Fumarate induces vesicular release of mtDNA to drive innate immunity

• Published in: Nature (London) Vol. 615; no. 7952; pp. 499 - 506
• Main Authors: Zecchini, Vincent, Paupe, Vincent, Herranz-Montoya, Irene, Janssen, Joëlle, Wortel, Inge M. N., Morris, Jordan L., Ferguson, Ashley, Chowdury, Suvagata Roy, Segarra-Mondejar, Marc, Costa, Ana S. H., Pereira, Gonçalo C., Tronci, Laura, Young, Timothy, Nikitopoulou, Efterpi, Yang, Ming, Bihary, Dóra, Caicci, Federico, Nagashima, Shun, Speed, Alyson, Bokea, Kalliopi, Baig, Zara, Samarajiwa, Shamith, Tran, Maxine, Mitchell, Thomas, Johnson, Mark, Prudent, Julien, Frezza, Christian
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16.03.2023; Nature Publishing Group
• Subjects: 13/106; 13/109; 13/89; 14; 14/19; 38; 38/91; 631/45/320; 631/80/304; 631/80/642/333; Animals; Cells; Chemokines; Cloning; Cytokines; Cytosol; Cytosol - metabolism; DNA, Mitochondrial - metabolism; Enzymes; Fibroids; Fumarase; Fumarate Hydratase - genetics; Fumarate Hydratase - metabolism; Fumarates - metabolism; Genotype & phenotype; Humanities and Social Sciences; Immune response; Immune system; Immunity, Innate; Inflammation; Inflammatory response; Innate immunity; Kidney - enzymology; Kidney - metabolism; Kidney - pathology; Kidney cancer; Kidneys; Kinases; Metabolism; Mice; Mitochondria - enzymology; Mitochondria - genetics; Mitochondria - metabolism; Mitochondria - pathology; Mitochondrial DNA; Morphology; multidisciplinary; Mutation; Nexin; Phenotypes; Proteins; Renal cell carcinoma; Science; Science (multidisciplinary); Signal transduction; Stimulators; Tumors; Vesicles
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-023-05770-w

Mutations in fumarate hydratase (FH) cause hereditary leiomyomatosis and renal cell carcinoma 1 . Loss of FH in the kidney elicits several oncogenic signalling cascades through the accumulation of the oncometabolite fumarate 2 . 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. Fumarate metabolism regulates the innate immune response through a mechanism in which high levels of fumarate result in the generation of mitochondrial-derived vesicles and the release of mitochondrial DNA into the cytosol, which activates inflammatory pathways.