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Fumarate induces vesicular release of mtDNA to drive innate immunity.

Accepted version
Peer-reviewed

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Authors

Paupe, Vincent 
Herranz-Montoya, Irene  ORCID logo  https://orcid.org/0000-0001-9644-0585
Janssen, Joëlle 
Wortel, Inge MN 

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.

Description

Keywords

Kidney Disease, Genetics, Prevention, 2.1 Biological and endogenous factors, 2 Aetiology

Journal Title

Nature

Conference Name

Journal ISSN

0028-0836
1476-4687

Volume Title

Publisher

Springer Science and Business Media LLC
Sponsorship
MRC (MC_UU_00028/5)
European Commission Horizon 2020 (H2020) Marie Sk?odowska-Curie actions (749926)
MRC (MC_UU_00015/7)
Medical Research Council (MC_UU_00015/7)
Medical Research Council (MC_UU_12022/6)
Swiss National Science Foundation (SNSF) (CRSII5_180326/1)
Cancer Research UK (A27453)
European Research Council (819920)