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 kinase 1 (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 nexin 9 (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.

富马酸水合酶 (FH) 突变会导致遗传性平滑肌瘤病和肾细胞癌¹ 。肾脏中 FH 的缺失会通过致癌代谢物富马酸盐的积累引发多种致癌信号级联反应² 。然而，尽管 FH 丧失的长期后果已被描述，但迄今为止尚未研究其急性反应。在这里，我们生成了一个诱导型小鼠模型来研究肾脏中 FH 丢失的时间顺序。我们发现 FH 的丢失会导致线粒体形态的早期改变以及线粒体 DNA (mtDNA) 释放到细胞质中，从而触发环 GMP-AMP 合酶 (cGAS) 的激活-干扰素基因刺激剂 (STING)- TANK 结合激酶 1 (TBK1) 通路并刺激炎症反应，该炎症反应也部分依赖于视黄酸诱导基因 I (RIG-I)。从机制上讲，我们表明这种表型是由富马酸介导的，并通过线粒体衍生的囊泡以取决于分选 nexin 9 (SNX9) 的方式选择性发生。这些结果表明，细胞内富马酸水平的增加会诱导线粒体网络的重塑和线粒体衍生囊泡的产生，从而允许线粒体DNA在细胞质中释放，并随后激活先天免疫反应。