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American Journal of Health-system... Jan 2022
Topics: Humans; Protein Kinase Inhibitors; Succinates; Succinic Acid
PubMed: 34964824
DOI: 10.1093/ajhp/zxab395 -
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 -
Current Opinion in Biotechnology Apr 2021Macrophages are the prominent innate immune cells to combat infection and then restore tissue homeostasis after clearance of pathogens. Intracellular metabolic... (Review)
Review
Macrophages are the prominent innate immune cells to combat infection and then restore tissue homeostasis after clearance of pathogens. Intracellular metabolic reprogramming is required for macrophage activation and function, as such adaptations confer macrophages with sufficient energy and metabolites to support biosynthesis and diverse functions. During the last 10 years, knowledge in this field has been greatly extended by outstanding advances demonstrating that several metabolic intermediates possess the ability to directly control macrophage activation and effector functions by various mechanisms. Of note, citrate and succinate contribute to the inflammatory activation of macrophages while tricarboxylic acid cycle-derived metabolite itaconate has a variety of immunomodulatory effects. Such progress not only encourages a further exploration into the emerging new area immunometabolism, but also provides potential therapeutic targets to control unwanted inflammation due to infection.
Topics: Citric Acid Cycle; Humans; Inflammation; Macrophage Activation; Macrophages; Succinic Acid
PubMed: 33610128
DOI: 10.1016/j.copbio.2021.01.020 -
Khirurgiia 2021The ischemia-reperfusion syndrome complicates the course of a number of emergency conditions in various fields of clinical medicine, determines the course, prognosis and... (Review)
Review
The ischemia-reperfusion syndrome complicates the course of a number of emergency conditions in various fields of clinical medicine, determines the course, prognosis and outcome of the disease. This review examines various aspects of the etiology, pathogenesis, and clinical manifestations of this syndrome. Particular attention is paid to its prevention and treatment. It is indicated that most of the studies devoted to this problem are of an experimental nature. The use of preparations based on succinic acid in the clinic is seen as the most promising direction in solving this issue.
Topics: Humans; Ischemia; Reperfusion; Reperfusion Injury; Succinic Acid
PubMed: 34480458
DOI: 10.17116/hirurgia202109171 -
Pharmacological Research Aug 2023Succinate is a vital signaling metabolite produced by the host and gut microbiota. Succinate has been shown to regulate host metabolic homeostasis and inhibit...
Succinate is a vital signaling metabolite produced by the host and gut microbiota. Succinate has been shown to regulate host metabolic homeostasis and inhibit obesity-associated inflammation in macrophages by engaging its cognate receptor, SUCNR1. However, the contribution of the succinate-SUCNR1 axis to intestinal barrier dysfunction in obesity remains unclear. In the present study, we explored the effects of succinate-SUCNR1 signaling on high-fat diet (HFD)-induced intestinal barrier dysfunction. Using a SUCNR1-deficient mouse model under HFD feeding conditions, we identified the effects of succinate-SUCNR1 axis on obesity-associated intestinal barrier impairment. Our results showed that HFD administration decreased goblet cell numbers and mucus production, promoted intestinal pro-inflammatory responses, induced gut microbiota composition imbalance, increased intestinal permeability, and caused mucosal barrier dysfunction. Dietary succinate supplementation was sufficient to activate a type 2 immune response, trigger the differentiation of barrier-promoting goblet cells, suppress intestinal inflammation, restore HFD-induced mucosal barrier impairment and intestinal dysbiosis, and eventually exert anti-obesity effects. However, SUNNR1-deficient mice failed to improve the intestinal barrier function and metabolic phenotype in HFD mice. Our data indicate the protective role of the succinate-SUCNR1 axis in HFD-induced intestinal barrier dysfunction.
Topics: Mice; Animals; Succinic Acid; Diet, High-Fat; Obesity; Signal Transduction; Inflammation; Intestinal Diseases; Gastrointestinal Diseases; Mice, Inbred C57BL
PubMed: 37482326
DOI: 10.1016/j.phrs.2023.106865 -
Proceedings of the National Academy of... Jun 2023Succinate produced by the commensal protist () stimulates chemosensory tuft cells, resulting in intestinal type 2 immunity. Tuft cells express the succinate receptor...
Succinate produced by the commensal protist () stimulates chemosensory tuft cells, resulting in intestinal type 2 immunity. Tuft cells express the succinate receptor SUCNR1, yet this receptor does not mediate antihelminth immunity nor alter protist colonization. Here, we report that microbial-derived succinate increases Paneth cell numbers and profoundly alters the antimicrobial peptide (AMP) landscape in the small intestine. Succinate was sufficient to drive this epithelial remodeling, but not in mice lacking tuft cell chemosensory components required to detect this metabolite. Tuft cells respond to succinate by stimulating type 2 immunity, leading to interleukin-13-mediated epithelial and AMP expression changes. Moreover, type 2 immunity decreases the total number of mucosa-associated bacteria and alters the small intestinal microbiota composition. Finally, tuft cells can detect short-term bacterial dysbiosis that leads to a spike in luminal succinate levels and modulate AMP production in response. These findings demonstrate that a single metabolite produced by commensals can markedly shift the intestinal AMP profile and suggest that tuft cells utilize SUCNR1 and succinate sensing to modulate bacterial homeostasis.
Topics: Mice; Animals; Intestinal Mucosa; Intestine, Small; Intestines; Succinic Acid; Anti-Infective Agents
PubMed: 37253002
DOI: 10.1073/pnas.2216908120 -
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 -
Molecular Cell Jun 2020Metabolites have functions in the immune system independent of their conventional roles as sources or intermediates in biosynthesis and bioenergetics. We are still in... (Review)
Review
Metabolites have functions in the immune system independent of their conventional roles as sources or intermediates in biosynthesis and bioenergetics. We are still in the pioneering phase of gathering information about the functions of specific metabolites in immunoregulation. In this review, we cover succinate, itaconate, α-ketoglutarate, and lactate as examples. Each of these metabolites has a different story of how their immunoregulatory functions were discovered and how their roles in the complex process of inflammation were revealed. Parallels and interactions are emerging between metabolites and cytokines, well-known immunoregulators. We depict molecular mechanisms by which metabolites prime cellular and often physiological changes focusing on intra- and extra-cellular activities and signaling pathways. Possible therapeutic opportunities for immune and inflammatory diseases are emerging.
Topics: Animals; Carboxylic Acids; Citric Acid Cycle; Cytokines; Energy Metabolism; Humans; Immunity; Inflammation; Ketoglutaric Acids; Lactic Acid; Signal Transduction; Succinates; Succinic Acid
PubMed: 32333837
DOI: 10.1016/j.molcel.2020.04.002 -
Current Opinion in Biotechnology Dec 2023The tumor microenvironment (TME) consists of a network of metabolically interconnected tumor and immune cell types. Macrophages influence the metabolic composition... (Review)
Review
The tumor microenvironment (TME) consists of a network of metabolically interconnected tumor and immune cell types. Macrophages influence the metabolic composition within the TME, which directly impacts the metabolic state and drug response of tumors. The accumulation of oncometabolites, such as succinate, fumarate, and 2-hydroxyglutarate, represents metabolic vulnerabilities in cancer that can be targeted therapeutically. Immunometabolites are emerging as metabolic regulators of the TME impacting immune cell functions and cancer cell growth. Here, we discuss recent discoveries on the potential impact of itaconate on the TME. We highlight how itaconate influences metabolic pathways relevant to immune responses and cancer cell proliferation. We also consider the therapeutic implications of manipulating itaconate metabolism as an immunotherapeutic strategy to constrain tumor growth.
Topics: Humans; Tumor Microenvironment; Succinates; Neoplasms; Succinic Acid
PubMed: 37806082
DOI: 10.1016/j.copbio.2023.102996 -
Journal of Neuroinflammation Dec 2023Pathological neovascularization is a pivotal biological process in wet age-related macular degeneration (AMD), retinopathy of prematurity (ROP) and proliferative...
Pathological neovascularization is a pivotal biological process in wet age-related macular degeneration (AMD), retinopathy of prematurity (ROP) and proliferative diabetic retinopathy (PDR), in which macrophages (Mφs) play a key role. Tip cell specialization is critical in angiogenesis; however, its interconnection with the surrounding immune environment remains unclear. Succinate is an intermediate in the tricarboxylic acid (TCA) cycle and was significantly elevated in patients with wet AMD by metabolomics. Advanced experiments revealed that SUCNR1 expression in Mφ and M2 polarization was detected in abnormal vessels of choroidal neovascularization (CNV) and oxygen-induced retinopathy (OIR) models. Succinate-induced M2 polarization via SUCNR1, which facilitated vascular endothelial cell (EC) migration, invasion, and tubulation, thus promoting angiogenesis in pathological neovascularization. Furthermore, evidence indicated that succinate triggered the release of RBP4 from Mφs into the surroundings to regulate endothelial sprouting and pathological angiogenesis via VEGFR2, a marker of tip cell formation. In conclusion, our results suggest that succinate represents a novel class of vasculature-inducing factors that modulate Mφ polarization and the RBP4/VEGFR2 pathway to induce pathological angiogenic signaling through tip cell specialization.
Topics: Infant, Newborn; Humans; Animals; Succinic Acid; Eye; Choroidal Neovascularization; Retinopathy of Prematurity; Macrophages; Disease Models, Animal; Retinol-Binding Proteins, Plasma
PubMed: 38129891
DOI: 10.1186/s12974-023-02998-1