美国加州大学圣地亚哥分校Michael Karin研究组发现氧化的 DNA 片段通过 mPTP 和 VDAC 依赖性通道离开线粒体，激活 NLRP3 炎症小体和干扰素信号传导。相关论文发表在2022年7月13日出版的《免疫》杂志上。

他们发现多种 NLRP3 炎症小体激活子迅速刺激单向转运体介导的钙摄取，以打开线粒体通透性转换孔 (mPTP) 并触发 VDAC 寡聚化。这与诱导 Ox-线粒体 DNA (mtDNA)生成的 mtDNA 或活性氧物质无关。在线粒体内，Ox-mtDNA 要么被 DNA 糖基化酶 OGG1 修复，要么被核酸内切酶 FEN1 切割成 500-650 bp 的片段，这些片段通过 mPTP 和 VDAC 依赖性通道离开线粒体以启动胞质 NLRP3 炎性体激活。Ox-mtDNA 片段还激活 cGAS-STING 信号并产生促炎细胞外 DNA。了解这一过程将推动慢性炎症性疾病潜在治疗方法的开发，例如抑制小鼠白细胞介素 1β (IL-1β) 产生和 mtDNA 释放的 FEN1 抑制剂。

据了解，逃逸应激线粒体的mtDNA通过 cGAS-STING 通路激活引发炎症，当被氧化 (Ox-mtDNA) 时，它与细胞溶质 NLRP3 结合，从而触发炎性体激活。然而，尚不清楚 Ox-mtDNA 如何以及以何种形式离开非凋亡巨噬细胞中的应激线粒体。

附：英文原文

Title: Oxidized DNA fragments exit mitochondria via mPTP- and VDAC-dependent channels to activate NLRP3 inflammasome and interferon signaling

Author: Hongxu Xian, Kosuke Watari, Elsa Sanchez-Lopez, Joseph Offenberger, Janset Onyuru, Harini Sampath, Wei Ying, Hal M. Hoffman, Gerald S. Shadel, Michael Karin

Issue&Volume: 2022-07-13

Abstract: Mitochondrial DNA (mtDNA) escaping stressed mitochondria provokes inflammation viacGAS-STING pathway activation and, when oxidized (Ox-mtDNA), it binds cytosolic NLRP3,thereby triggering inflammasome activation. However, it is unknown how and in whichform Ox-mtDNA exits stressed mitochondria in non-apoptotic macrophages. We found thatdiverse NLRP3 inflammasome activators rapidly stimulated uniporter-mediated calciumuptake to open mitochondrial permeability transition pores (mPTP) and trigger VDAColigomerization. This occurred independently of mtDNA or reactive oxygen species,which induce Ox-mtDNA generation. Within mitochondria, Ox-mtDNA was either repairedby DNA glycosylase OGG1 or cleaved by the endonuclease FEN1 to 500–650 bp fragmentsthat exited mitochondria via mPTP- and VDAC-dependent channels to initiate cytosolicNLRP3 inflammasome activation. Ox-mtDNA fragments also activated cGAS-STING signalingand gave rise to pro-inflammatory extracellular DNA. Understanding this process willadvance the development of potential treatments for chronic inflammatory diseases,exemplified by FEN1 inhibitors that suppressed interleukin-1β (IL-1β) production andmtDNA release in mice.

DOI: 10.1016/j.immuni.2022.06.007

Source: https://www.cell.com/immunity/fulltext/S1074-7613(22)00280-1