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Biochemistry. Biokhimiia Aug 2022The Complex II family encompasses membrane bound succinate:quinones reductases and quinol:fumarate reductases that catalyze interconversion of succinate and fumarate... (Review)
Review
The Complex II family encompasses membrane bound succinate:quinones reductases and quinol:fumarate reductases that catalyze interconversion of succinate and fumarate coupled with reduction and oxidation of quinone. These enzymes are found in all biological genres and share a modular structure where a highly conserved soluble domain is bound to a membrane-spanning domain that is represented by distinct variations. The current classification of the complex II family members is based on the number of subunits and co-factors in the membrane anchor (types A-F). This classification also provides insights into possible evolutionary paths and suggests that some of the complex II enzymes (types A-C) co-evolved as the whole assembly. Origin of complex II types D and F may have arisen from independent events of de novo association of the conserved soluble domain with a new anchor. Here we analyze a recent structure of Mycobacterium smegmatis Sdh2, a complex II enzyme with two transmembrane subunits and two heme b molecules. This analysis supports an earlier hypothesis suggesting that mitochondrial complex II (type C) with a single heme b may have evolved as an assembled unit from an ancestor similar to M. smegmatis Sdh2.
Topics: Benzoquinones; Binding Sites; Fumarates; Heme; Hydroquinones; Quinones; Succinate Dehydrogenase; Succinic Acid
PubMed: 36171656
DOI: 10.1134/S0006297922080077 -
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 -
Phytomedicine : International Journal... Jan 2024Sepsis-related cardiac dysfunction is believed to be a primary cause of high morbidity and mortality. Metabolic reprogramming is closely linked to NLRP3 inflammasome...
BACKGROUND
Sepsis-related cardiac dysfunction is believed to be a primary cause of high morbidity and mortality. Metabolic reprogramming is closely linked to NLRP3 inflammasome activation and dysregulated glycolysis in activated macrophages, leading to inflammatory responses in septic cardiomyopathy. Succinate dehydrogenase (SDH) and succinate play critical roles in the progression of metabolic reprogramming in macrophages. Inhibition of SDH may be postulated as an effective strategy to attenuate macrophage activation and sepsis-induced cardiac injury.
PURPOSE
This investigation was designed to examine the role of potential compounds that target SDH in septic cardiomyopathy and the underlying mechanisms involved.
METHODS/RESULTS
From a small molecule pool containing about 179 phenolic compounds, we found that chicoric acid (CA) had the strongest ability to inhibit SDH activity in macrophages. Lipopolysaccharide (LPS) exposure stimulated SDH activity, succinate accumulation and superoxide anion production, promoted mitochondrial dysfunction, and induced the expression of hypoxia-inducible factor-1α (HIF-1α) in macrophages, while CA ameliorated these changes. CA pretreatment reduced glycolysis by elevating the NAD/NADH ratio in activated macrophages. In addition, CA promoted the dissociation of K(lysine) acetyltransferase 2A (KAT2A) from α-tubulin, and thus reducing α-tubulin acetylation, a critical event in the assembly and activation of NLRP3 inflammasome. Overexpression of KAT2A neutralized the effects of CA, indicating that CA inactivated NLRP3 inflammasome in a specific manner that depended on KAT2A inhibition. Importantly, CA protected the heart against endotoxin insult and improved sepsis-induced cardiac mitochondrial structure and function disruption. Collectively, CA downregulated HIF-1α expression via SDH inactivation and glycolysis downregulation in macrophages, leading to NLRP3 inflammasome inactivation and the improvement of sepsis-induced myocardial injury.
CONCLUSION
These results highlight the therapeutic role of CA in the resolution of sepsis-induced cardiac inflammation.
Topics: Humans; NLR Family, Pyrin Domain-Containing 3 Protein; Inflammasomes; Tubulin; Metabolic Reprogramming; Macrophages; Succinates; Cardiomyopathies; Sepsis; Succinic Acid; Lipopolysaccharides; Caffeic Acids
PubMed: 37951150
DOI: 10.1016/j.phymed.2023.155175 -
Frontiers in Immunology 2022Inflammation is an important driver of atherosclerosis. Succinate is a new extracellular inflammatory alarm released by activated macrophages. Succinate is sensed by...
Inflammation is an important driver of atherosclerosis. Succinate is a new extracellular inflammatory alarm released by activated macrophages. Succinate is sensed by succinate receptor 1 (Sucnr1) and then transferred to effector cells. It is worth exploring whether succinate is capable of facilitating the inflammatory response in atherosclerosis. In this study, we firstly found that arterial serum of Coronary Heart Disease (CHD) patients contained significantly higher succinate and interleukin (IL)-1β than Health control (HC) subjects, and succinate was positively correlated with IL-1β. As demonstrated by the study, succinate/hypoxia-inducible factor 1α (Hif)-1α/IL-1β signal axis existed and significantly facilitated the inflammatory program in human umbilical vein endothelial cells (HUVECs). Under the coculture, activated macrophages released succinate, which would be transferred to HUVECs Sucnr1 and then activate Hif-1α to produce a greater amount of IL-1β. Likewise, the aortic sinus's inflammatory phenotype was found to be more significant within Apoe mice that were injected with succinate. Furthermore, Sucnr1 inhibitor (NF-56-EJ40) could significantly interrupt succinate/IL-1β signal in HUVECs and macrophages. As revealed by this study, glycolytic metabolism following the release of succinate could be found in atherosclerotic pathology, and succinate would drive succinate/IL-1β signal dependent on Sucnr1 and then exacerbate inflammatory responses. Sucnr1 might be a novel target for cutting off the transduction of succinate signal to prevent the inflammation of atherosclerosis.
Topics: Animals; Atherosclerosis; Human Umbilical Vein Endothelial Cells; Humans; Inflammation; Mice; Signal Transduction; Succinic Acid
PubMed: 35273600
DOI: 10.3389/fimmu.2022.817572 -
European Journal of Pharmacology Feb 2023This study aimed to investigate the alterations of myocardial succinate and fumarate levels with or without succinate dehydrogenase (SDH) inhibitor dimethyl malonate...
Succinate level is increased and succinate dehydrogenase exerts forward and reverse catalytic activities in lipopolysaccharides-stimulated cardiac tissue: The protective role of dimethyl malonate.
This study aimed to investigate the alterations of myocardial succinate and fumarate levels with or without succinate dehydrogenase (SDH) inhibitor dimethyl malonate during 24 h of lipopolysaccharides (LPS) challenge, as well as the effects of dimethyl malonate on the impaired cardiac tissue. Myocardial succinate and fumarate levels were increased in the initial 9 h of LPS challenge. During this time, dimethyl malonate increased the succinate level, decreased the fumarate level, aggravated the cardiac dysfunction, reduced the oxidative stress, had little effect on interleukin-1β production, promoted interleukin-10 production and bothered the ATP production. Co-treatment with exogenous succinate significantly increased interleukin-1β production in this period. After 12 h of LPS challenge, myocardial the succinate level increased sharply, while the fumarate level gradually decreased. During 12-24 h of LPS challenge, dimethyl malonate effectively reduced the succinate level, increased the fumarate level, improved cardiac dysfunction, inhibited interleukin-1β production, and had little effect on oxidative stress, interleukin-10 production, and ATP production. LPS challenge also significantly increased the myocardial succinate receptor 1 expression and circulating succinate level. Inhibition of succinate receptor 1 significantly reduced the mRNA expression of interleukin-1β. In conclusion, the current study suggests that myocardial succinate accumulates during LPS challenge, and that SDH activity may be transformed (from forward to reversed) and involved in a line of stress response. Dimethyl malonate inhibits SDH and, depending on the time of treatment, reduces LPS-induced cardiac impairment. Furthermore, accumulated succinate exerts pro-inflammatory effects partly via succinate receptor 1 signaling.
Topics: Humans; Succinate Dehydrogenase; Lipopolysaccharides; Succinic Acid; Interleukin-1beta; Interleukin-10; Heart Diseases; Fumarates; Adenosine Triphosphate
PubMed: 36549501
DOI: 10.1016/j.ejphar.2022.175472 -
Frontiers in Cellular and Infection... 2022Necrotizing enterocolitis (NEC) is the most prevalent gastrointestinal disorder that predominantly threatens preterm newborns. Succinate is an emerging metabolic...
BACKGROUND
Necrotizing enterocolitis (NEC) is the most prevalent gastrointestinal disorder that predominantly threatens preterm newborns. Succinate is an emerging metabolic signaling molecule that was recently studied in relation to the regulation of intestinal immunity and homeostasis. We aimed to investigate the relationship between NEC and gut luminal succinate and preliminarily explored the effect of succinate on NEC pathogenesis.
METHODS
Fecal samples from human neonates and mouse pups were analyzed by HPLC - MS/MS and 16S rRNA gene sequencing. C57BL/6 mice were randomly divided into four groups: control, NEC, Lsuc, and Hsuc. The mortality, weight gain, and intestinal pathological changes in four mouse groups were observed. Inflammatory cytokines and markers of macrophages were identified by quantitative real-time PCR. Succinate receptor 1 (SUCNR1) localization was visualized by immunohistochemistry. The protein levels of SUCNR1 and hypoxia-inducible factor 1a (HIF-1a) were quantified by western blotting.
RESULTS
The levels of succinate in feces from NEC patients were higher than those in feces from non-NEC patients (0.05). In the murine models, succinate levels in intestinal content samples were also higher in the NEC group than in the control group (0.05). The change in succinate level was closely related to intestinal flora composition. In samples from human neonates, relative to the control group, the NEC group showed a higher abundance of and a lower abundance of and . In the murine models, relative to the control group, increased abundance was observed for , , , and , whereas decreased abundance was observed for and . Increased succinate levels prevented mice from gaining weight, damaged their intestines, and increased their mortality; upregulated the gene expression of interleukin-1β (IL-1β), IL-6, IL-18 and tumor necrosis factor (TNF); and downregulated the gene expression of IL-10 and transforming growth factor (TGF)-β. Exogenous succinic acid increased inducible nitric oxide synthase (iNOS) gene expression but decreased Arginase-1 (Arg1) gene expression; and increased the protein expression of SUCNR1 and HIF-1a.
CONCLUSION
Succinate plays an important role in the development of necrotizing enterocolitis severity, and the activation of the HIF-1a signaling pathway may lead to disease progression.
Topics: Animals; Mice; Animals, Newborn; Disease Models, Animal; Enterocolitis, Necrotizing; Intestinal Diseases; Intestinal Mucosa; Mice, Inbred C57BL; RNA, Ribosomal, 16S; Succinic Acid; Tandem Mass Spectrometry; Humans; Infant, Newborn
PubMed: 36519131
DOI: 10.3389/fcimb.2022.1064462 -
MBio Aug 2022Succinate is a major focal point in mycobacterial metabolism and respiration, serving as both an intermediate of the tricarboxylic acid (TCA) cycle and a direct electron...
Succinate is a major focal point in mycobacterial metabolism and respiration, serving as both an intermediate of the tricarboxylic acid (TCA) cycle and a direct electron donor for the respiratory chain. Mycobacterium tuberculosis encodes multiple enzymes predicted to be capable of catalyzing the oxidation of succinate to fumarate, including two different succinate dehydrogenases (Sdh1 and Sdh2) and a separate fumarate reductase (Frd) with possible bidirectional behavior. Previous attempts to investigate the essentiality of succinate oxidation in M. tuberculosis have relied on the use of single-gene deletion mutants, raising the possibility that the remaining enzymes could catalyze succinate oxidation in the absence of the other. To address this, we report on the use of mycobacterial CRISPR interference (CRISPRi) to construct single, double, and triple transcriptional knockdowns of , , and in M. tuberculosis. We show that the simultaneous knockdown of and is required to prevent succinate oxidation and overcome the functional redundancy within these enzymes. Succinate oxidation was demonstrated to be essential for the optimal growth of M. tuberculosis, with the combined knockdown of and significantly impairing the activity of the respiratory chain and preventing growth on a range of carbon sources. Moreover, impaired succinate oxidation was shown to influence the activity of cell wall-targeting antibiotics and bioenergetic inhibitors against M. tuberculosis. Together, these data provide fundamental insights into mycobacterial physiology, energy metabolism, and antimicrobial susceptibility. New drugs are urgently required to combat the tuberculosis epidemic that claims 1.5 million lives annually. Inhibitors of mycobacterial energy metabolism have shown significant promise clinically; however, further advancing this nascent target space requires a more fundamental understanding of the respiratory enzymes and pathways used by Mycobacterium tuberculosis. Succinate is a major focal point in mycobacterial metabolism and respiration; yet, the essentiality of succinate oxidation and the consequences of inhibiting this process are poorly defined. In this study, we demonstrate that impaired succinate oxidation prevents the optimal growth of M. tuberculosis on a range of carbon sources and significantly reduces the activity of the electron transport chain. Moreover, we show that impaired succinate oxidation both positively and negatively influences the activity of a variety of antituberculosis drugs. Combined, these findings provide fundamental insights into mycobacterial physiology and drug susceptibility that will be useful in the continued development of bioenergetic inhibitors.
Topics: Carbon; Humans; Mycobacterium tuberculosis; Succinate Dehydrogenase; Succinates; Succinic Acid; Tuberculosis
PubMed: 35856639
DOI: 10.1128/mbio.01672-22 -
Bioresource Technology Jan 2022As a result of environmental concerns and the depletion of biomass assets, eco-friendly, renewable biomass-based chemical extraction has recently received significant... (Review)
Review
As a result of environmental concerns and the depletion of biomass assets, eco-friendly, renewable biomass-based chemical extraction has recently received significant attention. Bio-based chemicals can be prepared using different renewable feedstockbio-resources through microbial fermentation. Chemicals produced from renewable feedstockscan reduce ecological consequences from improper disposal and repurpose them into valuable products. Biodegradability, biocompatibility and non-toxicity, particularly in biomedical applications, have inspired researchers towards developing novel technologies that have social benefit. Among semi-synthetic and synthetic polymeric materials, utilization of natural bio-based monomeric materials can provide opportunities for sustainable development of novel non-toxic, biodegradable and biocompatible products. The purpose of this work is to give a summary of research into the generation of natural bio-based succinic acid (SA) monomer, the development of poly(butylene succinate) (PBS) as biodegradable polymer, PBS-based nanocomposites and their innovative uses.
Topics: Biomass; Fermentation; Polymers; Succinic Acid
PubMed: 34695587
DOI: 10.1016/j.biortech.2021.126156 -
Frontiers in Endocrinology 2023Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors originating from chromaffin cells, holding significant clinical importance due to their... (Review)
Review
Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors originating from chromaffin cells, holding significant clinical importance due to their capacity for excessive catecholamine secretion and associated cardiovascular complications. Roughly 80% of cases are associated with genetic mutations. Based on the functionality of these mutated genes, PPGLs can be categorized into distinct molecular clusters: the pseudohypoxia signaling cluster (Cluster-1), the kinase signaling cluster (Cluster-2), and the WNT signaling cluster (Cluster-3). A pivotal factor in the pathogenesis of PPGLs is hypoxia-inducible factor-2α (HIF2α), which becomes upregulated even under normoxic conditions, activating downstream transcriptional processes associated with pseudohypoxia. This adaptation provides tumor cells with a growth advantage and enhances their ability to thrive in adverse microenvironments. Moreover, pseudohypoxia disrupts immune cell communication, leading to the development of an immunosuppressive tumor microenvironment. Within Cluster-1a, metabolic perturbations are particularly pronounced. Mutations in enzymes associated with the tricarboxylic acid (TCA) cycle, such as succinate dehydrogenase (SDHx), fumarate hydratase (FH), isocitrate dehydrogenase (IDH), and malate dehydrogenase type 2 (MDH2), result in the accumulation of critical oncogenic metabolic intermediates. Notable among these intermediates are succinate, fumarate, and 2-hydroxyglutarate (2-HG), which promote activation of the HIFs signaling pathway through various mechanisms, thus inducing pseudohypoxia and facilitating tumorigenesis. SDHx mutations are prevalent in PPGLs, disrupting mitochondrial function and causing succinate accumulation, which competitively inhibits α-ketoglutarate-dependent dioxygenases. Consequently, this leads to global hypermethylation, epigenetic changes, and activation of HIFs. In FH-deficient cells, fumarate accumulation leads to protein succination, impacting cell function. FH mutations also trigger metabolic reprogramming towards glycolysis and lactate synthesis. IDH1/2 mutations generate D-2HG, inhibiting α-ketoglutarate-dependent dioxygenases and stabilizing HIFs. Similarly, MDH2 mutations are associated with HIF stability and pseudohypoxic response. Understanding the intricate relationship between metabolic enzyme mutations in the TCA cycle and pseudohypoxic signaling is crucial for unraveling the pathogenesis of PPGLs and developing targeted therapies. This knowledge enhances our comprehension of the pivotal role of cellular metabolism in PPGLs and holds implications for potential therapeutic advancements.
Topics: Humans; Pheochromocytoma; Citric Acid Cycle; Ketoglutaric Acids; Paraganglioma; Adrenal Gland Neoplasms; Mutation; Succinates; Succinic Acid; Signal Transduction; Fumarates; Dioxygenases; Tumor Microenvironment
PubMed: 37867526
DOI: 10.3389/fendo.2023.1274239 -
International Journal of Molecular... Dec 2022Scientists have long established that fatty acids are the primary substrates for kidney mitochondria. However, to date we still do not know how long-chain and...
Scientists have long established that fatty acids are the primary substrates for kidney mitochondria. However, to date we still do not know how long-chain and middle-chain fatty acids are oxidized at the mitochondrial level. Our previous research has shown that mitochondria from the heart, brain, and kidney oxidize palmitoylcarnitine at a high rate only in the presence of succinate, glutamate, or pyruvate. In this paper, we report properties of the isolated kidney mitochondria and how malate and succinate affect the oxidation of C16 and C8 acylcarnitines. The isolated kidney mitochondria contain very few endogenous substrates and require malate to oxidize pyruvate, glutamate, and C16 or C8 acylcarnitines. We discovered that with 10 µM of C16 or C8 acylcarnitines, low concentrations of malate (0.2 mM) or succinate (0.5 mM) enhance the States 4 and 3 respiratory rates several times. The highest respiration rates were observed with C16 or C8 acylcarnitines and 5 mM succinate mixtures. Results show that kidney mitochondria, unlike the heart and brain mitochondria, lack the intrinsic inhibition of succinate dehydrogenase. Additionally, results show that the oxidation of fatty acid by the small respirasome's supercomplex generates a high level of CoQH2, and this makes SDH in the presence of succinate reverse the flow of electrons from CoQH2 to reduce fumarate to succinate. Finally, we report evidence that succinate dehydrogenase is a key mitochondrial enzyme that allows fast oxidation of fatty acids and turns the TCA cycle function from the catabolic to the anabolic and anaplerotic metabolic pathways.
Topics: Mice; Animals; Succinate Dehydrogenase; Malates; Mitochondria; Fatty Acids; Energy Metabolism; Oxidation-Reduction; Succinic Acid; Succinates; Pyruvic Acid; Glutamates; Kidney
PubMed: 36613826
DOI: 10.3390/ijms24010379