Succinate Dehydrogenase Supports Metabolic Repurposing of Mitochondria to Drive Inflammatory Macrophages.

TitleSuccinate Dehydrogenase Supports Metabolic Repurposing of Mitochondria to Drive Inflammatory Macrophages.
Publication TypeJournal Article
Year of Publication2016
AuthorsMills, EL, Kelly, B, Logan, A, Costa, ASH, Varma, M, Bryant, CE, Tourlomousis, P, J Däbritz, HM, Gottlieb, E, Latorre, I, Corr, SC, McManus, G, Ryan, D, Jacobs, HT, Szibor, M, Xavier, RJ, Braun, T, Frezza, C, Murphy, MP, O'Neill, LA
JournalCell
Volume167
Issue2
Pagination457-470.e13
Date Published2016 Oct 06
ISSN1097-4172
KeywordsAdenosine Triphosphate, Animals, Carbonyl Cyanide m-Chlorophenyl Hydrazone, Citric Acid Cycle, Glycolysis, Hypoxia-Inducible Factor 1, alpha Subunit, Inflammation, Interleukin-10, Lipopolysaccharides, Macrophage Activation, Macrophages, Malonates, Membrane Potential, Mitochondrial, Mice, Mice, Inbred C57BL, Mitochondria, Mitochondrial Proteins, Oxidation-Reduction, Oxidative Phosphorylation, Oxidoreductases, Plant Proteins, Reactive Oxygen Species, Sequence Analysis, RNA, Succinate Dehydrogenase, Succinic Acid, Transcriptome
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.

DOI10.1016/j.cell.2016.08.064
Alternate JournalCell
Citation Key10.1016/j.cell.2016.08.064
PubMed ID27667687
Grant ListMC_U105663142 / / Medical Research Council / United Kingdom
MC_UU_12022/6 / / Medical Research Council / United Kingdom
/ / Wellcome Trust / United Kingdom
/ / European Research Council / International