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Cell. 2016 Oct 6;167(2):457-470.e13. doi: 10.1016/j.cell.2016.08.064. Epub 2016 Sep 22.

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

Author information

1
School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
2
MRC Mitochondrial Biology Unit, Hills Road, Cambridge CB2 0XY, UK.
3
MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Box 197, Cambridge Biomedical Campus, Cambridge CB2 0XZ, UK.
4
Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
5
Department of Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge CB23 8AQ, UK.
6
Cancer Metabolism Research Unit, Cancer Research UK, Beatson Institute, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK.
7
Department of Microbiology, Moyne Institute for Preventative Medicine, School of Genetics and Microbiology, Trinity College Dublin, Dublin 2, Ireland.
8
Institute of Biotechnology, 00014 University of Helsinki, P.O. Box 56, Helsinki 00014, Finland; BioMediTech and Tampere University Hospital, University of Tampere, Tampere 33014, Finland.
9
Institute of Biotechnology, 00014 University of Helsinki, P.O. Box 56, Helsinki 00014, Finland; BioMediTech and Tampere University Hospital, University of Tampere, Tampere 33014, Finland; Max-Planck-Institute for Heart and Lung Research, Ludwigstrasse 43, 61231 Bad Nauheim, Germany.
10
Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Gastrointestinal Unit, Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
11
Max-Planck-Institute for Heart and Lung Research, Ludwigstrasse 43, 61231 Bad Nauheim, Germany.
12
MRC Mitochondrial Biology Unit, Hills Road, Cambridge CB2 0XY, UK. Electronic address: mpm@mrc-mbu.cam.ac.uk.
13
School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland. Electronic address: laoneill@tcd.ie.

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.

KEYWORDS:

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

PMID:
27667687
PMCID:
PMC5863951
DOI:
10.1016/j.cell.2016.08.064
[Indexed for MEDLINE]
Free PMC Article

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