Journal Article

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

Armstrong, Neali, Simarro, Maria, Hooftman, Alexander, Annes, Justin P., O’Sullivan, Maureen J., Peace, Christian G., O’Neill, Luke A. J., Min, Yukun, Zoller, Aline, Zotta, Alessia, O’Carroll, Shane M., Kehoe, Louise, Charki, Sara, Toller-Kawahisa, Juliana E., Day, Emily A., Mcgettrick, Anne F.

2024

Overview

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. O’Carroll and Peace et al. provide a mechanism for the induction of type I interferons by the immunomodulatory compound itaconate, which involves inhibition of succinate dehydrogenase and release of mitochondrial double-stranded RNA.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/250/2504/342 / 631/250/262/2106/2518 / 631/443/319/333 / 631/45/127/1212 / Animals / Biomedical and Life Sciences / Citric Acid Cycle - drug effects / DEAD Box Protein 58 - metabolism / Dehydrogenases / Double-stranded RNA / Experiments / Humans / Immunomodulation / Interferon / Interferon Type I - metabolism / Interferon-Induced Helicase, IFIH1 - metabolism / Letter / Life Sciences / Macrophages / Macrophages - drug effects / Macrophages - metabolism / Metabolites / Mice / Mitochondria / Mitochondria - drug effects / Mitochondria - metabolism / Receptors, Immunologic / RNA, Double-Stranded - metabolism / RNA, Mitochondrial - metabolism / Succinate dehydrogenase / Succinate Dehydrogenase - antagonists & inhibitors / Succinate Dehydrogenase - metabolism / Succinates - metabolism / Succinates - pharmacology / Tricarboxylic acid cycle / Tumors / Variance analysis / Voltage-Dependent Anion Channel 1 - antagonists & inhibitors / Voltage-Dependent Anion Channel 1 - metabolism / β-Interferon