Fumarate induces vesicular release of mtDNA to drive innate immunity

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

doi:10.1038/s41586-023-05770-w

articleNatureMar 8, 2023HYBRID OA

Fumarate induces vesicular release of mtDNA to drive innate immunity

VZVincent Zecchini VPVincent Paupe IHIrene Herranz-Montoya JJJoëlle J. E. Janssen IMInge M. N. Wortel

University of Cambridge · Medical Research Council · +15 more institutions

PubMed

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Abstract

Abstract 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…

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Topics & keywords

Topics

Keywords

Fumarase
Cell biology
Biology
Innate immune system
Mitochondrion
Mitochondrial DNA
Dimethyl fumarate
mitochondrial fusion

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