Itaconate Drives MtRNA-mediated Type I Interferon Production Through Inhibition of Succinate Dehydrogenase

Overview

Journal Nat Metab

Publisher Springer Nature

Specialty Endocrinology

Date 2024 Oct 15

PMID 39406969

Authors

Shane M OCarroll

Christian G Peace

Juliana E Toller-Kawahisa

Yukun Min

Alexander Hooftman

Sara Charki

Louise Kehoe

Maureen J OSullivan

Aline Zoller

Anne F Mcgettrick

Alessia Zotta

Emily A Day

Maria Simarro

Neali Armstrong

Justin P Annes

Luke A J ONeill

Affiliations

Soon will be listed here.

Abstract

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.

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