Fumarate induces vesicular release of mtDNA to drive innate immunity

Vincent Zecchini, Vincent Paupe, Irene Herranz-Montoya, Joëlle Janssen, Inge M. N. Wortel, Jordan L. Morris, Ashley Ferguson, Suvagata Roy Chowdury, Marc Segarra-Mondejar, Ana S. H. Costa, Gonçalo C. Pereira, Laura Tronci, Timothy Young, Efterpi Nikitopoulou, Ming Yang, Dóra Bihary, Federico Caicci, Shun Nagashima, Alyson Speed, Kalliopi Bokea, Zara Baig, Shamith Samarajiwa, Maxine Tran, Thomas Mitchell, Mark Johnson, Julien Prudent () and Christian Frezza ()
Additional contact information
Vincent Zecchini: University of Cambridge
Vincent Paupe: University of Cambridge
Irene Herranz-Montoya: University of Cambridge
Joëlle Janssen: University of Cambridge
Inge M. N. Wortel: University of Cambridge
Jordan L. Morris: University of Cambridge
Ashley Ferguson: University of Cambridge
Suvagata Roy Chowdury: University of Cambridge
Marc Segarra-Mondejar: University of Cambridge
Ana S. H. Costa: University of Cambridge
Gonçalo C. Pereira: University of Cambridge
Laura Tronci: University of Cambridge
Timothy Young: University of Cambridge
Efterpi Nikitopoulou: University of Cambridge
Ming Yang: University of Cambridge
Dóra Bihary: University of Cambridge
Federico Caicci: University of Padova
Shun Nagashima: University of Cambridge
Alyson Speed: University of Cambridge
Kalliopi Bokea: UCL
Zara Baig: UCL
Shamith Samarajiwa: University of Cambridge
Maxine Tran: UCL
Thomas Mitchell: Wellcome Genome Campus
Mark Johnson: University of Cambridge
Julien Prudent: University of Cambridge
Christian Frezza: University of Cambridge

Nature, 2023, vol. 615, issue 7952, 499-506

Abstract: 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 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.

Date: 2023
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DOI: 10.1038/s41586-023-05770-w

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