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The Journal of Clinical Investigation May 2024Pancreatic β-cell dysfunction is a key feature of type 2 diabetes, and novel regulators of insulin secretion are desirable. Here we report that the succinate receptor...
Pancreatic β-cell dysfunction is a key feature of type 2 diabetes, and novel regulators of insulin secretion are desirable. Here we report that the succinate receptor (SUCNR1) is expressed in β-cells and is up-regulated in hyperglycemic states in mice and humans. We found that succinate acts as a hormone-like metabolite and stimulates insulin secretion via a SUCNR1-Gq-PKC-dependent mechanism in human β-cells. Mice with β-cell-specific Sucnr1 deficiency exhibit impaired glucose tolerance and insulin secretion on a high-fat diet, indicating that SUCNR1 is essential for preserving insulin secretion in diet-induced insulin resistance. Patients with impaired glucose tolerance show an enhanced nutritional-related succinate response, which correlates with the potentiation of insulin secretion during intravenous glucose administration. These data demonstrate that the succinate/SUCNR1 axis is activated by high glucose and identify a GPCR-mediated amplifying pathway for insulin secretion relevant to the hyperinsulinemia of prediabetic states.
PubMed: 38713514
DOI: 10.1172/JCI173214 -
IMeta Aug 2023Cardiovascular diseases (CVDs) continue to be a significant contributor to global mortality, imposing a substantial burden and emphasizing the urgent need for disease... (Review)
Review
Cardiovascular diseases (CVDs) continue to be a significant contributor to global mortality, imposing a substantial burden and emphasizing the urgent need for disease control to save lives and prevent disability. With advancements in technology and scientific research, novel mechanisms underlying CVDs have been uncovered, leading to the exploration of promising treatment targets aimed at reducing the global burden of the disease. One of the most intriguing findings is the relationship between CVDs and gut microbiota, challenging the traditional understanding of CVDs mechanisms and introducing the concept of the gut-heart axis. The gut microbiota, through changes in microbial compositions and functions, plays a crucial role in influencing local and systemic effects on host physiology and disease development, with its metabolites acting as key regulators. In previous studies, we have emphasized the importance of specific metabolites such as betaine, putrescine, trimethylamine oxide, and -trimethyl-5-aminovaleric acid in the potential treatment of CVDs. Particularly noteworthy is the gut microbiota-associated metabolite succinate, which has garnered significant attention due to its involvement in various pathophysiological pathways closely related to CVDs pathogenesis, including immunoinflammatory responses, oxidative stress, and energy metabolism. Furthermore, we have identified succinate as a potential biomarker, highlighting its therapeutic feasibility in managing aortic dissection and aneurysm. This review aims to comprehensively outline the characteristics of succinate, including its biosynthetic process, summarize the current evidence linking it to CVDs causation, and emphasize the host-microbial crosstalk involved in modulating CVDs. The insights presented here offer a novel paradigm for future management and control of CVDs.
PubMed: 38867936
DOI: 10.1002/imt2.124 -
Biofilm Dec 2023infection associated to gut microbiome dysbiosis is the leading cause for nosocomial diarrhea. The ability of to form biofilms has been progressively linked to its...
infection associated to gut microbiome dysbiosis is the leading cause for nosocomial diarrhea. The ability of to form biofilms has been progressively linked to its pathogenesis as well as its persistence in the gut. Although has been reported to form biofilms in an increasing number of conditions, little is known about how these biofilms are formed in the gut and what factors may trigger their formation. Here we report that succinate, a metabolite abundantly produced by the dysbiotic gut microbiota, induces biofilm formation of strains. We characterized the morphology and spatial composition of succinate-induced biofilms, and compared to non-induced or deoxycholate (DCA) induced biofilms. Biofilms induced by succinate are significantly thicker, structurally more complex, and poorer in proteins and exopolysaccharides (EPS). We then applied transcriptomics and genetics to characterize the early stages of succinate-induced biofilm formation and we showed that succinate-induced biofilm results from major metabolic shifts and cell-wall composition changes. Similar to DCA-induced biofilms, biofilms induced by succinate depend on the presence of a rapidly metabolized sugar. Finally, although succinate can be consumed by the bacteria, we found that the extracellular succinate is in fact responsible for the induction of biofilm formation through complex regulation involving global metabolic regulators and the osmotic stress response. Thus, our work suggests that as a gut signal, succinate may drive biofilm formation and help persistence of in the gut, increasing the risk of relapse.
PubMed: 37214349
DOI: 10.1016/j.bioflm.2023.100125 -
Frontiers in Cell and Developmental... 2023Succinate serves as an essential circulating metabolite within the tricarboxylic acid (TCA) cycle and functions as a substrate for succinate dehydrogenase (SDH), thereby... (Review)
Review
Succinate serves as an essential circulating metabolite within the tricarboxylic acid (TCA) cycle and functions as a substrate for succinate dehydrogenase (SDH), thereby contributing to energy production in fundamental mitochondrial metabolic pathways. Aberrant changes in succinate concentrations have been associated with pathological states, including chronic inflammation, ischemia/reperfusion (IR) injury, and cancer, resulting from the exaggerated response of specific immune cells, thereby rendering it a central area of investigation. Recent studies have elucidated the pivotal involvement of succinate and SDH in immunity beyond metabolic processes, particularly in the context of cancer. Current scientific endeavors are concentrated on comprehending the functional repercussions of metabolic modifications, specifically pertaining to succinate and SDH, in immune cells operating within a hypoxic milieu. The efficacy of targeting succinate and SDH alterations to manipulate immune cell functions in hypoxia-related diseases have been demonstrated. Consequently, a comprehensive understanding of succinate's role in metabolism and the regulation of SDH is crucial for effectively targeting succinate and SDH as therapeutic interventions to influence the progression of specific diseases. This review provides a succinct overview of the latest advancements in comprehending the emerging functions of succinate and SDH in metabolic processes. Furthermore, it explores the involvement of succinate, an intermediary of the TCA cycle, in chronic inflammation, IR injury, and cancer, with particular emphasis on the mechanisms underlying succinate accumulation. This review critically assesses the potential of modulating succinate accumulation and metabolism within the hypoxic milieu as a means to combat various diseases. It explores potential targets for therapeutic interventions by focusing on succinate metabolism and the regulation of SDH in hypoxia-related disorders.
PubMed: 37808079
DOI: 10.3389/fcell.2023.1266973 -
International Journal of Molecular... Nov 2023Oxygen deficiency is an environmental challenge which affects plant growth, the development and distribution in land and aquatic ecosystems, as well as crop yield losses... (Review)
Review
Oxygen deficiency is an environmental challenge which affects plant growth, the development and distribution in land and aquatic ecosystems, as well as crop yield losses worldwide. The capacity to exist in the conditions of deficiency or the complete lack of oxygen depends on a number of anatomic, developmental and molecular adaptations. The lack of molecular oxygen leads to an inhibition of aerobic respiration, which causes energy starvation and the acceleration of glycolysis passing into fermentations. We focus on systemic metabolic alterations revealed with the different approaches of metabolomics. Oxygen deprivation stimulates the accumulation of glucose, pyruvate and lactate, indicating the acceleration of the sugar metabolism, glycolysis and lactic fermentation, respectively. Among the Krebs-cycle metabolites, only the succinate level increases. Amino acids related to glycolysis, including the phosphoglycerate family (Ser and Gly), shikimate family (Phe, Tyr and Trp) and pyruvate family (Ala, Leu and Val), are greatly elevated. Members of the Asp family (Asn, Lys, Met, Thr and Ile), as well as the Glu family (Glu, Pro, Arg and GABA), accumulate as well. These metabolites are important members of the metabolic signature of oxygen deficiency in plants, linking glycolysis with an altered Krebs cycle and allowing alternative pathways of NAD(P)H reoxidation to avoid the excessive accumulation of toxic fermentation products (lactate, acetaldehyde, ethanol). Reoxygenation induces the downregulation of the levels of major anaerobically induced metabolites, including lactate, succinate and amino acids, especially members of the pyruvate family (Ala, Leu and Val), Tyr and Glu family (GABA and Glu) and Asp family (Asn, Met, Thr and Ile). The metabolic profiles during native and environmental hypoxia are rather similar, consisting in the accumulation of fermentation products, succinate, fumarate and amino acids, particularly Ala, Gly and GABA. The most intriguing fact is that metabolic alterations during oxidative stress are very much similar, with plant response to oxygen deprivation but not to reoxygenation.
Topics: Humans; Oxygen; Ecosystem; Amino Acids; Hypoxia; Lactates; Pyruvates; Succinates; gamma-Aminobutyric Acid; Peptide Fragments; Trypsin
PubMed: 38003412
DOI: 10.3390/ijms242216222 -
Redox Biology Apr 2024Inflammatory macrophages are key drivers of atherosclerosis that can induce rupture-prone vulnerable plaques. Skewing the plaque macrophage population towards a more...
Inflammatory macrophages are key drivers of atherosclerosis that can induce rupture-prone vulnerable plaques. Skewing the plaque macrophage population towards a more protective phenotype and reducing the occurrence of clinical events is thought to be a promising method of treating atherosclerotic patients. In the current study, we investigate the immunomodulatory properties of itaconate, an immunometabolite derived from the TCA cycle intermediate cis-aconitate and synthesised by the enzyme Aconitate Decarboxylase 1 (ACOD1, also known as IRG1), in the context of atherosclerosis. Ldlr atherogenic mice transplanted with Acod1 bone marrow displayed a more stable plaque phenotype with smaller necrotic cores and showed increased recruitment of monocytes to the vessel intima. Macrophages from Acod1 mice contained more lipids whilst also displaying reduced induction of apoptosis. Using multi-omics approaches, we identify a metabolic shift towards purine metabolism, in addition to an altered glycolytic flux towards production of glycerol for triglyceride synthesis. Overall, our data highlight the potential of therapeutically blocking ACOD1 with the aim of stabilizing atherosclerotic plaques.
Topics: Humans; Animals; Mice; Plaque, Atherosclerotic; Atherosclerosis; Succinates; Macrophages
PubMed: 38309122
DOI: 10.1016/j.redox.2024.103054 -
Advanced Biology Jul 2023Certain metabolic interventions such as caloric restriction, fasting, exercise, and a ketogenic diet extend lifespan and/or health span. However, their benefits are... (Review)
Review
Certain metabolic interventions such as caloric restriction, fasting, exercise, and a ketogenic diet extend lifespan and/or health span. However, their benefits are limited and their connections to the underlying mechanisms of aging are not fully clear. Here, these connections are explored in terms of the tricarboxylic acid (TCA) cycle (Krebs cycle, citric acid cycle) to suggest reasons for the loss of effectiveness and ways of overcoming it. Specifically, the metabolic interventions deplete acetate and likely reduce the conversion of oxaloacetate to aspartate, thereby inhibiting the mammalian target of rapamycin (mTOR) and upregulating autophagy. Synthesis of glutathione may provide a high-capacity sink for amine groups, facilitating autophagy, and prevent buildup of alpha-ketoglutarate, supporting stem cell maintenance. Metabolic interventions also prevent the accumulation of succinate, thereby slowing DNA hypermethylation, facilitating the repair of DNA double-strand breaks, reducing inflammatory and hypoxic signaling, and lowering reliance on glycolysis. In part through these mechanisms, metabolic interventions may decelerate aging, extending lifespan. Conversely, with overnutrition or oxidative stress, these processes function in reverse, accelerating aging and impairing longevity. Progressive damage to aconitase, inhibition of succinate dehydrogenase, and downregulation of hypoxia-inducible factor-1α, and phosphoenolpyruvate carboxykinase (PEPCK) emerge as potentially modifiable reasons for the loss of effectiveness of metabolic interventions.
Topics: Citric Acid Cycle; Aconitate Hydratase; Glycolysis; DNA
PubMed: 37132059
DOI: 10.1002/adbi.202300095 -
Science Advances Jun 2023P23, historically known as a heat shock protein 90 (HSP90) co-chaperone, exerts some of its critical functions in an HSP90-independent manner, particularly when it...
P23, historically known as a heat shock protein 90 (HSP90) co-chaperone, exerts some of its critical functions in an HSP90-independent manner, particularly when it translocates into the nucleus. The molecular nature underlying how this HSP90-independent p23 function is achieved remains as a biological mystery. Here, we found that p23 is a previously unidentified transcription factor of COX-2, and its nuclear localization predicts the poor clinical outcomes. Intratumor succinate promotes p23 succinylation at K7, K33, and K79, which drives its nuclear translocation for COX-2 transcription and consequently fascinates tumor growth. We then identified M16 as a potent p23 succinylation inhibitor from 1.6 million compounds through a combined virtual and biological screening. M16 inhibited p23 succinylation and nuclear translocation, attenuated COX-2 transcription in a p23-dependent manner, and markedly suppressed tumor growth. Therefore, our study defines p23 as a succinate-activated transcription factor in tumor progression and provides a rationale for inhibiting p23 succinylation as an anticancer chemotherapy.
Topics: Humans; Succinic Acid; Transcription Factors; Cyclooxygenase 2; Pyridinolcarbamate; Carcinogenesis; Cell Transformation, Neoplastic; Succinates; Adenocarcinoma of Lung; Molecular Chaperones; HSP90 Heat-Shock Proteins; Lung Neoplasms
PubMed: 37390202
DOI: 10.1126/sciadv.ade0387 -
Basic Research in Cardiology Aug 2023In the context of myocardial infarction, the burst of superoxide generated by reverse electron transport (RET) at complex I in mitochondria is a crucial trigger for... (Review)
Review
In the context of myocardial infarction, the burst of superoxide generated by reverse electron transport (RET) at complex I in mitochondria is a crucial trigger for damage during ischaemia/reperfusion (I/R) injury. Here we outline the necessary conditions for superoxide production by RET at complex I and how it can occur during reperfusion. In addition, we explore various pathways that are implicated in generating the conditions for RET to occur and suggest potential therapeutic strategies to target RET, aiming to achieve cardioprotection.
Topics: Humans; Electron Transport; Superoxides; Oxidative Phosphorylation; Mitochondria; Myocardial Infarction; Reperfusion Injury
PubMed: 37639068
DOI: 10.1007/s00395-023-01002-4