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The International Journal of... Oct 2019During tissue ischemia succinate accumulates. Herein, literature spanning the past nine decades is reviewed leaning towards the far greater role of Krebs cycle's... (Review)
Review
During tissue ischemia succinate accumulates. Herein, literature spanning the past nine decades is reviewed leaning towards the far greater role of Krebs cycle's canonical activity yielding succinate through α-ketoglutarate -> succinyl-CoA -> succinate even in hypoxia, as opposed to reversal of succinate dehydrogenase. Furthermore, the concepts of i) a diode-like property of succinate dehydrogenase rendering it difficult to reverse, and ii) the absence of mammalian mitochondrial quinones exhibiting redox potentials in the [-60, -80] mV range needed for fumarate reduction, are discussed. Finally, it is emphasized that a "fumarate reductase" enzyme entity reducing fumarate to succinate found in some bacteria and lower eukaryotes remains to be discovered in mammalian mitochondria.
Topics: Animals; Humans; Ischemia; Mitochondria; Succinate Dehydrogenase; Succinic Acid
PubMed: 31394174
DOI: 10.1016/j.biocel.2019.105580 -
Succinate based polymers drive immunometabolism in dendritic cells to generate cancer immunotherapy.Journal of Controlled Release :... Jun 2023Boosting the metabolism of immune cells while restricting cancer cell metabolism is challenging. Herein, we report that using biomaterials for the controlled delivery of...
Boosting the metabolism of immune cells while restricting cancer cell metabolism is challenging. Herein, we report that using biomaterials for the controlled delivery of succinate metabolite to phagocytic immune cells activates them and modulates their metabolism in the presence of metabolic inhibitors. In young immunocompetent mice, polymeric microparticles, with succinate incorporated in the backbone, induced strong pro-inflammatory anti-melanoma responses. Administration of poly(ethylene succinate) (PES MP)-based vaccines and glutaminase inhibitor to young immunocompetent mice with aggressive and large, established B16F10 melanoma tumors increased their survival three-fold, a result of increased cytotoxic T cells expressing RORγT (Tc17). Mechanistically, PES MPs directly modulate glutamine and glutamate metabolism, upregulate succinate receptor SUCNR1, activate antigen presenting cells through and HIF-1alpha, TNFa and TSLP-signaling pathways, and are dependent on alpha-ketoglutarate dehydrogenase for their activity, which demonstrates correlation of succinate delivery and these pathways. Overall, our findings suggest that immunometabolism-modifying PES MP strategies provide an approach for developing robust cancer immunotherapies.
Topics: Animals; Mice; Polymers; Succinic Acid; Immunotherapy; Signal Transduction; Melanoma; Dendritic Cells; Cancer Vaccines
PubMed: 37182805
DOI: 10.1016/j.jconrel.2023.05.014 -
Science Advances Jun 2023Acute hemorrhage commonly leads to coagulopathy and organ dysfunction or failure. Recent evidence suggests that damage to the endothelial glycocalyx contributes to these...
Acute hemorrhage commonly leads to coagulopathy and organ dysfunction or failure. Recent evidence suggests that damage to the endothelial glycocalyx contributes to these adverse outcomes. The physiological events mediating acute glycocalyx shedding are undefined, however. Here, we show that succinate accumulation within endothelial cells drives glycocalyx degradation through a membrane reorganization-mediated mechanism. We investigated this mechanism in a cultured endothelial cell hypoxia-reoxygenation model, in a rat model of hemorrhage, and in trauma patient plasma samples. We found that succinate metabolism by succinate dehydrogenase mediates glycocalyx damage through lipid oxidation and phospholipase A2-mediated membrane reorganization, promoting the interaction of matrix metalloproteinase 24 (MMP24) and MMP25 with glycocalyx constituents. In a rat hemorrhage model, inhibiting succinate metabolism or membrane reorganization prevented glycocalyx damage and coagulopathy. In patients with trauma, succinate levels were associated with glycocalyx damage and the development of coagulopathy, and the interaction of MMP24 and syndecan-1 was elevated compared to healthy controls.
Topics: Animals; Rats; Endothelial Cells; Hemorrhage; Lipid Metabolism; Hypoxia; Succinates; Succinic Acid
PubMed: 37315138
DOI: 10.1126/sciadv.adf6600 -
DNA and Cell Biology Mar 2022Succinate is an important intermediate product of mitochondrial energy metabolism. Recent studies revealed that beyond its known traditional metabolic functions,... (Review)
Review
Succinate is an important intermediate product of mitochondrial energy metabolism. Recent studies revealed that beyond its known traditional metabolic functions, succinate plays important roles in signal transduction, immunity, inflammation, and posttranslational modification. Recent studies showed that patients and mouse models with cardiovascular disease have high levels of serum succinate and succinate accumulation. Atherosclerosis (As) is the pathological basis of cardiovascular and peripheral vascular diseases, such as coronary heart disease, cerebral infarction, and peripheral vascular disease, and is a major factor affecting human health. This article reviews the progression of succinate in As diseases and its underlying mechanisms.
Topics: Animals; Atherosclerosis; Disease Progression; Endothelial Cells; Humans; Macrophages; Mice; Models, Cardiovascular; Myocytes, Smooth Muscle; Oxidative Stress; Renin-Angiotensin System; Signal Transduction; Succinic Acid
PubMed: 35138943
DOI: 10.1089/dna.2021.0345 -
Endocrinology and Metabolism (Seoul,... Aug 2023Hepatic stellate cells (HSCs) are the major cells which play a pivotal role in liver fibrosis. During injury, extracellular stimulators can induce HSCs...
BACKGRUOUND
Hepatic stellate cells (HSCs) are the major cells which play a pivotal role in liver fibrosis. During injury, extracellular stimulators can induce HSCs transdifferentiated into active form. Phloretin showed its ability to protect the liver from injury, so in this research we would like to investigate the effect of phloretin on succinate-induced HSCs activation in vitro and liver fibrosis in vivo study.
METHODS
In in vitro, succinate was used to induce HSCs activation, and then the effect of phloretin on activated HSCs was examined. In in vivo, succinate was used to generated liver fibrosis in mouse and phloretin co-treated to check its protection on the liver.
RESULTS
Phloretin can reduce the increase of fibrogenic markers and inhibits the proliferation, migration, and contraction caused by succinate in in vitro experiments. Moreover, an upregulation of proteins associated with aerobic glycolysis occurred during the activation of HSCs, which was attenuated by phloretin treatment. In in vivo experiments, intraperitoneal injection of phloretin decreased expression of fibrotic and glycolytic markers in the livers of mice with sodium succinate diet-induced liver fibrosis. These results suggest that aerobic glycolysis plays critical role in activation of HSCs and succinate can induce liver fibrosis in mice, whereas phloretin has therapeutic potential for treating hepatic fibrosis.
CONCLUSION
Intraperitoneal injection of phloretin attenuated succinate-induced hepatic fibrosis and alleviates the succinate-induced HSCs activation.
Topics: Mice; Animals; Succinic Acid; Phloretin; Hepatic Stellate Cells; Liver Cirrhosis
PubMed: 37533177
DOI: 10.3803/EnM.2023.1661 -
Cell Reports Sep 2022Periodontal disease (PD) is one of the most common inflammatory diseases in humans and is initiated by an oral microbial dysbiosis that stimulates inflammation and bone...
Periodontal disease (PD) is one of the most common inflammatory diseases in humans and is initiated by an oral microbial dysbiosis that stimulates inflammation and bone loss. Here, we report an abnormal elevation of succinate in the subgingival plaque of subjects with severe PD. Succinate activates succinate receptor-1 (SUCNR1) and stimulates inflammation. We detected SUCNR1 expression in the human and mouse periodontium and hypothesize that succinate activates SUCNR1 to accelerate periodontitis through the inflammatory response. Administration of exogenous succinate enhanced periodontal disease, whereas SUCNR1 knockout mice were protected from inflammation, oral dysbiosis, and subsequent periodontal bone loss in two different models of periodontitis. Therapeutic studies demonstrated that a SUCNR1 antagonist inhibited inflammatory events and osteoclastogenesis in vitro and reduced periodontal bone loss in vivo. Our study reveals succinate's effect on periodontitis pathogenesis and provides a topical treatment for this disease.
Topics: Alveolar Bone Loss; Animals; Dysbiosis; Humans; Inflammation; Mice; Mice, Knockout; Periodontal Diseases; Periodontitis; Succinic Acid
PubMed: 36130514
DOI: 10.1016/j.celrep.2022.111389 -
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. Cell... Aug 2021Carbon monoxide (CO) is an odorless and colorless gas with multiple sources that include engine exhaust, faulty furnaces, and other sources of incomplete combustion of... (Review)
Review
Carbon monoxide (CO) is an odorless and colorless gas with multiple sources that include engine exhaust, faulty furnaces, and other sources of incomplete combustion of carbon compounds such as house fires. The most serious complications for survivors of consequential CO exposure are persistent neurological sequelae occurring in up to 50% of patients. CO inhibits mitochondrial respiration by specifically binding to the heme a in the active site of CIV-like hydrogen sulfide, cyanide, and phosphides. Although hyperbaric oxygen remains the cornerstone for treatment, it has variable efficacy requiring new approaches to treatment. There is a paucity of cellular-based therapies in the area of CO poisoning, and there have been recent advancements that include antioxidants and a mitochondrial substrate prodrug. The succinate prodrugs derived from chemical modification of succinate are endeavored to enhance delivery of succinate to cells, increasing uptake of succinate into the mitochondria, and providing metabolic support for cells. The therapeutic intervention of succinate prodrugs is thus potentially applicable to patients with CO poisoning via metabolic support for fuel oxidation and possibly improving efficacy of HBO therapy.
Topics: Animals; Carbon Monoxide; Carbon Monoxide Poisoning; Cell- and Tissue-Based Therapy; Humans; Mitochondria; Prodrugs; Succinic Acid
PubMed: 34133239
DOI: 10.1152/ajpcell.00022.2021 -
American Journal of Physiology.... Apr 2023Succinate is released by skeletal muscle during exercise and activates /GPR91. Signaling of SUCNR1 is involved in metabolite-sensing paracrine communication in skeletal...
Succinate is released by skeletal muscle during exercise and activates /GPR91. Signaling of SUCNR1 is involved in metabolite-sensing paracrine communication in skeletal muscle during exercise. However, the specific cell types responding to succinate and the directionality of communication are unclear. We aim to characterize the expression of SUCNR1 in human skeletal muscle. De novo analysis of transcriptomic datasets demonstrated that mRNA is expressed in immune, adipose, and liver tissues, but scarce in skeletal muscle. In human tissues, mRNA was associated with macrophage markers. Single-cell RNA sequencing and fluorescent RNAscope demonstrated that in human skeletal muscle, mRNA is not expressed in muscle fibers but coincided with macrophage populations. Human M2-polarized macrophages exhibit high levels of mRNA and stimulation with selective agonists of SUCNR1 triggered Gq- and Gi-coupled signaling. Primary human skeletal muscle cells were unresponsive to SUCNR1 agonists. In conclusion, SUCNR1 is not expressed in muscle cells and its role in the adaptive response of skeletal muscle to exercise is most likely mediated via paracrine mechanisms involving M2-like macrophages within the muscle. Macrophages but not skeletal muscle cells respond to extracellular succinate via SUCNR1/GPR91.
Topics: Humans; Muscles; Obesity; Receptors, G-Protein-Coupled; Signal Transduction; Succinic Acid
PubMed: 36812387
DOI: 10.1152/ajpendo.00009.2023 -
The Journal of Allergy and Clinical... Sep 2022
Topics: Animals; Food Hypersensitivity; Humans; Intestinal Mucosa; Nippostrongylus; Succinic Acid
PubMed: 35934085
DOI: 10.1016/j.jaci.2022.07.016