Fumarate induces vesicular release of mtDNA to drive innate immunity.

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 t

SUBMITTER: Zecchini V 

PROVIDER: S-EPMC10017517 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature