Itaconate drives mtRNA-mediated type I interferon production through inhibition of succinate dehydrogenase

• DOI: 10.1038/s42255-024-01145-1
• Publication Date: 2024-10-15T10:02:28Z
• Authors: Shane M. O’Carroll; Christian G. Peace; Juliana E. Toller...; Yukun Min; Alexander Hooftman; Sara Charki; Louise Kehoe; Maureen J. O’Sull...; Aline Zoller; Anne F. Mcgettrick; Alessia Zotta; Emily A. Day; Maria Simarro; Neali Armstrong; Justin P. Annes; Luke A. J. O’Neill
• Keywords: Interferon γ

Itaconate is one of the most highly upregulated metabolites in inflammatory macrophages and has been shown to have immunomodulatory properties. Here, we show that itaconate promotes type I interferon production through inhibition of succinate dehydrogenase (SDH). Using pharmacological and genetic approaches, we show that SDH inhibition by endogenous or exogenous itaconate leads to double-stranded mitochondrial RNA (mtRNA) release, which is dependent on the mitochondrial pore formed by VDAC1. In addition, the double-stranded RNA sensors MDA5 and RIG-I are required for IFNβ production in response to SDH inhibition by itaconate. Collectively, our data indicate that inhibition of SDH by itaconate links TCA cycle modulation to type I interferon production through mtRNA release.