Endoplasmic reticulum BIK initiates DRP1-regulated remodelling of mitochondrial cristae during apoptosis
Endoplasmic reticulum BIK initiates DRP1-regulated remodelling of mitochondrial cristae during apoptosis
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DOI：
10.1038/sj.emboj.7600592
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发表时间：
2005-04-20
期刊：
影响因子：
11.4
通讯作者：
Shore, GC
中科院分区：
文献类型：
--
作者：
Germain, M;Mathai, JP;Shore, GC
内质网（ER）可以引发凋亡前信号，导致Ca2+传递到线粒体，这反过来刺激裂变酶DRP1募集到细胞器表面。在这里，我们发现BH3-only BIK激活了完整细胞内质网的这一途径，导致线粒体断裂，但细胞色素c很少释放到细胞质中。bik诱导的线粒体转化本质上是动态的，涉及drp1依赖性的重构和嵴的打开，而嵴是细胞色素c主要储存的地方。DRP1的这种新功能不同于它在调节线粒体裂变中的作用。洋地黄苷对外膜的选择性渗透证实了BIK刺激导致线粒体内细胞色素c的动员。值得注意的是，BIK可以与靶向线粒体的弱BH3-only蛋白（如NOXA）合作，通过独立于DRP1酶活性的机制激活BAX。当BIK和NOXA一起表达时，会导致被动员的细胞色素c的快速释放和半胱天蛋白酶的激活。
The endoplasmic reticulum ( ER) can elicit proapoptotic signalling that results in transmission of Ca2+ to the mitochondria, which in turn stimulates recruitment of the fission enzyme DRP1 to the surface of the organelle. Here, we show that BH3-only BIK activates this pathway at the ER in intact cells, resulting in mitochondrial fragmentation but little release of cytochrome c to the cytosol. The BIK-induced transformations in mitochondria are dynamic in nature and involve DRP1-dependent remodelling and opening of cristae, where the major stores of cytochrome c reside. This novel function for DRP1 is distinct from its recognized role in regulating mitochondrial fission. Selective permeabilization of the outer membrane with digitonin confirmed that BIK stimulation results in mobilization of intramitochondrial cytochrome c. Of note, BIK can cooperate with a weak BH3-only protein that targets mitochondria, such as NOXA, to activate BAX by a mechanism that is independent of DRP1 enzyme activity. When expressed together, BIK and NOXA cause rapid release of mobilized cytochrome c and activation of caspases.