Bak regulates mitochondrial morphology and pathology during apoptosis by interacting with mitofusins
Bak regulates mitochondrial morphology and pathology during apoptosis by interacting with mitofusins
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DOI：
10.1073/pnas.0703976104
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发表时间：
2007-07-10
影响因子：
11.1
通讯作者：
Dong, Zheng
中科院分区：
文献类型：
--
作者：
Brooks, Craig;Wei, Qingqing;Dong, Zheng
线粒体损伤的特征是外膜透化和随之而来的凋亡因子的释放，是哺乳动物细胞凋亡的关键。 Bax 和 Bak 是两种多域 Bcl-2 家族蛋白，为线粒体损伤提供了必要的途径。然而，目前尚不清楚 Bax 和 Bak 如何合作引起线粒体损伤以及它们的作用是否多余。在这里，我们发现了 Bak 在线粒体断裂中的独特作用，线粒体断裂是一种看似形态学的事件，导致细胞凋亡过程中的线粒体损伤。我们发现，在 Bak 缺陷小鼠胚胎成纤维细胞、幼鼠肾细胞中，以及重要的是，从 Bak 缺陷小鼠大脑皮层中分离的初级神经元中，线粒体断裂减弱。与此形成鲜明对比的是，Bax 缺乏并不能阻止细胞凋亡过程中线粒体的断裂。 Bcl-2和Bcl-XL抑制线粒体断裂，其抑制作用取决于Bak的存在。将 Bak 重建到 Bax/Bak 双敲除细胞中可恢复线粒体碎片，而 Bax 重建的效果要差得多。 Bak 与两种线粒体融合蛋白 Mfn1 和 Mfn2 相互作用。在细胞凋亡过程中，Bak 与 Mfn2 解离并增强与 Mfn1 的关联。 BH3 结构域中的 Bak 突变阻止其与 Mfn2 解离，并降低其线粒体断裂活性。这项研究揭示了 Bak 在细胞凋亡过程中线粒体形态动力学调节中的一种先前未被认识的功能。通过这种功能，Bak 可能与 Bax 合作，使线粒体外膜透化，释放细胞凋亡级联反应。
Mitochondrial injury, characterized by outer membrane permeabilization and consequent release of apoptogenic factors, is a key to apoptosis of mammalian cells. Bax and Bak, two multidomain Bcl-2 family proteins, provide a requisite gateway to mitochondrial injury. However it is unclear how Bax and Bak cooperate to provoke mitochondrial injury and whether their roles are redundant. Here, we have identified a unique role of Bak in mitochondrial fragmentation, a seemingly morphological event that contributes to mitochondrial injury during apoptosis. We show that mitochondrial fragmentation is attenuated in Bak-deficient mouse embryonic fibroblasts, baby mouse kidney cells, and, importantly, also in primary neurons isolated from brain cortex of Bak-deficient mice. In sharp contrast, Bax deficiency does not prevent mitochondrial fragmentation during apoptosis. Bcl-2 and Bcl-XL inhibit mitochondrial fragmentation, and their inhibitory effects depend on the presence of Bak. Reconstitution of Bak into Bax/Bak double-knockout cells restores mitochondrial fragmentation, whereas reconstitution of Bax is much less effective. Bak interacts with Mfn1 and Mfn2, two mitochondrial fusion proteins. During apoptosis, Bak dissociates from Mfn2 and enhances the association with Mfn1. Mutation of Bak in the BH3 domain prevents its dissociation from Mfn2 and diminishes its mitochondrial fragmentation activity. This study has uncovered a previously unrecognized function of Bak in the regulation of mitochondrial morphological dynamics during apoptosis. By this function, Bak may collaborate with Bax to permeabilize the outer membrane of mitochondria, unleashing the apoptotic cascade.