Mitochondrial fumarate implicated in inflammation

Metabolic reprogramming in macrophages is known to contribute to dysregulated immune responses in rheumatic diseases including systemic lupus erythematosus (SLE), but the underlying mechanisms are unclear. Research led by Luke O’Neill now published in Nature suggests that inhibition of the tricarboxylic acid (TCA) cycle enzyme fumarate hydratase (FH) leads to the release of nucleic acids that then promote an inflammatory response.

“We found that the suppression of FH leads to the release of mitochondrial RNA (mtRNA), which in turn drives the release of type I interferons,” explains Alexander Hooftman, co-first author of the publication along with Christian Peace and Dylan Ryan. “Type I interferons are highly inflammatory cytokines which are predominantly associated with an antiviral immune response, but their excessive release is associated with certain inflammatory disorders such as SLE.”