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Frontiers in Immunology 2024Succinate, traditionally viewed as a mere intermediate of the tricarboxylic acid (TCA) cycle, has emerged as a critical mediator in inflammation. Disruptions within the... (Review)
Review
Succinate, traditionally viewed as a mere intermediate of the tricarboxylic acid (TCA) cycle, has emerged as a critical mediator in inflammation. Disruptions within the TCA cycle lead to an accumulation of succinate in the mitochondrial matrix. This excess succinate subsequently diffuses into the cytosol and is released into the extracellular space. Elevated cytosolic succinate levels stabilize hypoxia-inducible factor-1α by inhibiting prolyl hydroxylases, which enhances inflammatory responses. Notably, succinate also acts extracellularly as a signaling molecule by engaging succinate receptor 1 on immune cells, thus modulating their pro-inflammatory or anti-inflammatory activities. Alterations in succinate levels have been associated with various inflammatory disorders, including rheumatoid arthritis, inflammatory bowel disease, obesity, and atherosclerosis. These associations are primarily due to exaggerated immune cell responses. Given its central role in inflammation, targeting succinate pathways offers promising therapeutic avenues for these diseases. This paper provides an extensive review of succinate's involvement in inflammatory processes and highlights potential targets for future research and therapeutic possibilities development.
Topics: Humans; Succinic Acid; Inflammation; Signal Transduction; Animals; Citric Acid Cycle; Receptors, G-Protein-Coupled
PubMed: 38933270
DOI: 10.3389/fimmu.2024.1404441 -
Biochimica Et Biophysica Acta.... Feb 2024Succinate, one of the intermediates of the tricarboxylic acid (TCA) cycle, plays an essential role in the metabolism of mitochondria and the production of energy, and is... (Review)
Review
Succinate, one of the intermediates of the tricarboxylic acid (TCA) cycle, plays an essential role in the metabolism of mitochondria and the production of energy, and is considered as a signaling molecule in metabolism as well as in initiation and progression of hepatic diseases. Of note, succinate activates a downstream signaling pathway through GPR91, and elicits a variety of intracellular responses, such as succinylation, production of reactive oxygen species (ROS), stabilization of hypoxia-inducible factor-1α (HIF-1α), and significant impact in cellular metabolism because of the pivotal role in the TCA cycle. Therefore, it is intriguing to deeply elucidate signaling mechanisms of succinate in hepatic fibrosis, metabolic reprogramming in inflammatory or immune responses, as well as carcinogenesis. This manuscript intends to review current understanding of succinate in mediating metabolism, inflammatory and immunologic reactions in liver diseases in order to establish molecular basis for the development of therapeutic strategies.
Topics: Humans; Succinic Acid; Succinates; Signal Transduction; Citric Acid Cycle; Liver Cirrhosis
PubMed: 37976628
DOI: 10.1016/j.bbadis.2023.166935 -
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 -
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 -
The European Respiratory Journal Feb 2023
Topics: Animals; Mice; Gastrointestinal Microbiome; Succinic Acid; Acute Lung Injury; Succinates; Respiratory Distress Syndrome; Ischemia
PubMed: 36796848
DOI: 10.1183/13993003.02233-2022 -
Medicine Nov 2022Lysine succinylation is a novel, broad-spectrum, dynamic, non-enzymatic protein post-translational modification (PTM). Succinylation is essential for the regulation of... (Review)
Review
Lysine succinylation is a novel, broad-spectrum, dynamic, non-enzymatic protein post-translational modification (PTM). Succinylation is essential for the regulation of protein function and control of various signaling and regulatory pathways. It is involved in several life activities, including glucose metabolism, amino acid metabolism, fatty acid metabolism, ketone body synthesis, and reactive oxygen species clearance, by regulating protease activity and gene expression. The level of succinylation is mainly regulated by succinyl donor, succinyltransferase, and desuccinylase. Many studies have confirmed that succinylation plays a role in tumorigenesis by creating tissue heterogeneity, and can promote or inhibit various cancers via the regulation of different substrate targets or signaling pathways. The mechanism of action of some antineoplastic drugs is related to succinylation. To better understand the role of succinylation modification in cancer development and treatment, the present study reviewed the current research content and latest progress of succinylation modification in cancer, which might provide a new direction and target for the prevention and treatment of cancer.
Topics: Humans; Succinic Acid; Lysine; Protein Processing, Post-Translational; Signal Transduction; Neoplasms
PubMed: 36397343
DOI: 10.1097/MD.0000000000031493 -
Nature Metabolism Mar 2024Uptake of circulating succinate by brown adipose tissue (BAT) and beige fat elevates whole-body energy expenditure, counteracts obesity and antagonizes systemic tissue...
Uptake of circulating succinate by brown adipose tissue (BAT) and beige fat elevates whole-body energy expenditure, counteracts obesity and antagonizes systemic tissue inflammation in mice. The plasma membrane transporters that facilitate succinate uptake in these adipocytes remain undefined. Here we elucidate a mechanism underlying succinate import into BAT via monocarboxylate transporters (MCTs). We show that succinate transport is strongly dependent on the proportion that is present in the monocarboxylate form. MCTs facilitate monocarboxylate succinate uptake, which is promoted by alkalinization of the cytosol driven by adrenoreceptor stimulation. In brown adipocytes, we show that MCT1 primarily facilitates succinate import. In male mice, we show that both acute pharmacological inhibition of MCT1 and congenital depletion of MCT1 decrease succinate uptake into BAT and consequent catabolism. In sum, we define a mechanism of succinate uptake in BAT that underlies its protective activity in mouse models of metabolic disease.
Topics: Male; Mice; Animals; Adipocytes, Brown; Succinic Acid; Adipose Tissue, Brown; Biological Transport; Membrane Transport Proteins
PubMed: 38378996
DOI: 10.1038/s42255-024-00981-5 -
Kidney International Oct 2023Previous studies have indicated that succinate accumulation during kidney ischemia, and its oxidation during reperfusion, results in the production of excessive reactive...
Previous studies have indicated that succinate accumulation during kidney ischemia, and its oxidation during reperfusion, results in the production of excessive reactive oxygen species, mitochondrial dysfunction, and kidney injury. In this issue, Oh et al. have reported that pyruvate dehydrogenase kinase 4 (PDK4) inhibition in proximal tubules ameliorates kidney ischemia/reperfusion injury via suppressed succinate accumulation. This study suggests that PDK4 inhibition is a promising new treatment strategy for ischemic acute kidney injury.
Topics: Humans; Succinic Acid; Succinates; Kidney; Ischemia; Acute Kidney Injury
PubMed: 37739613
DOI: 10.1016/j.kint.2023.07.011 -
Journal of Ethnopharmacology Dec 2023Inflammatory injury is an important pathological factor for the formation of atherosclerotic plaque. It is well known that Puerarin and Tanshinone IIA (Pue-Tan) can...
ETHNOPHARMACOLOGICAL RELEVANCE
Inflammatory injury is an important pathological factor for the formation of atherosclerotic plaque. It is well known that Puerarin and Tanshinone IIA (Pue-Tan) can significantly reduce interleukin-1β (IL-1β) levels and delay the atherosclerosis (AS) process clinically in China. Previous evidence has shown that the Succinate/HIF-1α/IL-1β inflammatory signaling axis (Succinate axis) promotes the progression of atherosclerotic inflammatory plaques. It is not clear whether Pue-Tan inhibits inflammatory plaques by reducing the level of IL-1β through the succinate signaling axis.
AIM OF STUDY
Find out the interaction between Pue-Tan targets and the succinate axis by means of network pharmacology and bioinformatics analysis and to further confirm whether Pue-Tan can inhibit vascular inflammation and delay the formation of atherosclerotic inflammatory plaques by targeting the succinate signaling axis.
MATERIALS AND METHODS
Firstly, animal experiments were conducted to verify the changing relationship between Succinate and IL-1β under Pue-Tan intervention. Secondly, network pharmacology approach was employed to uncover the specific targets of Pue-Tan in the intervention of AS from multiple levels of components, proteins, and pathways, and at the same time, the target must be a key factor of the succinate signaling axis. Autodock vina1.5.6 was applied to molecular docking for Pue-Tan and target protein. Subsequently, cells experiment and animal experiment were performed to verify Pue-Tan inhibiting the inflammatory progression of atherosclerosis by targeting succinate signaling axis.
RESULTS
Firstly, we first found that the reduction of IL-1β was positively correlated with succinate in the serum of Pue-Tan-treated mice. Secondly, network pharmacology compared with molecular docking showed that hypoxia-induced factor-1α (HIF-1α) was the key target of Pue-Tan and the key node of succinate singling axis. Finally, in vitro study, Pue-Tan significantly reduced the factors of succinate axis just as HIF-1α siRNA; in vivo study, we confirmed a decreased expression of succinate axis and ICAM-1 in the aorta of ApoE mice under Pue-Tan intervention, which was consistent with the in vitro results.
CONCLUSION
This study confirmed that Pue-Tan blocked the succinate axis by targeting HIF-1α to prevent the formation of atherosclerotic inflammatory plaques and delay the pathological process of AS. Network Pharmacology, Bioinformatics of Molecular Docking, and Molecular Biology Validation can be used as a effective way to discover and verify the pharmacological mechanism of TCM.
Topics: Mice; Animals; Plaque, Atherosclerotic; Succinic Acid; Interleukin-1beta; Molecular Docking Simulation; Atherosclerosis; Hypoxia; Succinates
PubMed: 37257708
DOI: 10.1016/j.jep.2023.116675 -
Biochimica Et Biophysica Acta. Reviews... Dec 2020Macrophages are innate phagocytic leukocytes that are highly present in solid tumors, where they are referred to as tumor-associated macrophages (TAMs). In solid tumors,... (Review)
Review
Macrophages are innate phagocytic leukocytes that are highly present in solid tumors, where they are referred to as tumor-associated macrophages (TAMs). In solid tumors, the microenvironment is often immunosuppressive and hypoxic regions are prevalent. These hypoxic conditions impose tumor cells to reprogram their metabolism, shifting from oxidative phosphorylation to anaerobic glycolysis. This so-called glycolytic switch enables hypoxic tumor cells to survive, proliferate, and eventually to outcompete untransformed cells. The hypoxia-induced change in tumor cell metabolism leads to the production of oncometabolites, among which are the glycolytic end-metabolite lactate and the tricarboxylic acid cycle intermediate succinate. TAMs can react to these oncometabolites, resulting in an altered maturation and the adoption of pro-angiogenic features. These angiogenesis-promoting TAMs have been reported to cooperate with tumor cells in the formation of new vessels, and even have been considered an important cause of resistance against anti-angiogenic therapies. For a long time, the mechanisms by which lactate and succinate activated pro-angiogenic TAMs were not understood. Researchers now start to unravel and understand some of the underlying mechanisms. Here, the importance of microenvironmental cues in inducing different macrophage activation states is discussed, as well as the role of hypoxia in the recruitment and activation of pro-angiogenic macrophages. In addition, the latest findings on the oncometabolites lactate and succinate in the activation of angiogenesis supporting macrophages are reviewed. Finally, various oncometabolite-targeting therapeutic strategies are proposed that could improve the response to anti-angiogenic therapies. SIGNIFICANCE STATEMENT: Tumor-associated macrophages (TAMs) are known promotors of tumor neovascularization, and significantly contribute to the emergence of resistance to anti-angiogenic therapies. Recent evidence suggests that the angiogenesis promoting phenotype of TAMs can be activated by hypoxic tumor cell-derived oncometabolites, including lactate and succinate. Here, the latest findings into the lactate- and succinate-mediated mechanistic activation of pro-angiogenic TAMs are reviewed, and therapeutic strategies that interfere with this mechanism and may delay or even prevent acquired resistance to anti-angiogenic agents are discussed.
Topics: Angiogenesis Inhibitors; Cell Hypoxia; Cellular Reprogramming; Drug Resistance, Neoplasm; Humans; Lactic Acid; Neoplasms; Succinic Acid; Tumor Microenvironment; Tumor-Associated Macrophages
PubMed: 32961257
DOI: 10.1016/j.bbcan.2020.188427