2026-04-29T04:09:25Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/231102024-11-29T13:32:48Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597
Repisalud
author
Zecchini, Vincent
author
Paupe, Vincent
author
Herranz-Montoya, Irene
author
Janssen, Joëlle
author
Wortel, Inge M N
author
Morris, Jordan L
author
Ferguson, Ashley
author
Chowdury, Suvagata Roy
author
Segarra-Mondejar, Marc
author
Costa, Ana SH
author
Pereira, Gonçalo C
author
Tronci, Laura
author
Young, Timothy
author
Nikitopoulou, Efterpi
author
Yang, Ming
author
Bihary, Dóra
author
Caicci, Federico
author
Nagashima, Shun
author
Speed, Alyson
author
Bokea, Kalliopi
author
Baig, Zara
author
Samarajiwa, Shamith
author
Tran, Maxine
author
Mitchell, Thomas
author
Johnson, Mark
author
Prudent, Julien
author
Frezza, Christian
funder
UK Research and Innovation
funder
Unión Europea
funder
Unión Europea. Comisión Europea. European Research Council (ERC)
funder
Cancer Research UK (Reino Unido)
funder
Medical Research Council UK (MRC)
funder
WWCR grant
funder
CRUK Programme Foundation
funder
Swiss National Science Foundation (SNSF)
2024-09-16T08:17:07Z
2024-09-16T08:17:07Z
2023-03
Nature . 2023 ;615(7952):499-506.
https://hdl.handle.net/20.500.12105/23110
36890229
10.1038/s41586-023-05770-w
1476-4687
Nature
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.
eng
Fumarate induces vesicular release of mtDNA to drive innate immunity
research article