Succinate Dehydrogenase Supports Metabolic Repurposing of Mitochondria to Drive Inflammatory Macrophages

Evanna L. Mills, Beth Kelly, Angela Logan, Ana S.H. Costa, Mukund Varma, Clare E. Bryant, Panagiotis Tourlomousis, J. Henry M. Däbritz, Eyal Gottlieb, Isabel Latorre, Sinéad C. Corr, Gavin McManus, Dylan Ryan, Howard T. Jacobs, Marten Szibor, Ramnik J. Xavier, Thomas Braun, Christian Frezza, Michael P. Murphy, Luke A. O'Neill

Research output: Contribution to journalArticlepeer-review

Abstract

Activated macrophages undergo metabolic reprogramming, which drives their pro-inflammatory phenotype, but the mechanistic basis for this remains obscure. Here, we demonstrate that upon lipopolysaccharide (LPS) stimulation, macrophages shift from producing ATP by oxidative phosphorylation to glycolysis while also increasing succinate levels. We show that increased mitochondrial oxidation of succinate via succinate dehydrogenase (SDH) and an elevation of mitochondrial membrane potential combine to drive mitochondrial reactive oxygen species (ROS) production. RNA sequencing reveals that this combination induces a pro-inflammatory gene expression profile, while an inhibitor of succinate oxidation, dimethyl malonate (DMM), promotes an anti-inflammatory outcome. Blocking ROS production with rotenone by uncoupling mitochondria or by expressing the alternative oxidase (AOX) inhibits this inflammatory phenotype, with AOX protecting mice from LPS lethality. The metabolic alterations that occur upon activation of macrophages therefore repurpose mitochondria from ATP synthesis to ROS production in order to promote a pro-inflammatory state.

Original languageEnglish (US)
Pages (from-to)457-470.e13
JournalCell
Volume167
Issue number2
DOIs
StatePublished - Oct 6 2016
Externally publishedYes

Keywords

  • immunometabolism
  • innate immunity
  • macrophage
  • reverse electron transport
  • succinate
  • succinate dehydrogenase
  • toll-like receptors

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

Fingerprint

Dive into the research topics of 'Succinate Dehydrogenase Supports Metabolic Repurposing of Mitochondria to Drive Inflammatory Macrophages'. Together they form a unique fingerprint.

Cite this