BOK controls apoptosis by Ca(2+) transfer through ER-mitochondrial contact sites.
BOK controls apoptosis by Ca(2+) transfer through ER-mitochondrial contact sites.
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DOI：
10.1016/j.celrep.2021.108827
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发表时间：
2021-03-09
期刊：
影响因子：
8.8
通讯作者：
Katz SG
中科院分区：
文献类型：
--
作者：
Carpio MA;Means RE;Brill AL;Sainz A;Ehrlich BE;Katz SG
钙从内质网（ER）转移到线粒体是细胞凋亡的关键因素。B细胞淋巴瘤2 （BCL-2）卵巢杀手（BOK）定位于内质网并结合肌醇1,4,5-三磷酸受体（IP3R）。在这里，我们发现BOK对于基线线粒体钙水平和刺激诱导的钙从内质网转移到线粒体是必要的。缺乏BOK的小鼠胚胎成纤维细胞降低了内质网与线粒体的接近程度，并改变了线粒体相关膜（MAMs）的蛋白质组成，后者形成了必需的钙微结构域。对er -线粒体并置与药物诱导的细胞器间连接物的修复揭示了一种动力学破坏，当在Bok - / -细胞中克服这种破坏时，仍不足以修复thapsigargin诱导的钙转移和细胞凋亡。同样，不能与IP3R相互作用的BOK突变体恢复er -线粒体接近性，但不能恢复er -线粒体钙转移、MAM蛋白组成或凋亡。这项工作确定了BOK对er -线粒体接触的动态协调是细胞凋亡的重要控制点。Carpio等人证实，促凋亡的BCL-2家族成员BOK存在于线粒体相关膜（MAMs）中。BOK与IP3Rs的相互作用对Ca2+转移到线粒体、er -线粒体接触位点和细胞凋亡的调控至关重要。
Calcium transfer from the endoplasmic reticulum (ER) to mitochondria is a critical contributor to apoptosis. B cell lymphoma 2 (BCL-2) ovarian killer (BOK) localizes to the ER and binds the inositol 1,4,5-trisphosophate receptor (IP3R). Here, we show that BOK is necessary for baseline mitochondrial calcium levels and stimulus-induced calcium transfer from the ER to the mitochondria. Murine embryonic fibroblasts deficient for BOK have decreased proximity of the ER to the mitochondria and altered protein composition of mitochondria-associated membranes (MAMs), which form essential calcium microdomains. Rescue of the ER-mitochondrial juxtaposition with drug-inducible interorganelle linkers reveals a kinetic disruption, which when overcome in Bok−/− cells is still insufficient to rescue thapsigargin-induced calcium transfer and apoptosis. Likewise, a BOK mutant unable to interact with IP3R restores ER-mitochondrial proximity, but not ER-mitochondrial calcium transfer, MAM protein composition, or apoptosis. This work identifies the dynamic coordination of ER-mitochondrial contact by BOK as an important control point for apoptosis. Carpio et al. demonstrate that the proapoptotic BCL-2 family member BOK is present in mitochondrial associated membranes (MAMs). The interaction of BOK with the IP3Rs is critical for its regulation of Ca2+ transfer to the mitochondria, ER-mitochondrial contact sites, and apoptosis.
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