According to the endosymbiotic theory, most of the DNA of the original bacterial endosymbiont has been lost or transferred to the nucleus, leaving a much smaller (∼16 kb in mammals), circular molecule that is the present-day mitochondrial DNA (mtDNA). The ability of mtDNA to escape mitochondria and integrate into the nuclear genome was discovered in budding yeast, along with genes that regulate this process. Mitochondria have emerged as key regulators of innate immunity, and it is now recognized that mtDNA released into the cytoplasm, outside of the cell, or into circulation activates multiple innate immune signaling pathways. Here, we first review the mechanisms through which mtDNA is released into the cytoplasm, including several inducible mitochondrial pores and defective mitophagy or autophagy. Next, we cover how the different forms of released mtDNA activate specific innate immune nucleic acid sensors and inflammasomes. Finally, we discuss how intracellular and extracellular mtDNA release, including circulating cell-free mtDNA that promotes systemic inflammation, are implicated in human diseases, bacterial and viral infections, senescence and aging.

中文翻译：

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先天免疫信号传导中的线粒体 DNA 释放


根据内共生理论，原始细菌内共生体的大部分 DNA 已经丢失或转移到细胞核中，留下一个更小的（哺乳动物中约为 16 kb）圆形分子，即当今的线粒体 DNA (mtDNA)。在芽殖酵母中发现了线粒体DNA逃离线粒体并整合到核基因组中的能力，以及调节这一过程的基因。线粒体已成为先天免疫的关键调节因子，现在人们认识到，释放到细胞质、细胞外或循环中的线粒体DNA会激活多种先天免疫信号通路。在这里，我们首先回顾 mtDNA 释放到细胞质中的机制，包括几个可诱导的线粒体孔和有缺陷的线粒体自噬或自噬。接下来，我们将介绍不同形式的释放线粒体 DNA 如何激活特定的先天免疫核酸传感器和炎症小体。最后，我们讨论了细胞内和细胞外 mtDNA 的释放，包括促进全身炎症的循环游离细胞 mtDNA，如何与人类疾病、细菌和病毒感染、衰老和衰老有关。