Succinate Dehydrogenase Supports Metabolic Repurposing of Mitochondria to Drive Inflammatory Macrophages
Open accessAbstract
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.
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NLRP3 inflammasome activation increases glycolytic metabolites such as fructose 1,6-biphosphate via PFK-1 and reduces NAD, with no change in cystine or betaine.
“NLRP3 inflammasome activation also increased glycolytic metabolites45 such as fructose 1, 6-biphosphate via phosphofructokinase-1,46 alongside reduced nicotinamide adenine dinucleotide (NAD) (Figure 2A), a key cofactor in redox reactions,47 with no change in cystine (the oxidized dimeric form of cysteine) or betaine, an organic osmolyte in the methionine cycle (Figures 2B and Figure S2C).”
From Taurine lowers inflammaging by regulating the NLRP3 inflammasome in macrophages (2026) · cites this paper as [45]
The Results section, under “Glycolytic ATP production,” reports that LPS boosts glycolysis in macrophages, supporting the general glycolysis point attached to citation 45. It does not establish that NLRP3 inflammasome activation increases glycolytic metabolite concentrations. The PFK-1 and NAD statements have separate citations, while the cystine and betaine observations refer to the citing paper’s figures; they are not attributed to this source. Page numbers are unavailable in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measuredMitochondrial membrane potential increases following the pro-inflammatory effect of LPS.
“the mitochondrial membrane potential (MMP) results increased following the pro-inflammatory effect of LPS [53].”
From Effects of Mangiferin on LPS-Induced Inflammation and SARS-CoV-2 Viral Adsorption in Human Lung Cells (2022) · cites this paper as [53]
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- Authors
- Mills, E. L., Kelly, B., Logan, A., Costa, A. S. H., Varma, M., Bryant, C. E., Tourlomousis, P., Däbritz, J. H. M., Gottlieb, E., Latorre, I., Corr, S. C., McManus, G., Ryan, D., Jacobs, H. T., Szibor, M., Xavier, R. J., Braun, T., Frezza, C., Murphy, M. P., & O’Neill, L. A.
- Affiliations
- Trinity College Dublin (IE)
- MRC Mitochondrial Biology Unit (GB)
- University of Cambridge (GB)
- Harvard University (US)
- Cancer Research UK Scotland Institute (GB)
- University of Helsinki (FI)
- Max Planck Institute for Heart and Lung Research (DE)
- Corresponding author
- Murphy, Michael P.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2016-10
- Volume
- 167
- Issue
- 2
- Pages
- 457-470.e13
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC5863951
- OpenAlex
- W2522038806
- Cited by
- 2,291
- References
- 11
- Citations by year
- 2026: 323 · 2025: 312 · 2024: 283 · 2023: 257 · 2022: 244 · 2021: 259 · 2020: 220 · 2019: 164 · 2018: 132 · 2017: 87 · 2016: 6 · 2012: 1
- FWCI
- 78.64
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion)
- Max Planck Digital Library (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Apollo (University of Cambridge) (submittedVersion)
- Apollo
- Funders
- Wellcome Trust (110158/Z/15/Z, 108045/Z/15/Z, 110159/Z/ 15/Z, 109443/Z/15/Z)
- Cancer Research UK (18278)
- Medical Research Council (MC_UU_12022/6)
- Biotechnology and Biological Sciences Research Council (BB/K006436/1)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- succinate dehydrogenase, macrophage metabolic reprogramming, mitochondrial reactive oxygen species, succinate oxidation, glycolysis, oxidative phosphorylation, lipopolysaccharide, mitochondrial membrane potential, alternative oxidase, dimethyl malonate, pro-inflammatory gene expression, rotenone
- MeSH terms
- Alternative Oxidase, Adenosine Triphosphate, Animals, Carbonyl Cyanide m-Chlorophenyl Hydrazone, Citric Acid Cycle, Glycolysis, Inflammation, Lipopolysaccharides, Macrophage Activation, Macrophages, Malonates, Mice, Inbred C57BL, Mitochondria, Oxidation-Reduction, Oxidative Phosphorylation, Oxidoreductases, Plant Proteins, Succinate Dehydrogenase, Interleukin-10, Reactive Oxygen Species, Sequence Analysis, RNA, Succinic Acid, Mitochondrial Proteins, Mice, Hypoxia-Inducible Factor 1, alpha Subunit, Membrane Potential, Mitochondrial, Transcriptome
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