德国科隆大学Christian Frezza等研究人员合作发现，富马酸可诱导mtDNA的囊泡释放来驱动先天免疫。相关论文于2023年3月8日在线发表在《自然》杂志上。

研究人员产生了一个可诱导的小鼠模型来研究肾脏中富马酸水合酶（FH）丢失的时间顺序。结果表明，FH的缺失导致线粒体形态的早期改变和线粒体DNA（mtDNA）释放到细胞液中，在那里它引发了环状GMP-AMP合成酶（cGAS）-干扰素基因刺激因子（STING）-TANK结合激酶1（TBK1）途径的激活，并刺激了部分依赖于视黄酸诱导基因I（RIG-I）的炎症反应。从机制上讲，这种表型是由富马酸介导的，并以依赖sorting nexin 9（SNX9）的方式选择性地通过线粒体衍生的囊泡发生。这些结果显示，细胞内富马酸水平的增加诱发了线粒体网络的重塑和线粒体源性囊泡的产生，这使得mtDNA在细胞膜上的释放和随后先天免疫反应的激活。

研究人员表示，FH的突变导致遗传性白肌病和肾细胞癌。肾脏中FH的缺失通过原癌代谢物富马酸的积累引发了一些致癌信号级联。然而，尽管已经描述了FH缺失的长期后果，但迄今为止还没有调查过急性反应。

附：英文原文

Title: Fumarate induces vesicular release of mtDNA to drive innate immunity

Author: Zecchini, Vincent, Paupe, Vincent, Herranz-Montoya, Irene, Janssen, Jolle, Wortel, Inge M. N., Morris, Jordan L., Ferguson, Ashley, Chowdury, Suvagata Roy, Segarra-Mondejar, Marc, Costa, Ana S. H., Pereira, Gonalo C., Tronci, Laura, Young, Timothy, Nikitopoulou, Efterpi, Yang, Ming, Bihary, Dra, Caicci, Federico, Nagashima, Shun, Speed, Alyson, Bokea, Kalliopi, Baig, Zara, Samarajiwa, Shamith, Tran, Maxine, Mitchell, Thomas, Johnson, Mark, Prudent, Julien, Frezza, Christian

Issue&Volume: 2023-03-08

Abstract: Mutations in fumarate hydratase (FH) cause hereditary leiomyomatosis and renal cell carcinoma1. Loss of FH in the kidney elicits several oncogenic signalling cascades through the accumulation of the oncometabolite fumarate2. However, although the long-term consequences of FH loss have been described, the acute response has not so far been investigated. Here we generated an inducible mouse model to study the chronology of FH loss in the kidney. We show that loss of FH leads to early alterations of mitochondrial morphology and the release of mitochondrial DNA (mtDNA) into the cytosol, where it triggers the activation of the cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING)–TANK-binding kinase1 (TBK1) pathway and stimulates an inflammatory response that is also partially dependent on retinoic-acid-inducible gene I (RIG-I). Mechanistically, we show that this phenotype is mediated by fumarate and occurs selectively through mitochondrial-derived vesicles in a manner that depends on sorting nexin9 (SNX9). These results reveal that increased levels of intracellular fumarate induce a remodelling of the mitochondrial network and the generation of mitochondrial-derived vesicles, which allows the release of mtDNAin the cytosol and subsequent activation of the innate immune response.

DOI: 10.1038/s41586-023-05770-w

Source: https://www.nature.com/articles/s41586-023-05770-w