation and ensuing apoptosis. Apoptosis is also associated with massive mitochondrial fragmentation and cristae remodeling. Dynamin-related protein 1 (Drp1), a protein of the mitochondrial fission machinery, has been reported to participate in apoptotic mitochondrial fragmentation. Several theories explaining the mechanisms of cytochome c release have been proposed. One suggests that it relies on the activation of Drp1-mediated mitochondrial fission. Here, we report that downregulation of Drp1 inhibits fragmentation of the mitochondrial network and partially prevents the release of cytochrome c but fails to prevent the release of other mitochondrial factors such as second mitochondria-derived activator of caspase/direct IAP-binding protein with low pI, Omi/HtrA2, adenylate kinase 2 and deafness dystonia peptide/TIMM8a. An explanation for the prevention of cytochrome c release is provided by our observation that inhibiting Drp1-mediated mitochondrial fission prevents the mitochondrial release of soluble OPA1 that was proposed to regulate cristae remodeling and complete cytochrome c release during apoptosis. Finally, we observed that downregulation of Drp1 delays but does not inhibit apoptosis, suggesting that mitochondrial fragmentation is not a prerequisite for apoptosis.