BAK/BAX macropores facilitate mitochondrial herniation and mtDNA efflux during apoptosis
BAK/BAX macropores facilitate mitochondrial herniation and mtDNA efflux during apoptosis
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DOI：
10.1126/science.aao6047
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发表时间：
2018-02-23
期刊：
影响因子：
56.9
通讯作者：
Kile, Benjamin T.
中科院分区：
文献类型：
--
作者：
McArthur, Kate;Whitehead, Lachlan W.;Kile, Benjamin T.
线粒体凋亡是由Bak和Bax介导的，Bak和Bax是两种诱导线粒体外膜通透性的蛋白质，导致细胞色素C释放和凋亡胱天蛋白酶的激活。在没有活性胱天蛋白酶的情况下，线粒体DNA（mtDNA）会触发先天的免疫CGA/刺激途径，从而导致垂死的细胞分泌I型Intyferon。 CGA如何获得MTDNA的访问尚不清楚。我们使用活细胞晶格灯场显微镜检查小鼠胚胎成纤维细胞中的线粒体网络。我们发现，在BAK/BAX激活和细胞色素C损失之后，线粒体网络破裂，外膜出现在外膜中。这些BAK/BAX大孔使线粒体内膜内部疝进入细胞质，并带有线粒体基质组件，包括线粒体基因组。凋亡的胱天蛋白酶没有阻止疝气，而是拆除了垂死的细胞以抑制mtDNA诱导的先天免疫信号传导。
Mitochondrial apoptosis is mediated by BAK and BAX, two proteins that induce mitochondrial outer membrane permeabilization, leading to cytochrome c release and activation of apoptotic caspases. In the absence of active caspases, mitochondrial DNA (mtDNA) triggers the innate immune cGAS/STING pathway, causing dying cells to secrete type I interferon. How cGAS gains access to mtDNA remains unclear. We used live-cell lattice light-sheet microscopy to examine the mitochondrial network in mouse embryonic fibroblasts. We found that after BAK/BAX activation and cytochrome c loss, the mitochondrial network broke down and large BAK/BAX pores appeared in the outer membrane. These BAK/BAX macropores allowed the inner mitochondrial membrane to herniate into the cytosol, carrying with it mitochondrial matrix components, including the mitochondrial genome. Apoptotic caspases did not prevent herniation but dismantled the dying cell to suppress mtDNA-induced innate immune signaling.