线粒体DNA“大逃亡”?Science首次揭示这一微妙时刻
2018/02/26
线粒体DNA是线粒体中的遗传物质。最新一期《Science》发表一篇文章揭示:当细胞凋亡时,这类DNA会从线粒体内“逃逸”。更重要的是,这一“大逃亡”是引发自身免疫性疾病的关键因素。


Monash BDI researchers Professor Ben Kile (左) 、Dr Kate McArthur

线粒体是维持细胞能量供给、有氧呼吸的主要场所。一旦遭受破坏,它们能够引发机体免疫反应,从而造成更大的伤害。因为线粒体DNA(mtDNA)与细菌DNA有很多相似之处,所以一旦细胞接触到逃脱线粒体的DNA,就会接收到类似于病原体入侵的信号,从而激活免疫系统。

虽然mtDNA的释放被认为是引发自身免疫性疾病的原因之一,但是这类DNA如何从线粒体内逃脱?这一直是个谜。


DOI: 10.1126/science.aao6047

现在,借助于先进的显微镜系统,莫纳什大学生物医学研究所(BDI)的Benjamin Kile教授团队发现并记录下这一过程。

在细胞凋亡过程中过程中,线粒体DNA(绿色)“逃离”线粒体(红色)。视频来源:Dr Kate McArthur (Monash BDI) and Dr Lachlan Whitehead (WEHI) and The Advanced Imaging Centre at Janelia Research Campus。

Benjamin Kile团队发现,当细胞凋亡时,两种蛋白——BAK和BAX会被激活。“这些‘杀手’蛋白会在线粒体外膜上‘开孔’,导致细胞内容物溢出,包括mtDNA。” Kile教授解释道。

这一微妙的时刻被蒙纳士大学的Titan Krios冷冻电镜、Eliza Hall研究所的晶格层光显微镜捕捉到。其中,晶格层光显微镜由诺贝尔奖获得者Eric Betzig开发,能够以高分辨率观察活体细胞。

BAK和BAX旨在终结细胞,但是溢出的DNA会造成间接伤害。如果已不能正常控制,mtDNA会引发免疫反应、带来炎症。“这一发现是罕见的,但是它能够加深对于自身免疫性疾病的理解。”研究人员强调道。

参考资料:

DNA gets away: Scientists catch the rogue molecule that can trigger autoimmunity

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  • BAK/BAX macropores facilitate mitochondrial herniation and mtDNA efflux during apoptosis

    INTRODUCTION There has been an explosion of interest in the role of cell death pathways and damage-associated molecular pattern (DAMP) signaling in shaping inflammatory and immune responses. Mitochondria are central to the intrinsic apoptosis pathway, the classical form of programmed cell death. Several mitochondrial constituents have been implicated as DAMPs, including mitochondrial DNA (mtDNA). Recent work has shown that activation of intrinsic BAK and BAX–mediated apoptosis results in mtDNA-dependent triggering of the innate immune cGAS/STING pathway, resulting in type I interferon production by dying cells. The apoptotic caspase cascade normally functions to suppress this mtDNA-induced cGAS/STING signaling, rendering apoptosis “immunologically silent.” RATIONALE It is thought that during apoptosis, mtDNA is released into the cytoplasm. In addition to apoptosis, loss of mtDNA from the matrix has been associated with conditions including HIV and dengue infection, calcium overload, irradiation, or inflammatory diseases such as systemic lupus erythematosus or rheumatoid arthritis. However, mtDNA escape from the mitochondria has not been documented in real time. RESULTS Using a combination of live-cell lattice light-sheet microscopy, 3D structured illumination microscopy, correlative light electron microscopy, and electron cryotomography, 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 membrane an outlet through which it herniated, carrying with it mitochondrial matrix components, including the mitochondrial genome. A subset of the herniated inner membranes lost their integrity, allowing mtDNA to be exposed to the cytoplasm. CONCLUSION An extensive literature suggests that mtDNA is found outside the mitochondria—and, indeed, outside the cell—in a wide range of circumstances. Our study provides a mechanistic description of its release from the mitochondria. mtDNA release from mitochondria during apoptosis occurs irrespective of caspase activity, but in normal cells, caspases attenuate the subsequent cGAS/STING-mediated interferon response by driving rapid cellular collapse and clearance. Mitochondrial herniation might represent a general mechanism of mtDNA escape. In addition to BAK and BAX oligomerization, there may be alternative triggers—for example, other pore-forming proteins (host- or pathogen-derived) or mitochondrial stresses—that lead to the occurrence of this phenomenon.

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