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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 -
Cellular and Molecular Life Sciences :... Jun 2018In the last decade, metabolism has been recognized as a major determinant of immunological processes. During an inflammatory response, macrophages undergo striking... (Review)
Review
In the last decade, metabolism has been recognized as a major determinant of immunological processes. During an inflammatory response, macrophages undergo striking changes in their metabolism. This metabolic reprogramming is governed by a complex interplay between metabolic enzymes and metabolites of different pathways and represents the basis for proper macrophage function. It is now evident that these changes go far beyond the well-known Warburg effect and the perturbation of metabolic targets is being investigated as a means to treat infections and auto-immune diseases. In the present review, we will aim to provide an overview of the metabolic responses during proinflammatory macrophage activation and show how these changes modulate the immune response.
Topics: Animals; Communicable Diseases; Energy Metabolism; Glycolysis; Humans; Inflammation; Macrophage Activation; Macrophages; Metabolic Networks and Pathways; Reactive Oxygen Species; Succinates; Succinic Acid
PubMed: 29502308
DOI: 10.1007/s00018-018-2784-1 -
American Journal of Physiology. Cell... Feb 2023Succinate has long been known to be only an intermediate product of the tricarboxylic acid cycle until identified as a natural ligand for SUCNR1 in 2004. SUCNR1 is...
Succinate has long been known to be only an intermediate product of the tricarboxylic acid cycle until identified as a natural ligand for SUCNR1 in 2004. SUCNR1 is widely expressed throughout the body, especially in the kidney. Abnormally elevated succinate is associated with many diseases, including obesity, type 2 diabetes, nonalcoholic fatty liver disease, and ischemia injury, but it is not known whether succinate can cause kidney damage. This study showed that succinate induced apparent renal injury after treatment for 12 wk, characterized by a reduction in 24 h urine and the significant detachment of the brush border of proximal tubular epithelial cells, tubular dilation, cast formation, and vacuolar degeneration of tubular cells in succinate-treated mice. Besides, succinate caused tubular epithelial cell apoptosis in kidneys and HK-2 cells. Mechanistically, succinate triggered cell apoptosis via SUCNR1 activation. In addition, succinate upregulated ERK by binding to SUCNR1, and inhibition of ERK using PD98059 abolished the proapoptotic effects of succinate in HK-2 cells. In summary, our study provides the first evidence that succinate acts as a risk factor and contributes to renal injury, and further research is required to discern the pathological effects of succinate on renal functions.
Topics: Animals; Mice; Apoptosis; Diabetes Mellitus, Type 2; Epithelial Cells; Kidney; Receptors, G-Protein-Coupled; Succinates; Succinic Acid
PubMed: 36622070
DOI: 10.1152/ajpcell.00327.2022 -
American Journal of Physiology.... Mar 2023Obesity is one of the leading noncommunicable diseases in the world. Despite intense efforts to develop strategies to prevent and treat obesity, its prevalence continues...
Obesity is one of the leading noncommunicable diseases in the world. Despite intense efforts to develop strategies to prevent and treat obesity, its prevalence continues to rise worldwide. A recent study has shown that the tricarboxylic acid intermediate succinate increases body energy expenditure by promoting brown adipose tissue thermogenesis through the activation of uncoupling protein-1; this has generated interest surrounding its potential usefulness as an approach to treat obesity. It is currently unknown how succinate impacts brown adipose tissue protein expression, and how exogenous succinate impacts body mass reduction promoted by a drug approved to treat human obesity, the glucagon-like-1 receptor agonist, liraglutide. In the first part of this study, we used bottom-up shotgun proteomics to determine the acute impact of exogenous succinate on the brown adipose tissue. We show that succinate rapidly affects the expression of 177 brown adipose tissue proteins, which are mostly associated with mitochondrial structure and function. In the second part of this study, we performed a short-term preclinical pharmacological intervention, treating diet-induced obese mice with a combination of exogenous succinate and liraglutide. We show that the combination was more efficient than liraglutide alone in promoting body mass reduction, food energy efficiency reduction, food intake reduction, and an increase in body temperature. Using serum metabolomics analysis, we showed that succinate, but not liraglutide, promoted a significant increase in the blood levels of several medium and long-chain fatty acids. In conclusion, exogenous succinate promotes rapid changes in brown adipose tissue mitochondrial proteins, and when used in association with liraglutide, increases body mass reduction. Exogenous succinate induces major changes in brown adipose tissue protein expression affecting particularly mitochondrial respiration and structural proteins. When given exogenously in drinking water, succinate mitigates body mass gain in a rodent model of diet-induced obesity; in addition, when given in association with the glucagon-like peptide-1 receptor agonist, liraglutide, succinate increases body mass reduction promoted by liraglutide alone.
Topics: Animals; Mice; Adipose Tissue, Brown; Energy Metabolism; Liraglutide; Obesity; Proteome; Succinic Acid; Thermogenesis; Uncoupling Protein 1
PubMed: 36724126
DOI: 10.1152/ajpendo.00231.2022 -
Pflugers Archiv : European Journal of... Jan 2013One emerging topic in renin-angiotensin system (RAS) research is the direct local control of renin synthesis and release by endogenous metabolic intermediates. During... (Review)
Review
One emerging topic in renin-angiotensin system (RAS) research is the direct local control of renin synthesis and release by endogenous metabolic intermediates. During the past few years, our laboratory has characterized the localization and signaling of the novel metabolic receptor GPR91 in the normal and diabetic kidney and established GPR91 as a new, direct link between high glucose and RAS activation in diabetes. GPR91 (also called SUCNR1) binds tricarboxylic acid (TCA) cycle intermediate succinate which can rapidly accumulate in the local tissue environment when energy supply and demand are out of balance. In a variety of physiological and pathological conditions associated with metabolic stress, succinate signaling via GPR91 appears to be an important mediator or modulator of renin secretion. This review summarizes our current knowledge on the control of renin release by molecules of endogenous metabolic pathways with the main focus on succinate/GPR91.
Topics: Animals; Diabetes Mellitus, Type 2; Humans; Receptors, G-Protein-Coupled; Renin; Renin-Angiotensin System; Stress, Physiological; Succinic Acid
PubMed: 22729752
DOI: 10.1007/s00424-012-1130-y -
Proceedings of the National Academy of... Jun 2023Gut microbiota imbalance (dysbiosis) is increasingly associated with pathological conditions, both within and outside the gastrointestinal tract. Intestinal Paneth cells...
Gut microbiota imbalance (dysbiosis) is increasingly associated with pathological conditions, both within and outside the gastrointestinal tract. Intestinal Paneth cells are considered to be guardians of the gut microbiota, but the events linking Paneth cell dysfunction with dysbiosis remain unclear. We report a three-step mechanism for dysbiosis initiation. Initial alterations in Paneth cells, as frequently observed in obese and inflammatorybowel diseases patients, cause a mild remodeling of microbiota, with amplification of succinate-producing species. SucnR1-dependent activation of epithelial tuft cells triggers a type 2 immune response that, in turn, aggravates the Paneth cell defaults, promoting dysbiosis and chronic inflammation. We thus reveal a function of tuft cells in promoting dysbiosis following Paneth cell deficiency and an unappreciated essential role of Paneth cells in maintaining a balanced microbiota to prevent inappropriate activation of tuft cells and deleterious dysbiosis. This succinate-tuft cell inflammation circuit may also contribute to the chronic dysbiosis observed in patients.
Topics: Humans; Dysbiosis; Mucous Membrane; Inflammation; Paneth Cells; Succinates; Succinic Acid
PubMed: 37307458
DOI: 10.1073/pnas.2219431120 -
Cell Communication and Signaling : CCS Jan 2016Since it was discovered, the citric acid cycle has been known to be central to cell metabolism and energy homeostasis. Mainly found in the mitochondrial matrix, some of... (Review)
Review
Since it was discovered, the citric acid cycle has been known to be central to cell metabolism and energy homeostasis. Mainly found in the mitochondrial matrix, some of the intermediates of the Krebs cycle are also present in the blood stream. Currently, there are several reports that indicate functional roles for Krebs intermediates out of its cycle. Succinate, for instance, acts as an extracellular ligand by binding to a G-protein coupled receptor, known as GPR91, expressed in kidney, liver, heart, retinal cells and possibly many other tissues, leading to a wide array of physiological and pathological effects. Through GPR91, succinate is involved in functions such as regulation of blood pressure, inhibition of lipolysis in white adipose tissue, development of retinal vascularization, cardiac hypertrophy and activation of stellate hepatic cells by ischemic hepatocytes. Along the current review, these new effects of succinate through GPR91 will be explored and discussed.
Topics: Animals; Blood Pressure; Citric Acid Cycle; Gene Expression; Humans; Liver; Models, Molecular; Myocardium; Receptors, G-Protein-Coupled; Retina; Signal Transduction; Succinic Acid
PubMed: 26759054
DOI: 10.1186/s12964-016-0126-1 -
British Journal of Pharmacology May 2017The succinate receptor (formerly GPR91 or SUCNR1) is described as a metabolic sensor that may be involved in homeostasis. Notwithstanding its implication in important...
BACKGROUND AND PURPOSE
The succinate receptor (formerly GPR91 or SUCNR1) is described as a metabolic sensor that may be involved in homeostasis. Notwithstanding its implication in important (patho)physiological processes, the function of succinate receptors has remained ill-defined because no pharmacological tools were available. We report on the discovery of the first family of potent synthetic agonists.
EXPERIMENTAL APPROACH
We screened a library of succinate analogues and analysed their activity on succinate receptors. Also, we modelled a pharmacophore and a binding site for this receptor. New agonists were identified based on the information provided by these two approaches. Their activity was studied in various bioassays, including measurement of cAMP levels, [Ca ] mobilization, TGF-α shedding and recruitment of arrestin 3. The in vivo effects of activating succinate receptors with these new agonists was evaluated on rat BP.
KEY RESULTS
We identified cis-epoxysuccinic acid and cis-1,2-cyclopropanedicarboxylic acid as agonists with an efficacy similar to that of succinic acid. Interestingly, cis-epoxysuccinic acid was 10- to 20-fold more potent than succinic acid on succinate receptors. For example, cis-epoxysuccinic acid reduced cAMP levels with a pEC = 5.57 ± 0.02 (EC = 2.7 μM), compared with succinate pEC = 4.54 ± 0.08 (EC = 29 μM). The rank order of potency of the three agonists was the same in all in vitro assays. Both cis-epoxysuccinic and cis-1,2-cyclopropanedicarboxylic acid were as potent as succinate in increasing rat BP.
CONCLUSIONS AND IMPLICATIONS
We describe new agonists at succinate receptors that should facilitate further research on this understudied receptor.
Topics: Animals; Binding Sites; Cyclic AMP; Dose-Response Relationship, Drug; HEK293 Cells; Humans; Male; Protein Structure, Secondary; Random Allocation; Rats; Rats, Wistar; Receptors, G-Protein-Coupled; Succinic Acid
PubMed: 28160606
DOI: 10.1111/bph.13738 -
The Journal of Biological Chemistry Jul 2016Metabolic reprogramming is emerging as a hallmark of the innate immune response, and the dynamic control of metabolites such as succinate serves to facilitate the...
Metabolic reprogramming is emerging as a hallmark of the innate immune response, and the dynamic control of metabolites such as succinate serves to facilitate the execution of inflammatory responses in macrophages and other immune cells. Immunoresponsive gene 1 (Irg1) expression is induced by inflammatory stimuli, and its enzyme product cis-aconitate decarboxylase catalyzes the production of itaconate from the tricarboxylic acid cycle. Here we identify an immunometabolic regulatory pathway that links Irg1 and itaconate production to the succinate accumulation that occurs in the context of innate immune responses. Itaconate levels and Irg1 expression correlate strongly with succinate during LPS exposure in macrophages and non-immune cells. We demonstrate that itaconate acts as an endogenous succinate dehydrogenase inhibitor to cause succinate accumulation. Loss of itaconate production in activated macrophages from Irg1(-/-) mice decreases the accumulation of succinate in response to LPS exposure. This metabolic network links the innate immune response and tricarboxylic acid metabolism to function of the electron transport chain.
Topics: Animals; Cell Line; Hydro-Lyases; Lipopolysaccharides; Macrophages; Mice; Succinate Dehydrogenase; Succinates; Succinic Acid
PubMed: 27189937
DOI: 10.1074/jbc.M115.685792 -
Cell Reports Feb 2023Succinate dehydrogenase (SDH) is a heterotetrameric enzyme complex belonging to the mitochondrial respiratory chain and uniquely links the tricarboxylic acid (TCA) cycle...
Succinate dehydrogenase (SDH) is a heterotetrameric enzyme complex belonging to the mitochondrial respiratory chain and uniquely links the tricarboxylic acid (TCA) cycle with oxidative phosphorylation. Cancer-related SDH mutations promote succinate accumulation, which is regarded as an oncometabolite. Post-translational modifications of SDH complex components are known to regulate SDH activity, although the contribution of SUMOylation remains unclear. Here, we show that SDHA is SUMOylated by PIAS3 and deSUMOylated by SENP2, events dictating the assembly and activity of the SDH complex. Moreover, CBP acetylation of SENP2 negatively regulates its deSUMOylation activity. Under glutamine deprivation, CBP levels decrease, and the ensuing SENP2 activation and SDHA deSUMOylation serve to concurrently dampen the TCA cycle and electron transport chain (ETC) activity. Along with succinate accumulation, this mechanism avoids excessive reactive oxygen species (ROS) production to promote cancer cell survival. This study elucidates a major function of mitochondrial-localized SENP2 and expands our understanding of the role of SUMOylation in resolving metabolic stress.
Topics: Humans; Mitochondria; Mitochondrial Membranes; Neoplasms; Succinic Acid; Stress, Physiological; Molecular Chaperones; Protein Inhibitors of Activated STAT; Cysteine Endopeptidases
PubMed: 36708515
DOI: 10.1016/j.celrep.2023.112041