Title | Succinate Dehydrogenase Supports Metabolic Repurposing of Mitochondria to Drive Inflammatory Macrophages. |
Publication Type | Journal Article |
Year of Publication | 2016 |
Authors | Mills, 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 |
Journal | Cell |
Volume | 167 |
Issue | 2 |
Pagination | 457-470.e13 |
Date Published | 2016 Oct 06 |
ISSN | 1097-4172 |
Keywords | Adenosine 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. |
DOI | 10.1016/j.cell.2016.08.064 |
Alternate Journal | Cell |
Citation Key | 10.1016/j.cell.2016.08.064 |
PubMed ID | 27667687 |
Grant List | MC_U105663142 / / Medical Research Council / United Kingdom MC_UU_12022/6 / / Medical Research Council / United Kingdom / / Wellcome Trust / United Kingdom / / European Research Council / International |