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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 -
Trends in Endocrinology and Metabolism:... Sep 2021There has been an explosion of interest in the signaling capacity of energy metabolites. A prime example is the Krebs cycle substrate succinate, an archetypal... (Review)
Review
There has been an explosion of interest in the signaling capacity of energy metabolites. A prime example is the Krebs cycle substrate succinate, an archetypal respiratory substrate with functions beyond energy production as an intracellular and extracellular signaling molecule. Long associated with inflammation, emerging evidence supports a key role for succinate in metabolic processes relating to energy management. As the natural ligand for SUCNR1, a G protein-coupled receptor, succinate is akin to hormones and likely functions as a reporter of metabolism and stress. In this review, we reconcile new and old observations to outline a regulatory role for succinate in metabolic homeostasis. We highlight the importance of the succinate-SUCNR1 axis in metabolic diseases as an integrator of macrophage immune response, and we discuss new metabolic functions recently ascribed to succinate in specific tissues. Because circulating succinate has emerged as a promising biomarker in chronic metabolic diseases, a better understanding of the physiopathological role of the succinate-SUCNR1 axis in metabolism might open new avenues for clinical use in patients with obesity or diabetes.
Topics: Animals; Energy Metabolism; Homeostasis; Humans; Receptors, G-Protein-Coupled; Succinic Acid
PubMed: 34301438
DOI: 10.1016/j.tem.2021.06.003 -
European Heart Journal Nov 2021
Topics: Aortic Diseases; Humans; Succinates; Succinic Acid
PubMed: 34564722
DOI: 10.1093/eurheartj/ehab514 -
Investigative Ophthalmology & Visual... Apr 2022Succinate is exported by the retina and imported by eyecup tissue. The transporters mediating this process have not yet been identified. Recent studies showed that...
PURPOSE
Succinate is exported by the retina and imported by eyecup tissue. The transporters mediating this process have not yet been identified. Recent studies showed that monocarboxylate transporter 1 (MCT1) can transport succinate across plasma membranes in cardiac and skeletal muscle. Retina and retinal pigment epithelium (RPE) both express multiple MCT isoforms including MCT1. We tested the hypothesis that MCTs facilitate retinal succinate export and RPE succinate import.
METHODS
We assessed retinal succinate export and eyecup succinate import in short-term ex vivo culture using gas chromatography-mass spectrometry. We tested the dependence of succinate export and import on pH, proton ionophores, conventional MCT substrates, and the MCT inhibitors AZD3965, AR-C155858, and diclofenac.
RESULTS
Succinate exits retinal tissue through MCT1 but does not enter the RPE through MCT1 or any other MCT. Intracellular succinate levels are a contributing factor that determines if an MCT1-expressing tissue will export succinate.
CONCLUSIONS
MCT1 facilitates export of succinate from retinas. An unidentified, non-MCT transporter facilitates import of succinate into RPE.
Topics: Membrane Transport Proteins; Retina; Retinal Pigment Epithelium; Succinates; Succinic Acid
PubMed: 35363247
DOI: 10.1167/iovs.63.4.1 -
Biomaterials Oct 2023Succinate is an important metabolite that modulates metabolism of immune cells and cancer cells in the tumor microenvironment (TME). Herein, we report that polyethylene...
Succinate is an important metabolite that modulates metabolism of immune cells and cancer cells in the tumor microenvironment (TME). Herein, we report that polyethylene succinate (PES) microparticles (MPs) biomaterial mediated controlled delivery of succinate in the TME modulates macrophage responses. Administering PES MPs locally with or without a BRAF inhibitor systemically in an immune-defective aging mice with clinically relevant BRAF mutated YUMM1.1 melanoma decreased tumor volume three-fold. PES MPs in the TME also led to maintenance of M1 macrophages with up-regulation of TSLP and type 1 interferon pathway. Impressively, this led to generation of pro-inflammatory adaptive immune responses in the form of increased T helper type 1 and T helper type 17 cells in the TME. Overall, our findings from this challenging tumor model suggest that immunometabolism-modifying PES MP strategies provide an approach for developing robust cancer immunotherapies.
Topics: Animals; Mice; Succinic Acid; Tumor-Associated Macrophages; Tumor Microenvironment; Proto-Oncogene Proteins B-raf; Succinates; Melanoma
PubMed: 37643489
DOI: 10.1016/j.biomaterials.2023.122292 -
International Immunopharmacology Jul 2023Intestinal ischemia-reperfusion (I/R) injury is a common pathophysiological process in various diseases, and the disruption of the intestinal barrier composed of tight...
Intestinal ischemia-reperfusion (I/R) injury is a common pathophysiological process in various diseases, and the disruption of the intestinal barrier composed of tight junction proteins is the initiating factor, which then leads to a large number of bacteria and endotoxins in the intestine into the bloodstream causing stress and distant organ damage. The release of inflammatory mediators and abnormal programmed death of intestinal epithelial cells are important factors of intestinal barrier damage. Succinate is an intermediate product of the tricarboxylic acid cycle with anti-inflammatory and pro-angiogenic activities, but its role in the maintenance of intestinal barrier homeostasis after I/R has not been fully elucidated. In this study, we explored the effect of succinate on intestinal ischemia-reperfusion injury and the possible mechanism of its role by flow cytometry, western blotting, real-time quantitative PCR and immunostaining. The results of pretreatment with succinate in the mouse intestinal I/R model and IEC-6 cells hypoxia-reoxygenation (H/R) model revealed a reduction in tissue damage, necroptosis and associated inflammation due to ischemia-reperfusion. Furthermore, it was found that the protective effect of succinate pretreatment may be associated with the transcriptional upregulation of the inflammatory protein KLF4 and the protective effect of intestinal barrier of succinate was diminished after inhibition of KLF4. Thus, our results suggest that succinate can exert a protective effect in intestinal ischemia-reperfusion injury through upregulation of KLF4 and also demonstrate the potential therapeutic value of succinate pretreatment in acute I/R injury of the intestine.
Topics: Animals; Mice; Rats; Inflammation; Intestines; Necroptosis; Reperfusion Injury; Succinates; Succinic Acid; Kruppel-Like Factor 4
PubMed: 37285681
DOI: 10.1016/j.intimp.2023.110425 -
International Immunopharmacology Sep 2022Sepsis is a life-threatening disease characterized by a defensive response to damage. The immune response in patients with sepsis is overenhanced in the early stages and... (Review)
Review
Sepsis is a life-threatening disease characterized by a defensive response to damage. The immune response in patients with sepsis is overenhanced in the early stages and suppressed in the later stages, leading to poor prognosis. Metabolic reprogramming and epigenetic changes play a role in sepsis. Metabolic intermediates such as elevated succinic acid levels are significantly altered in patients with sepsis. Succinic acid, a metabolic intermediate of the tricarboxylic acid cycle, participates in energy supply and plays a role in metabolic reprogramming. Simultaneously, as an epigenetic regulator, it participates in gene transcription, translation, and post-translational modifications. It also participates in the inflammatory response, hypoxia, and the production of reactive oxygen species via endocrine and paracrine pathways. In this review, we have discussed the effects of succinic acid on sepsis and its therapeutic potential.
Topics: Epigenesis, Genetic; Humans; Protein Processing, Post-Translational; Sepsis; Succinic Acid
PubMed: 35853278
DOI: 10.1016/j.intimp.2022.109065 -
Biotechnology Advances Dec 2017As an important intermediate feedstock, succinate is termed as one of the 12 bio-based platform chemicals. To improve its fermentative production, various strategies... (Review)
Review
As an important intermediate feedstock, succinate is termed as one of the 12 bio-based platform chemicals. To improve its fermentative production, various strategies have been developed, but challenges are still ahead for succinate biosynthesis to be cost-competitive. In this article, strategies for succinate production through metabolic engineering of Escherichia coli are critically reviewed, with a focus on engineering by-product formation and CO fixation, substrate utilization, reducing power balance, metabolic evolution and transcriptional regulation, which provide insights for the current state of succinate production and perspectives for further research for more efficient and economical production of bio-based succinate.
Topics: Carbon Dioxide; Escherichia coli; Fermentation; Metabolic Engineering; Succinic Acid
PubMed: 28939498
DOI: 10.1016/j.biotechadv.2017.09.007