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If deprived of exogenous glutamine, naive mouse embryonic stem cells are shown to be capable of generating the amino acid from other sources to enable their proliferation; the stem cells use glutamine and glucose catabolism to maintain a high level of intracellular α-ketoglutarate and promote demethylation of chromatin and ensure sufficient expression of pluripotency-associated genes. Alternative metabolism in stem cells The role of cellular metabolism in regulating stem cell proliferation and differentiation has not been explored in great detail. Craig Thompson and colleagues now show that naive mouse embryonic stem cells can proliferate in the absence of exogenous glutamine, an amino acid normally essential for the growth of mammalian cells, while consuming it avidly when it is present. The cells catabolize glutamine and glucose to maintain high levels of downstream metabolites controlling chromatin modifications and DNA methylation, so as to ensure sufficient expression of pluripotency-associated genes. The role of cellular metabolism in regulating cell proliferation and differentiation remains poorly understood 1 . For example, most mammalian cells cannot proliferate without exogenous glutamine supplementation even though glutamine is a non-essential amino acid 1 , 2 . Here we show that mouse embryonic stem (ES) cells grown under conditions that maintain naive pluripotency 3 are capable of proliferation in the absence of exogenous glutamine. Despite this, ES cells consume high levels of exogenous glutamine when the metabolite is available. In comparison to more differentiated cells, naive ES cells utilize both glucose and glutamine catabolism to maintain a high level of intracellular α-ketoglutarate (αKG). Consequently, naive ES cells exhibit an elevated αKG to succinate ratio that promotes histone/DNA demethylation and maintains pluripotency. Direct manipulation of the intracellular αKG/succinate ratio is sufficient to regulate multiple chromatin modifications, including H3K27me3 and ten-eleven translocation (Tet)-dependent DNA demethylation, which contribute to the regulation of pluripotency-associated gene expression. In vitro , supplementation with cell-permeable αKG directly supports ES-cell self-renewal while cell-permeable succinate promotes differentiation. This work reveals that intracellular αKG/succinate levels can contribute to the maintenance of cellular identity and have a mechanistic role in the transcriptional and epigenetic state of stem cells.

Succinate is a signaling metabolite sensed extracellularly by succinate receptor 1 (SUNCR1). The accumulation of succinate in macrophages is known to activate a pro-inflammatory program; however, the contribution of SUCNR1 to macrophage phenotype and function has remained unclear. Here we found that activation of SUCNR1 had a critical role in the anti-inflammatory responses in macrophages. Myeloid-specific deficiency in SUCNR1 promoted a local pro-inflammatory phenotype, disrupted glucose homeostasis in mice fed a normal chow diet, exacerbated the metabolic consequences of diet-induced obesity and impaired adipose-tissue browning in response to cold exposure. Activation of SUCNR1 promoted an anti-inflammatory phenotype in macrophages and boosted the response of these cells to type 2 cytokines, including interleukin-4. Succinate decreased the expression of inflammatory markers in adipose tissue from lean human subjects but not that from obese subjects, who had lower expression of SUCNR1 in adipose-tissue-resident macrophages. Our findings highlight the importance of succinate–SUCNR1 signaling in determining macrophage polarization and assign a role to succinate in limiting inflammation. Succinate is a signaling metabolite sensed extracellularly by SUNCR1. Fernandez-Veledo and colleagues show that activation of SUCNR1 promotes an anti-inflammatory phenotype in adipose-tissue macrophages in lean mice and people.

Thermogenesis by brown and beige adipose tissue, which requires activation by external stimuli, can counter metabolic disease 1 . Thermogenic respiration is initiated by adipocyte lipolysis through cyclic AMP–protein kinase A signalling; this pathway has been subject to longstanding clinical investigation 2 – 4 . Here we apply a comparative metabolomics approach and identify an independent metabolic pathway that controls acute activation of adipose tissue thermogenesis in vivo. We show that substantial and selective accumulation of the tricarboxylic acid cycle intermediate succinate is a metabolic signature of adipose tissue thermogenesis upon activation by exposure to cold. Succinate accumulation occurs independently of adrenergic signalling, and is sufficient to elevate thermogenic respiration in brown adipocytes. Selective accumulation of succinate may be driven by a capacity of brown adipocytes to sequester elevated circulating succinate. Furthermore, brown adipose tissue thermogenesis can be initiated by systemic administration of succinate in mice. Succinate from the extracellular milieu is rapidly metabolized by brown adipocytes, and its oxidation by succinate dehydrogenase is required for activation of thermogenesis. We identify a mechanism whereby succinate dehydrogenase-mediated oxidation of succinate initiates production of reactive oxygen species, and drives thermogenic respiration, whereas inhibition of succinate dehydrogenase supresses thermogenesis. Finally, we show that pharmacological elevation of circulating succinate drives UCP1-dependent thermogenesis by brown adipose tissue in vivo, which stimulates robust protection against diet-induced obesity and improves glucose tolerance. These findings reveal an unexpected mechanism for control of thermogenesis, using succinate as a systemically-derived thermogenic molecule. A comparative metabolomics approach is used to identify succinate as a key activator of thermogenesis in brown adipose tissue.

The hereditary cancer syndromes hereditary leiomyomatosis and renal cell cancer (HLRCC) and succinate dehydrogenase–related hereditary paraganglioma and pheochromocytoma (SDH PGL/PCC) are linked to germline loss-of-function mutations in genes encoding the Krebs cycle enzymes fumarate hydratase and succinate dehydrogenase, thus leading to elevated levels of fumarate and succinate, respectively 1 – 3 . Here, we report that fumarate and succinate both suppress the homologous recombination (HR) DNA-repair pathway required for the resolution of DNA double-strand breaks (DSBs) and for the maintenance of genomic integrity, thus rendering tumor cells vulnerable to synthetic-lethal targeting with poly(ADP)-ribose polymerase (PARP) inhibitors. These results identify HLRCC and SDH PGL/PCC as familial DNA-repair deficiency syndromes, providing a mechanistic basis to explain their cancer predisposition and suggesting a potentially therapeutic approach for advanced HLRCC and SDH PGL/PCC, both of which are incurable when metastatic. High levels of fumarate or succinate suppress the homologous-recombination DNA-repair pathway in cancer cells that are deficient for FH or SDH, respectively. These tumor cells are vulnerable to PARP inhibitors.

We studied the effects of original Russian derivatives of 3-hydroxypyridine and succinic acid (emoxipine, reamberin and mexidol) on the time course of endometrial leukocyte infiltration, blood levels of inflammatory cytokines (IL-1β and TNF-α), and indicators of affective status in women with exacerbation of the chronic inflammation of the uterus and adnexa. It was found that emoxipine, reamberin, and mexidol included in the complex therapy corrects anxiety and depressive disorders depending on the degree of reduction of endometrial leukocyte infiltration and blood levels of inflammatory cytokines. Derivatives of 3-hydroxypyridine (emoxipine and mexidol) exhibited efficiency, which were superior to derivative of succinic acid (reamberin) in the degree of reduction in endometrial leukocyte and neutrophyl infiltration and in severity of anxiety and depressive disorders. Mexidol, a 3-hydroxypyridine and succinic acid derivative, was most effective and surpassed emoxipine by the degree of reduction of inflammatory cytokine level in the blood and the severity of affective anxiety symptoms in women with exacerbation of the chronic inflammation of the uterus and adnexa.

The basic tendency in the field of plant protection concerns with reducing the use of pesticides and their replacement by environmentally acceptable biological preparations. The most promising approach to plant protection is application of microbial metabolites. In the last years, bactericidal, fungicidal, and nematodocidal activities were revealed for citric, succinic, α-ketoglutaric, palmitoleic, and other organic acids. It was shown that application of carboxylic acids resulted in acceleration of plant development and the yield increase. Of special interest is the use of arachidonic acid in very low concentrations as an inductor (elicitor) of protective functions in plants. The bottleneck in practical applications of these simple, nontoxic, and moderately priced preparations is the absence of industrial production of the mentioned organic acids of required quality since even small contaminations of synthetic preparations decrease their quality and make them dangerous for ecology and toxic for plants, animals, and human. This review gives a general conception on the use of organic acids for plant protection against the most dangerous pathogens and pests, as well as focuses on microbiological processes for production of these microbial metabolites of high quality from available, inexpensive, and renewable substrates.

Mitochondrial complex I (CI) deficiency is the most prevalent defect in the respiratory chain in paediatric mitochondrial disease. This heterogeneous group of diseases includes serious or fatal neurological presentations such as Leigh syndrome and there are very limited evidence-based treatment options available. Here we describe that cell membrane-permeable prodrugs of the complex II substrate succinate increase ATP-linked mitochondrial respiration in CI-deficient human blood cells, fibroblasts and heart fibres. Lactate accumulation in platelets due to rotenone-induced CI inhibition is reversed and rotenone-induced increase in lactate:pyruvate ratio in white blood cells is alleviated. Metabolomic analyses demonstrate delivery and metabolism of [ 13 C]succinate. In Leigh syndrome patient fibroblasts, with a recessive NDUFS2 mutation, respiration and spare respiratory capacity are increased by prodrug administration. We conclude that prodrug-delivered succinate bypasses CI and supports electron transport, membrane potential and ATP production. This strategy offers a potential future therapy for metabolic decompensation due to mitochondrial CI dysfunction. Mitochondrial complex I deficiency is the most common respiratory chain defect in mitochondrial disease in children and currently there is no effective treatment. In this study, the authors show that succinate prodrugs can alleviate metabolic decompensation in Leigh syndrome patient fibroblasts.

Background Growth regulators play an important role in activating the main signal transduction pathways in response to stress, and their activity is key in the general mechanism to understanding the formation of phytoimmunity under biotic stress. The study investigates the specificity of stress-protective reactions in winter wheat varieties with varying degrees of sensitivity to the phytopathogen Blumeria graminis (DC) Speer f. sp. tritici , and determined the effectiveness of exogenous salicylic and succinic acids as inducers of resistance to powdery mildew. Results Exogenous application of 0.1 mM salicylic acid induced stress-protective reactions in the resistant wheat, characterised by increased ethylene release, and phenylalanine amino-lyase and ascorbate peroxidase activity in the flag leaves. These steps help optimize its physiological state and productivity by preserving the integrity of cell membranes and its chlorophyll content. Exogenous succinic acid at a concentration of 0.1 mM also led to the activation of protective antioxidant systems, which did not have a positive effect on plant physiology or productivity during infection. The susceptible variety of winter wheat was unable to mobilize the necessary stress-protective systems, regardless of salicylic or succinic acid treatment, resulting in the spread of infection and reduced productivity. Conclusions The resistance of winter wheat to phytopathogen damage ( Blumeria graminis (DC) Speer f. sp. tritici ) is determined by the capacity of the plant to mobilize stress-protective reactions and optimize its metabolism. Salicylic acid (0.1 mM) effectively enhances plant defence systems, thus improving plant physiology and productivity during the spread of powdery mildew.

Recently, studies on the effects of non-toxic substances on cancer prophylaxis have gained value as an alternative to existing treatment options. Current studies have shown that succinic acid or its derivatives exhibit anticancer activity by inducing apoptosis. We aimed to investigate the anticancer activity of succinic acid on renal cancer for the first time in the literature. The cytotoxic activity of succinic acid on CAKI-2 and ACHN as renal cancer cell lines and MRC-5 as a healthy cell line was determined using the WST-1 cytotoxicity test. Apoptotic activity was measured by Annexin V test and cell death ELISA kit. The results showed that 25 μM and 50 μM doses of succinic acid for 24 h remarkably reduced the cell viability for CAKI-2 cells (89.77% and 90.77%) and ACHN cells (41.57% and 54.54%). Also, no significant effect was observed on the healthy cell line, as we expected. Additionally, administration of succinic acid at same doses resulted in apoptotic activity for ACHN cells (19.1 and 12.7) and CAKI-2 cells (19.85 and 29.55). ELISA results with same doses of succinic acid treatment increased the apoptotic fragment rates by 4.7 and 2.13-fold in CAKI-2 cells, and 32.92, 12.7-fold in ACHN cells. Succinic acid is a focal point for cancer treatments not only for its apoptotic success on cancer cells but also for its capacity to be metabolically active for humans. Our results suggest that succinic acid could be a potential therapeutic agent for individual cancer treatment approaches together with further molecular research.

Prevotella is a poorly understood symbiont within the gut microbiota, and its role in host health remains unclear. Here, we report a case-control analysis of a Chinese cohort, in which patients with obesity showed significantly lower fecal Prevotella copri abundance. The administration of P. copri can alleviate fat deposition and promote browning in inguinal white adipose tissue (iWAT) of mice with high-fat diet (HFD)-induced adiposity. We identify succinate as a key metabolite that activates succinate receptor 1 (SUCNR1) to mimic the effects of P. copri . Mice treated with either P. copri or succinate have increased iWAT-resident macrophage populations and IL-6-STAT3 pathway activation. Forkhead box M1 (FOXM1) directly upregulates IL-6 to activate IL-6-STAT3 signaling in P. copri - or succinate-induced iWAT browning. In human WAT, we identify that P. copri and succinate levels are positively correlated with TBX1 and UCP1 transcription. This study reveals the function of P. copri in promoting iWAT browning and suggests potential strategies for alleviating adiposity and associated disorders. The gut microbiome can regulate diverse host metabolic processes, including thermogenesis in adipose tissues. Here, the authors report a reduced abundance of Prevotella copri in patients with obesity and its role in alleviating adiposity.