Zecchini, Vincent;
Paupe, Vincent;
Herranz-Montoya, Irene;
Janssen, Joelle;
Wortel, Inge MN;
Morris, Jordan L;
Ferguson, Ashley;
... Frezza, Christian; + view all
(2023)
Fumarate induces vesicular release of mtDNA to drive innate immunity.
Nature
, 615
pp. 499-506.
10.1038/s41586-023-05770-w.
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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.
| Type: | Article |
|---|---|
| Title: | Fumarate induces vesicular release of mtDNA to drive innate immunity |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1038/s41586-023-05770-w |
| Publisher version: | https://doi.org/10.1038/s41586-023-05770-w |
| Language: | English |
| Additional information: | This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. |
| Keywords: | Science & Technology, Multidisciplinary Sciences, Science & Technology - Other Topics, RIG-I, MITOCHONDRIAL, DNA, FH, HYDRATASE, EXPRESSION, MUTATIONS, PROTEINS, PATHWAY, CANCER |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Surgery and Interventional Sci UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Surgery and Interventional Sci > Department of Surgical Biotechnology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10168998 |
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