Itaconate controls its own synthesis via feedback-inhibition of reverse TCA cycle activity at IDH2

Alexander Heinz, Yannic Nonnenmacher, Antonia Henne, Michelle Amirah Khalil, Ketlin Bejkollari, Catherine Dostert, Shirin Hosseini, Oliver Goldmann, Wei He, Roberta Palorini, Charlène Verschueren, Martin Korte, Ferdinando Chiaradonna, Eva Medina, Dirk Brenner, Karsten Hiller*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Macrophages undergo extensive metabolic reprogramming during classical pro-inflammatory polarization (M1-like). The accumulation of itaconate has been recognized as both a consequence and mediator of the inflammatory response. In this study we first examined the specific functions of itaconate inside fractionated mitochondria. We show that M1 macrophages produce itaconate de novo via aconitase decarboxylase 1 (ACOD1) inside mitochondria. The carbon for this reaction is not only supplied by oxidative TCA cycling, but also through the reductive carboxylation of α-ketoglutarate by isocitrate dehydrogenase (IDH). While macrophages are capable of sustaining a certain degree of itaconate production during hypoxia by augmenting the activity of IDH-dependent reductive carboxylation, we demonstrate that sufficient itaconate synthesis requires a balance of reductive and oxidative TCA cycle metabolism in mouse macrophages. In comparison, human macrophages increase itaconate accumulation under hypoxic conditions by augmenting reductive carboxylation activity. We further demonstrated that itaconate attenuates reductive carboxylation at IDH2, restricting its own production and the accumulation of the immunomodulatory metabolites citrate and 2-hydroxyglutarate. In line with this, reductive carboxylation is enhanced in ACOD1-depleted macrophages. Mechanistically, the inhibition of IDH2 by itaconate is linked to the alteration of the mitochondrial NADP+/NADPH ratio and competitive succinate dehydrogenase inhibition. Taken together, our findings extend the current model of TCA cycle reprogramming during pro-inflammatory macrophage activation and identified novel regulatory properties of itaconate.

Original languageEnglish
Article number166530
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1868
Issue number12
Early online date28 Aug 2022
DOIs
Publication statusE-pub ahead of print - 28 Aug 2022

Keywords

  • 2-hydroxyglutarate
  • Mitochondrial metabolism
  • Proinflammatory macrophage
  • Redox balance
  • Reductive carboxylation
  • TCA cycle

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