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Fumarate induces vesicular release of mtDNA to drive innate immunity

Published 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 M. N. 

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

Acknowledgements: This work was supported by the Medical Research Council to J.P. (MC_UU_00015/7 and MC_UU_00028/5) and C.F. (MRC_MC_UU_12022/6). V.P. was supported by the European Union’s Horizon 2020 research and innovation programme (MITODYN-749926) (2017–2019). V.Z. was supported by a WWCR grant (14-0319). I.M.N.W. was supported by a grant from the Nora Baart Foundation. T.Y. was supported by the European Research Council Consolidator Award to C.F. (ERC819920). E.N. was supported by a CRUK Programme Foundation award to C.F. (C51061/A27453). J.L.M. was supported by a MRC-funded graduate student fellowship. G.C.P. is supported by the Swiss National Science Foundation (Synergia project CRSII5_180326). S.N. was the recipient of a Daiichi Sankyo Foundation of Life Science postdoctoral fellowship (2017–2019). A.F. was supported by a Rotary Global Grant. M.S.-M is supported by CRUK. We thank M. Micaroni for the quantification of the volume of mitochondria from the TEM in Extended Data Fig. 2j. We apologize for some relevant studies not being cited in the manuscript owing to space limitations.

Keywords

Article, /631/80/304, /631/45/320, /631/80/642/333, /13/106, /13/89, /13/109, /14, /14/19, /38, /38/91, article

Journal Title

Nature

Conference Name

Journal ISSN

0028-0836
1476-4687

Volume Title

615

Publisher

Nature Publishing Group UK