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Nature Immunology May 2019Succinate is a signaling metabolite sensed extracellularly by succinate receptor 1 (SUNCR1). The accumulation of succinate in macrophages is known to activate a...
Succinate is a signaling metabolite sensed extracellularly by succinate receptor 1 (SUNCR1). The accumulation of succinate in macrophages is known to activate a pro-inflammatory program; however, the contribution of SUCNR1 to macrophage phenotype and function has remained unclear. Here we found that activation of SUCNR1 had a critical role in the anti-inflammatory responses in macrophages. Myeloid-specific deficiency in SUCNR1 promoted a local pro-inflammatory phenotype, disrupted glucose homeostasis in mice fed a normal chow diet, exacerbated the metabolic consequences of diet-induced obesity and impaired adipose-tissue browning in response to cold exposure. Activation of SUCNR1 promoted an anti-inflammatory phenotype in macrophages and boosted the response of these cells to type 2 cytokines, including interleukin-4. Succinate decreased the expression of inflammatory markers in adipose tissue from lean human subjects but not that from obese subjects, who had lower expression of SUCNR1 in adipose-tissue-resident macrophages. Our findings highlight the importance of succinate-SUCNR1 signaling in determining macrophage polarization and assign a role to succinate in limiting inflammation.
Topics: Adipose Tissue; Animals; Cells, Cultured; Cytokines; Gene Expression Profiling; Humans; Inflammation; Macrophages; Male; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Obesity; Receptors, G-Protein-Coupled; Succinic Acid; THP-1 Cells
PubMed: 30962591
DOI: 10.1038/s41590-019-0372-7 -
Circulation Research Dec 2023
Topics: Succinic Acid; Succinates; Heart
PubMed: 38112098
DOI: 10.1161/CIRCRESAHA.123.323651 -
Nature Chemical Biology May 2022Metabolites once considered solely in catabolism or anabolism turn out to have key regulatory functions. Among these, the citric acid cycle intermediate succinate stands... (Review)
Review
Metabolites once considered solely in catabolism or anabolism turn out to have key regulatory functions. Among these, the citric acid cycle intermediate succinate stands out owing to its multiple roles in disparate pathways, its dramatic concentration changes and its selective cell release. Here we propose that succinate has evolved as a signaling modality because its concentration reflects the coenzyme Q (CoQ) pool redox state, a central redox couple confined to the mitochondrial inner membrane. This connection is of general importance because CoQ redox state integrates three bioenergetic parameters: mitochondrial electron supply, oxygen tension and ATP demand. Succinate, by equilibrating with the CoQ pool, enables the status of this central bioenergetic parameter to be communicated from mitochondria to the rest of the cell, into the circulation and to other cells. The logic of this form of regulation explains many emerging roles of succinate in biology, and suggests future research questions.
Topics: Energy Metabolism; Mitochondria; Oxidation-Reduction; Succinic Acid; Ubiquinone
PubMed: 35484255
DOI: 10.1038/s41589-022-01004-8 -
Proceedings of the National Academy of... May 2023Aberrant accumulation of succinate has been detected in many cancers. However, the cellular function and regulation of succinate in cancer progression is not completely...
Aberrant accumulation of succinate has been detected in many cancers. However, the cellular function and regulation of succinate in cancer progression is not completely understood. Using stable isotope-resolved metabolomics analysis, we showed that the epithelial mesenchymal transition (EMT) was associated with profound changes in metabolites, including elevation of cytoplasmic succinate levels. The treatment with cell-permeable succinate induced mesenchymal phenotypes in mammary epithelial cells and enhanced cancer cell stemness. Chromatin immunoprecipitation and sequence analysis showed that elevated cytoplasmic succinate levels were sufficient to reduce global 5-hydroxymethylcytosinene (5hmC) accumulation and induce transcriptional repression of EMT-related genes. We showed that expression of procollagen-lysine,2-oxoglutarate 5-dioxygenase 2 (PLOD2) was associated with elevation of cytoplasmic succinate during the EMT process. Silencing of PLOD2 expression in breast cancer cells reduced succinate levels and inhibited cancer cell mesenchymal phenotypes and stemness, which was accompanied by elevated 5hmC levels in chromatin. Importantly, exogenous succinate rescued cancer cell stemness and 5hmC levels in PLOD2-silenced cells, suggesting that PLOD2 promotes cancer progression at least partially through succinate. These results reveal the previously unidentified function of succinate in enhancing cancer cell plasticity and stemness.
Topics: Cell Line, Tumor; Epithelial Cells; Epithelial-Mesenchymal Transition; Neoplasms; Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase; Succinates; Succinic Acid; Humans
PubMed: 37155842
DOI: 10.1073/pnas.2214942120 -
International Journal of Molecular... Jul 2023When tissues are under physiological stresses, such as vigorous exercise and cold exposure, skeletal muscle cells secrete succinate into the extracellular space for... (Review)
Review
When tissues are under physiological stresses, such as vigorous exercise and cold exposure, skeletal muscle cells secrete succinate into the extracellular space for adaptation and survival. By contrast, environmental toxins and injurious agents induce cellular secretion of succinate to damage tissues, trigger inflammation, and induce tissue fibrosis. Extracellular succinate induces cellular changes and tissue adaptation or damage by ligating cell surface succinate receptor-1 (SUCNR-1) and activating downstream signaling pathways and transcriptional programs. Since SUCNR-1 mediates not only pathological processes but also physiological functions, targeting it for drug development is hampered by incomplete knowledge about the characteristics of its physiological vs. pathological actions. This review summarizes the current status of extracellular succinate in health and disease and discusses the underlying mechanisms and therapeutic implications.
Topics: Humans; Succinic Acid; Succinates; Signal Transduction; Cell Membrane; Fibrosis
PubMed: 37446354
DOI: 10.3390/ijms241311165 -
Advanced Science (Weinheim,... Oct 2023Mitochondria are the pivot organelles to control metabolism and energy homeostasis. The capacity of mitochondrial metabolic adaptions to cold stress is essential for...
Mitochondria are the pivot organelles to control metabolism and energy homeostasis. The capacity of mitochondrial metabolic adaptions to cold stress is essential for adipocyte thermogenesis. How brown adipocytes keep mitochondrial fitness upon a challenge of cold-induced oxidative stress has not been well characterized. This manuscript shows that IFI27 plays an important role in cristae morphogenesis, keeping intact succinate dehydrogenase (SDH) function and active fatty acid oxidation to sustain thermogenesis in brown adipocytes. IFI27 protein interaction map identifies SDHB and HADHA as its binding partners. IFI27 physically links SDHB to chaperone TNF receptor associated protein 1 (TRAP1), which shields SDHB from oxidative damage-triggered degradation. Moreover, IFI27 increases hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit alpha (HADHA) catalytic activity in β-oxidation pathway. The reduced SDH level and fatty acid oxidation in Ifi27-knockout brown fat results in impaired oxygen consumption and defective thermogenesis. Thus, IFI27 is a novel regulator of mitochondrial metabolism and thermogenesis.
Topics: Succinic Acid; Adipocytes, Brown; Adipose Tissue, Brown; Fatty Acids; Thermogenesis
PubMed: 37544897
DOI: 10.1002/advs.202301855 -
American Journal of Physiology.... Apr 2023Succinate is released by skeletal muscle during exercise and activates /GPR91. Signaling of SUCNR1 is involved in metabolite-sensing paracrine communication in skeletal...
Succinate is released by skeletal muscle during exercise and activates /GPR91. Signaling of SUCNR1 is involved in metabolite-sensing paracrine communication in skeletal muscle during exercise. However, the specific cell types responding to succinate and the directionality of communication are unclear. We aim to characterize the expression of SUCNR1 in human skeletal muscle. De novo analysis of transcriptomic datasets demonstrated that mRNA is expressed in immune, adipose, and liver tissues, but scarce in skeletal muscle. In human tissues, mRNA was associated with macrophage markers. Single-cell RNA sequencing and fluorescent RNAscope demonstrated that in human skeletal muscle, mRNA is not expressed in muscle fibers but coincided with macrophage populations. Human M2-polarized macrophages exhibit high levels of mRNA and stimulation with selective agonists of SUCNR1 triggered Gq- and Gi-coupled signaling. Primary human skeletal muscle cells were unresponsive to SUCNR1 agonists. In conclusion, SUCNR1 is not expressed in muscle cells and its role in the adaptive response of skeletal muscle to exercise is most likely mediated via paracrine mechanisms involving M2-like macrophages within the muscle. Macrophages but not skeletal muscle cells respond to extracellular succinate via SUCNR1/GPR91.
Topics: Humans; Muscles; Obesity; Receptors, G-Protein-Coupled; Signal Transduction; Succinic Acid
PubMed: 36812387
DOI: 10.1152/ajpendo.00009.2023 -
Science Advances Jun 2023Acute hemorrhage commonly leads to coagulopathy and organ dysfunction or failure. Recent evidence suggests that damage to the endothelial glycocalyx contributes to these...
Acute hemorrhage commonly leads to coagulopathy and organ dysfunction or failure. Recent evidence suggests that damage to the endothelial glycocalyx contributes to these adverse outcomes. The physiological events mediating acute glycocalyx shedding are undefined, however. Here, we show that succinate accumulation within endothelial cells drives glycocalyx degradation through a membrane reorganization-mediated mechanism. We investigated this mechanism in a cultured endothelial cell hypoxia-reoxygenation model, in a rat model of hemorrhage, and in trauma patient plasma samples. We found that succinate metabolism by succinate dehydrogenase mediates glycocalyx damage through lipid oxidation and phospholipase A2-mediated membrane reorganization, promoting the interaction of matrix metalloproteinase 24 (MMP24) and MMP25 with glycocalyx constituents. In a rat hemorrhage model, inhibiting succinate metabolism or membrane reorganization prevented glycocalyx damage and coagulopathy. In patients with trauma, succinate levels were associated with glycocalyx damage and the development of coagulopathy, and the interaction of MMP24 and syndecan-1 was elevated compared to healthy controls.
Topics: Animals; Rats; Endothelial Cells; Hemorrhage; Lipid Metabolism; Hypoxia; Succinates; Succinic Acid
PubMed: 37315138
DOI: 10.1126/sciadv.adf6600 -
The EMBO Journal Jun 2022Influenza virus infection causes considerable morbidity and mortality, but current therapies have limited efficacy. We hypothesized that investigating the metabolic...
Influenza virus infection causes considerable morbidity and mortality, but current therapies have limited efficacy. We hypothesized that investigating the metabolic signaling during infection may help to design innovative antiviral approaches. Using bronchoalveolar lavages of infected mice, we here demonstrate that influenza virus induces a major reprogramming of lung metabolism. We focused on mitochondria-derived succinate that accumulated both in the respiratory fluids of virus-challenged mice and of patients with influenza pneumonia. Notably, succinate displays a potent antiviral activity in vitro as it inhibits the multiplication of influenza A/H1N1 and A/H3N2 strains and strongly decreases virus-triggered metabolic perturbations and inflammatory responses. Moreover, mice receiving succinate intranasally showed reduced viral loads in lungs and increased survival compared to control animals. The antiviral mechanism involves a succinate-dependent posttranslational modification, that is, succinylation, of the viral nucleoprotein at the highly conserved K87 residue. Succinylation of viral nucleoprotein altered its electrostatic interactions with viral RNA and further impaired the trafficking of viral ribonucleoprotein complexes. The finding that succinate efficiently disrupts the influenza replication cycle opens up new avenues for improved treatment of influenza pneumonia.
Topics: Animals; Antiviral Agents; Humans; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H3N2 Subtype; Influenza, Human; Mice; Nucleocapsid Proteins; Nucleoproteins; Orthomyxoviridae Infections; Pneumonia; Succinic Acid; Virus Replication
PubMed: 35506364
DOI: 10.15252/embj.2021108306 -
PLoS Pathogens Aug 2022Macrophages restrict bacterial infection partly by stimulating phagocytosis and partly by stimulating release of cytokines and complement components. Here, we treat...
Macrophages restrict bacterial infection partly by stimulating phagocytosis and partly by stimulating release of cytokines and complement components. Here, we treat macrophages with LPS and a bacterial pathogen, and demonstrate that expression of cytokine IL-1β and bacterial phagocytosis increase to a transient peak 8 to 12 h post-treatment, while expression of complement component 3 (C3) continues to rise for 24 h post-treatment. Metabolomic analysis suggests a correlation between the cellular concentrations of succinate and IL-1β and of inosine and C3. This may involve a regulatory feedback mechanism, whereby succinate stimulates and inosine inhibits HIF-1α through their competitive interactions with prolyl hydroxylase. Furthermore, increased level of inosine in LPS-stimulated macrophages is linked to accumulation of adenosine monophosphate and that exogenous inosine improves the survival of bacterial pathogen-infected mice and tilapia. The implications of these data suggests potential therapeutic tools to prevent, manage or treat bacterial infections.
Topics: Animals; Bacterial Infections; Cytokines; Inosine; Lipopolysaccharides; Mice; Phagocytosis; Succinic Acid
PubMed: 36026499
DOI: 10.1371/journal.ppat.1010796