Succinate Dehydrogenase Supports Metabolic Repurposing of Mitochondria to Drive Inflammatory Macrophages.
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.
School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
Evanna L
EL
Mills
School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
Beth
B
Kelly
MRC Mitochondrial Biology Unit, Hills Road, Cambridge CB2 0XY, UK.
Angela
A
Logan
MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Box 197, Cambridge Biomedical Campus, Cambridge CB2 0XZ, UK.
Ana S H
ASH
Costa
Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Mukund
M
Varma
Department of Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge CB23 8AQ, UK.
Clare E
CE
Bryant
Department of Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge CB23 8AQ, UK.
Panagiotis
P
Tourlomousis
Cancer Metabolism Research Unit, Cancer Research UK, Beatson Institute, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK.
J Henry M
JHM
Däbritz
Cancer Metabolism Research Unit, Cancer Research UK, Beatson Institute, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK.
Eyal
E
Gottlieb
Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Isabel
I
Latorre
Department of Microbiology, Moyne Institute for Preventative Medicine, School of Genetics and Microbiology, Trinity College Dublin, Dublin 2, Ireland.
Sinéad C
SC
Corr
School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
Gavin
G
McManus
School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
Dylan
D
Ryan
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.
Howard T
HT
Jacobs
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.
Marten
M
Szibor
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.
Ramnik J
RJ
Xavier
Max-Planck-Institute for Heart and Lung Research, Ludwigstrasse 43, 61231 Bad Nauheim, Germany.
Thomas
T
Braun
MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Box 197, Cambridge Biomedical Campus, Cambridge CB2 0XZ, UK.
Christian
C
Frezza
MRC Mitochondrial Biology Unit, Hills Road, Cambridge CB2 0XY, UK. Electronic address: mpm@mrc-mbu.cam.ac.uk.
Michael P
MP
Murphy
School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland. Electronic address: laoneill@tcd.ie.
Luke A
LA
O'Neill
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000494:pharmacology; D002952:Citric Acid Cycle; D006019:Glycolysis; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007249:Inflammation / Q000235:genetics / Q000276:immunology*; D016753:Interleukin-10 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D008314:Malonates / Q000494:pharmacology; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology*; D024101:Mitochondrial Proteins / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D010085:Oxidative Phosphorylation / Q000187:drug effects; D010088:Oxidoreductases / Q000378:metabolism; D010940:Plant Proteins / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D017423:Sequence Analysis, RNA; D013385:Succinate Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D019802:Succinic Acid / Q000378:metabolism*; D059467:Transcriptome; D000099188:Alternative Oxidase
D000255:Adenosine Triphosphate; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016753:Interleukin-10; D008070:Lipopolysaccharides; D008314:Malonates; D024101:Mitochondrial Proteins; D010088:Oxidoreductases; D010940:Plant Proteins; D017382:Reactive Oxygen Species; D013385:Succinate Dehydrogenase; D019802:Succinic Acid; D000099188:Alternative Oxidase; C497443:Hif1a protein, mouse; C556062:IL10 protein, mouse; C005230:methyl malonate
immunometabolism; innate immunity; macrophage; reverse electron transport; succinate; succinate dehydrogenase; toll-like receptors
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