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Gut Microbes 2023Succinate is a circulating metabolite, and the relationship between abnormal changes in the physiological concentration of succinate and inflammatory diseases caused by... (Review)
Review
Succinate is a circulating metabolite, and the relationship between abnormal changes in the physiological concentration of succinate and inflammatory diseases caused by the overreaction of certain immune cells has become a research focus. Recent investigations have shown that succinate produced by the gut microbiota has the potential to regulate host homeostasis and treat diseases such as inflammation. Gut microbes are important for maintaining intestinal homeostasis. Microbial metabolites serve as nutrients in energy metabolism, and act as signal molecules that stimulate host cell and organ function and affect the structural balance between symbiotic gut microorganisms. This review focuses on succinate as a metabolite of both host cells and gut microbes and its involvement in regulating the gut - immune tissue axis by activating intestinal mucosal cells, including macrophages, dendritic cells, and intestinal epithelial cells. We also examined its role as the mediator of microbiota - host crosstalk and its potential function in regulating intestinal microbiota homeostasis. This review explores feasible ways to moderate succinate levels and provides new insights into succinate as a potential target for microbial therapeutics for humans.
Topics: Humans; Gastrointestinal Microbiome; Host Microbial Interactions; Microbiota; Intestinal Mucosa; Succinic Acid; Succinates
PubMed: 36946592
DOI: 10.1080/19490976.2023.2190300 -
Cell Reports Dec 2022Neurotransmitters have been well documented to determine immune cell fates; however, whether and how γ-amino butyric acid (GABA) shapes the function of innate immune...
Neurotransmitters have been well documented to determine immune cell fates; however, whether and how γ-amino butyric acid (GABA) shapes the function of innate immune cells is still obscure. Here, we demonstrate that GABA orchestrates macrophage maturation and inflammation. GABA treatment during macrophage maturation inhibits interleukin (IL)-1β production from inflammatory macrophages. Mechanistically, GABA enhances succinate-flavin adenine dinucleotide (FAD)-lysine specific demethylase1 (LSD1) signaling to regulate histone demethylation of Bcl2l11 and Dusp2, reducing formation of the NLRP3-ASC-Caspase-1 complex. The GABA-succinate axis reduces succinylation of mitochondrial proteins to promote oxidative phosphorylation (OXPHOS). We also find that GABA alleviates lipopolysaccharides (LPS)-induced sepsis as well as high-fat-diet-induced obesity in mice. Our study shows that GABA regulates pro-inflammatory macrophage responses associated with metabolic reprogramming and protein succinylation, suggesting a strategy for treating macrophage-related inflammatory diseases.
Topics: Mice; Animals; Succinic Acid; Lysine; Mitochondrial Proteins; Macrophages; gamma-Aminobutyric Acid
PubMed: 36476877
DOI: 10.1016/j.celrep.2022.111770 -
Nutrients Dec 2018Succinate is a metabolic intermediate of the tricarboxylic acid (TCA) cycle within host cells. Succinate is also produced in large amounts during bacterial fermentation... (Review)
Review
Succinate is a metabolic intermediate of the tricarboxylic acid (TCA) cycle within host cells. Succinate is also produced in large amounts during bacterial fermentation of dietary fiber. Elevated succinate levels within the gut lumen have been reported in association with microbiome disturbances (dysbiosis), as well as in patients with inflammatory bowel disease (IBD) and animal models of intestinal inflammation. Recent studies indicate that succinate can activate immune cells via its specific surface receptor, succinate receptor 1(SUCNR1), and enhance inflammation. However, the role of succinate in inflammatory processes within the gut mucosal immune system is unclear. This review includes current literature on the association of succinate with intestinal inflammation and the potential role of succinate⁻SUCNR1 signaling in gut immune functions.
Topics: Animals; Bacteria; Dysbiosis; Gastrointestinal Microbiome; Humans; Immunity, Innate; Inflammatory Bowel Diseases; Intestinal Mucosa; Intestines; Receptors, G-Protein-Coupled; Signal Transduction; Succinic Acid
PubMed: 30583500
DOI: 10.3390/nu11010025 -
Journal of Biomedical Science Nov 2022Succinate is a tricarboxylic acid (TCA) cycle intermediate normally confined to the mitochondrial matrix. It is a substrate of succinate dehydrogenase (SDH). Mutation of... (Review)
Review
Succinate is a tricarboxylic acid (TCA) cycle intermediate normally confined to the mitochondrial matrix. It is a substrate of succinate dehydrogenase (SDH). Mutation of SDH subunits (SDHD and SDHB) in hereditary tumors such as paraganglioma or reduction of SDHB expression in cancer results in matrix succinate accumulation which is transported to cytoplasma and secreted into the extracellular milieu. Excessive cytosolic succinate is known to stabilize hypoxia inducible factor-1α (HIF-1α) by inhibiting prolyl hydroxylase. Recent reports indicate that cancer-secreted succinate enhances cancer cell migration and promotes cancer metastasis by activating succinate receptor-1 (SUCNR-1)-mediated signaling and transcription pathways. Cancer-derived extracellular succinate enhances cancer cell and macrophage migration through SUCNR-1 → PI-3 K → HIF-1α pathway. Extracellular succinate induces tumor angiogenesis through SUCNR-1-mediated ERK1/2 and STAT3 activation resulting in upregulation of vascular endothelial growth factor (VEGF) expression. Succinate increases SUCNR-1 expression in cancer cells which is considered as a target for developing new anti-metastasis drugs. Furthermore, serum succinate which is elevated in cancer patients may be a theranostic biomarker for selecting patients for SUCNR-1 antagonist therapy.
Topics: Humans; Neovascularization, Pathologic; Paraganglioma; Succinates; Succinic Acid; Vascular Endothelial Growth Factor A; Neoplasms; Neoplasm Metastasis; Extracellular Space
PubMed: 36344992
DOI: 10.1186/s12929-022-00878-z -
Cell Oct 2020In response to skeletal muscle contraction during exercise, paracrine factors coordinate tissue remodeling, which underlies this healthy adaptation. Here we describe a...
In response to skeletal muscle contraction during exercise, paracrine factors coordinate tissue remodeling, which underlies this healthy adaptation. Here we describe a pH-sensing metabolite signal that initiates muscle remodeling upon exercise. In mice and humans, exercising skeletal muscle releases the mitochondrial metabolite succinate into the local interstitium and circulation. Selective secretion of succinate is facilitated by its transient protonation, which occurs upon muscle cell acidification. In the protonated monocarboxylic form, succinate is rendered a transport substrate for monocarboxylate transporter 1, which facilitates pH-gated release. Upon secretion, succinate signals via its cognate receptor SUCNR1 in non-myofibrillar cells in muscle tissue to control muscle-remodeling transcriptional programs. This succinate-SUCNR1 signaling is required for paracrine regulation of muscle innervation, muscle matrix remodeling, and muscle strength in response to exercise training. In sum, we define a bioenergetic sensor in muscle that utilizes intracellular pH and succinate to coordinate tissue adaptation to exercise.
Topics: Animals; Humans; Hydrogen-Ion Concentration; Inflammation; Mice; Mitochondria; Monocarboxylic Acid Transporters; Muscle Contraction; Muscle, Skeletal; Receptors, G-Protein-Coupled; Signal Transduction; Succinates; Succinic Acid; Symporters
PubMed: 32946811
DOI: 10.1016/j.cell.2020.08.039 -
Nature Metabolism Jan 2019Metabolic reprogramming has become a key focus for both immunologists and cancer biologists, with exciting advances providing new insights into underlying mechanisms of... (Review)
Review
Metabolic reprogramming has become a key focus for both immunologists and cancer biologists, with exciting advances providing new insights into underlying mechanisms of disease. Metabolites traditionally associated with bioenergetics or biosynthesis have been implicated in immunity and malignancy in transformed cells, with a particular focus on intermediates of the mitochondrial pathway known as the Krebs cycle. Among these, the intermediates succinate, fumarate, itaconate, 2-hydroxyglutarate isomers (D-2-hydroxyglutarate and L-2-hydroxyglutarate) and acetyl-CoA now have extensive evidence for "non-metabolic" signalling functions in both physiological immune contexts and in disease contexts, such as the initiation of carcinogenesis. This review will describe how metabolic reprogramming, with emphasis placed on these metabolites, leads to altered immune cell and transformed cell function. The latest findings are informative for new therapeutic approaches which could be transformative for a range of diseases.
Topics: Citric Acid Cycle; Humans; Immunity, Innate; Macrophages; Neoplasms; Signal Transduction; Succinate Dehydrogenase; Succinates; Succinic Acid
PubMed: 31032474
DOI: 10.1038/s42255-018-0014-7 -
Cell Aug 2018Krebs cycle intermediates traditionally link to oxidative phosphorylation whilst also making key cell components. It is now clear that some of these metabolites also act... (Review)
Review
Krebs cycle intermediates traditionally link to oxidative phosphorylation whilst also making key cell components. It is now clear that some of these metabolites also act as signals. Succinate plays an important role in inflammatory, hypoxic, and metabolic signaling, while itaconate (from another Krebs cycle intermediate, cis-aconitate) has an anti-inflammatory role.
Topics: Animals; Citric Acid Cycle; Humans; Signal Transduction; Succinates; Succinic Acid
PubMed: 30096309
DOI: 10.1016/j.cell.2018.07.030 -
Nature Chemical Biology Jan 2011Of the 20 ribosomally coded amino acid residues, lysine is the most frequently post-translationally modified, which has important functional and regulatory consequences....
Of the 20 ribosomally coded amino acid residues, lysine is the most frequently post-translationally modified, which has important functional and regulatory consequences. Here we report the identification and verification of a previously unreported form of protein post-translational modification (PTM): lysine succinylation. The succinyllysine residue was initially identified by mass spectrometry and protein sequence alignment. The identified succinyllysine peptides derived from in vivo proteins were verified by western blot analysis, in vivo labeling with isotopic succinate, MS/MS and HPLC coelution of their synthetic counterparts. We further show that lysine succinylation is evolutionarily conserved and that this PTM responds to different physiological conditions. Our study also implies that succinyl-CoA might be a cofactor for lysine succinylation. Given the apparent high abundance of lysine succinylation and the significant structural changes induced by this PTM, it is expected that lysine succinylation has important cellular functions.
Topics: Acyl Coenzyme A; Amino Acid Sequence; Blotting, Western; Chromatography, High Pressure Liquid; Escherichia coli Proteins; Lysine; Mass Spectrometry; Molecular Sequence Data; Peptides; Protein Processing, Post-Translational; Sequence Alignment; Succinic Acid
PubMed: 21151122
DOI: 10.1038/nchembio.495 -
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 -
Genes & Development Jun 2012Two Krebs cycle genes, fumarate hydratase (FH) and succinate dehydrogenase (SDH), are mutated in a subset of human cancers, leading to accumulation of their substrates,...
Two Krebs cycle genes, fumarate hydratase (FH) and succinate dehydrogenase (SDH), are mutated in a subset of human cancers, leading to accumulation of their substrates, fumarate and succinate, respectively. Here we demonstrate that fumarate and succinate are competitive inhibitors of multiple α-ketoglutarate (α-KG)-dependent dioxygenases, including histone demethylases, prolyl hydroxylases, collagen prolyl-4-hydroxylases, and the TET (ten-eleven translocation) family of 5-methlycytosine (5mC) hydroxylases. Knockdown of FH and SDH results in elevated intracellular levels of fumarate and succinate, respectively, which act as competitors of α-KG to broadly inhibit the activity of α-KG-dependent dioxygenases. In addition, ectopic expression of tumor-derived FH and SDH mutants inhibits histone demethylation and hydroxylation of 5mC. Our study suggests that tumor-derived FH and SDH mutations accumulate fumarate and succinate, leading to enzymatic inhibition of multiple α-KG-dependent dioxygenases and consequent alterations of genome-wide histone and DNA methylation. These epigenetic alterations associated with mutations of FH and SDH likely contribute to tumorigenesis.
Topics: Animals; Biocatalysis; Cells, Cultured; DNA Methylation; Dioxygenases; Endostatins; Fumarate Hydratase; Fumarates; Gene Expression Regulation; Gene Knockdown Techniques; Genome, Human; HEK293 Cells; Histone Demethylases; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Ketoglutaric Acids; Mice; Models, Biological; Mutation; Succinate Dehydrogenase; Succinic Acid; Tumor Suppressor Proteins
PubMed: 22677546
DOI: 10.1101/gad.191056.112