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Fumarate induces vesicular release of mtDNA to drive innate immunity.
Zecchini, Vincent; Paupe, Vincent; Herranz-Montoya, Irene; Janssen, Joëlle; Wortel, Inge M N; Morris, Jordan L; Ferguson, Ashley; Chowdury, Suvagata Roy; Segarra-Mondejar, Marc; Costa, Ana S H; Pereira, Gonçalo C; Tronci, Laura; Young, Timothy; Nikitopoulou, Efterpi; Yang, Ming; Bihary, Dóra; Caicci, Federico; Nagashima, Shun; Speed, Alyson; Bokea, Kalliopi; Baig, Zara; Samarajiwa, Shamith; Tran, Maxine; Mitchell, Thomas; Johnson, Mark; Prudent, Julien; Frezza, Christian.
Afiliación
  • Zecchini V; Medical Research Council Cancer Unit, University of Cambridge, Cambridge, UK.
  • Paupe V; Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK.
  • Herranz-Montoya I; Medical Research Council Cancer Unit, University of Cambridge, Cambridge, UK.
  • Janssen J; Molecular Oncology Programme, Growth Factors, Nutrients and Cancer Group Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain.
  • Wortel IMN; Medical Research Council Cancer Unit, University of Cambridge, Cambridge, UK.
  • Morris JL; Human and Animal Physiology, Wageningen University and Research, Wageningen, The Netherlands.
  • Ferguson A; Medical Research Council Cancer Unit, University of Cambridge, Cambridge, UK.
  • Chowdury SR; Department of Data Science, Institute for Computing and Information Sciences, Radboud University, Nijmegen, The Netherlands.
  • Segarra-Mondejar M; Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK.
  • Costa ASH; Medical Research Council Cancer Unit, University of Cambridge, Cambridge, UK.
  • Pereira GC; Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK.
  • Tronci L; Medical Research Council Cancer Unit, University of Cambridge, Cambridge, UK.
  • Young T; CECAD Research Centre, University of Cologne, Cologne, Germany.
  • Nikitopoulou E; Medical Research Council Cancer Unit, University of Cambridge, Cambridge, UK.
  • Yang M; Matterworks, Somerville, MA, USA.
  • Bihary D; Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK.
  • Caicci F; Medical Research Council Cancer Unit, University of Cambridge, Cambridge, UK.
  • Nagashima S; Cogentech SRL Benefit Corporation, Milan, Italy.
  • Speed A; Medical Research Council Cancer Unit, University of Cambridge, Cambridge, UK.
  • Bokea K; Medical Research Council Cancer Unit, University of Cambridge, Cambridge, UK.
  • Baig Z; Medical Research Council Cancer Unit, University of Cambridge, Cambridge, UK.
  • Samarajiwa S; CECAD Research Centre, University of Cologne, Cologne, Germany.
  • Tran M; Medical Research Council Cancer Unit, University of Cambridge, Cambridge, UK.
  • Mitchell T; VIB KU Leuven Center for Cancer Biology, Leuven, Belgium.
  • Johnson M; Department of Biology, University of Padova, Padova, Italy.
  • Prudent J; Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK.
  • Frezza C; Laboratory of Regenerative Medicine, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.
Nature ; 615(7952): 499-506, 2023 03.
Article en En | MEDLINE | ID: mdl-36890229
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: ADN Mitocondrial / Fumaratos / Inmunidad Innata / Mitocondrias Límite: Animals Idioma: En Revista: Nature Año: 2023 Tipo del documento: Article Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: ADN Mitocondrial / Fumaratos / Inmunidad Innata / Mitocondrias Límite: Animals Idioma: En Revista: Nature Año: 2023 Tipo del documento: Article Pais de publicación: Reino Unido