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Biomolecules Jul 2023Uterine endometrial cancer (UEC) is an estrogen-related tumor. Succinate and heme metabolism play important roles in the progression of multiple tumors. However, the...
Uterine endometrial cancer (UEC) is an estrogen-related tumor. Succinate and heme metabolism play important roles in the progression of multiple tumors. However, the relationship between estrogen, succinate, and heme metabolism and related regulatory mechanisms remain largely unknown. In this study, we observed that the expression of aminolevulinate delta synthase 1 (ALAS1) and solute carrier family member 38 (SLC25A38) in UEC tissues is significantly higher than that in normal tissues. Further analysis showed that estrogen and succinate increased the expression of ALAS1 and SLC25A38 in uterine endometrial cancer cells (UECC), and the administration of succinate upregulated the level of the estrogen receptor (ER). Silencing nuclear receptor coactivator 1 (NCOA1) reversed the effects of estrogen and succinate via downregulation of ALAS1 expression. Additionally, exposure of UECC to heme increased cell viability and invasiveness, while silencing the NCOA1 gene weakened this effect. These findings revealed that estrogen and succinate can synergistically increase the expression of ALAS1 and SLC25A38 via the ERβ/NCOA1 axis, promoting heme accumulation and increasing the proliferative and invasive potential of UECC.
Topics: Female; Humans; Succinic Acid; Heme; Estrogens; Endometrial Neoplasms; Receptors, Estrogen; Aminolevulinic Acid
PubMed: 37509133
DOI: 10.3390/biom13071097 -
PLoS Pathogens Dec 2023The mitochondrial electron transport chain (mETC) is a series of membrane embedded enzymatic complexes critical for energy conversion and mitochondrial metabolism. In...
The mitochondrial electron transport chain (mETC) is a series of membrane embedded enzymatic complexes critical for energy conversion and mitochondrial metabolism. In commonly studied eukaryotes, including humans and animals, complex II, also known as succinate dehydrogenase (SDH), is an essential four-subunit enzyme that acts as an entry point to the mETC, by harvesting electrons from the TCA cycle. Apicomplexa are pathogenic parasites with significant impact on human and animal health. The phylum includes Toxoplasma gondii which can cause fatal infections in immunocompromised people. Most apicomplexans, including Toxoplasma, rely on their mETC for survival, yet SDH remains largely understudied. Previous studies pointed to a divergent apicomplexan SDH with nine subunits proposed for the Toxoplasma complex, compared to four in humans. While two of the nine are homologs of the well-studied SDHA and B, the other seven have no homologs in SDHs of other systems. Moreover, SDHC and D, that anchor SDH to the membrane and participate in substrate bindings, have no homologs in Apicomplexa. Here, we validated five of the seven proposed subunits as bona fide SDH components and demonstrated their importance for SDH assembly and activity. We further find that all five subunits are important for parasite growth, and that disruption of SDH impairs mitochondrial respiration and results in spontaneous initiation of differentiation into bradyzoites. Finally, we provide evidence that the five subunits are membrane bound, consistent with their potential role in membrane anchoring, and we demonstrate that a DY motif in one of them, SDH10, is essential for complex formation and function. Our study confirms the divergent composition of Toxoplasma SDH compared to human, and starts exploring the role of the lineage-specific subunits in SDH function, paving the way for future mechanistic studies.
Topics: Animals; Humans; Succinate Dehydrogenase; Toxoplasma; Mitochondria; Mitochondrial Membranes; Citric Acid Cycle
PubMed: 38079448
DOI: 10.1371/journal.ppat.1011867 -
JCI Insight Sep 2023Lung contusion and gastric aspiration (LC and GA) are major risk factors for developing acute respiratory distress following trauma. Hypoxia from lung injury is mainly...
Lung contusion and gastric aspiration (LC and GA) are major risk factors for developing acute respiratory distress following trauma. Hypoxia from lung injury is mainly regulated by hypoxia-inducible factor 1α (HIF-1α). Published data from our group indicate that HIF-1α regulation in airway epithelial cells (AEC) drives the acute inflammatory response following LC and GA. Metabolomic profiling and metabolic flux of Type II AEC following LC revealed marked increases in glycolytic and TCA intermediates in vivo and in vitro that were HIF-1α dependent. GLUT-1/4 expression was also increased in HIF-1α+/+ mice, suggesting that increased glucose entry may contribute to increased intermediates. Importantly, lactate incubation in vitro on Type II cells did not significantly increase the inflammatory byproduct IL-1β. Contrastingly, succinate had a direct proinflammatory effect on human small AEC by IL-1β generation in vitro. This effect was reversed by dimethylmalonate, suggesting an important role for succinate dehydrogenase in mediating HIF-1α effects. We confirmed the presence of the only known receptor for succinate binding, SUCNR1, on Type II AEC. These results support the hypothesis that succinate drives HIF-1α-mediated airway inflammation following LC. This is the first report to our knowledge of direct proinflammatory activation of succinate in nonimmune cells such as Type II AEC in direct lung injury models.
Topics: Humans; Animals; Mice; Succinic Acid; Lung Injury; Succinates; Respiratory Distress Syndrome; Epithelial Cells; Hypoxia; Inflammation; Lung
PubMed: 37737265
DOI: 10.1172/jci.insight.166860 -
Foods (Basel, Switzerland) Nov 2023Obesity is a risk factor for many chronic diseases related to the overexpansion of adipose tissue during obesity, leading to metabolic dysfunction and ectopic lipids....
Obesity is a risk factor for many chronic diseases related to the overexpansion of adipose tissue during obesity, leading to metabolic dysfunction and ectopic lipids. Previous studies reported a close relationship between succinate and obesity and its co-morbidities, and studies have also reported on its anti-obesity potential. To confirm its efficacy in obesity interventions, we supplemented mice with obesity induced by a high-fat diet with succinate (1.5% / in drinking water) for 11 weeks without changing the diet. After succinate supplementation, the changes in body weight, adipose tissue deposition, glucose tolerance, energy expenditure and lipid metabolism were evaluated. It was found that succinate supplementation significantly decreased subcutaneous adipose tissue (HFD: 4239.3 ± 211.2 mg; HFD-SA: 3268.9 ± 265.7 mg. < 0.05), triglyceride contents (decreased by 1.53 mmol/g and 0.39 mmol/g in eWAT and ingWAT, respectively, < 0.05) and NEFA (decreased by 1.41 μmol/g and 1.31 μmol/g in eWAT and ingWAT, respectively, < 0.05). The adipocytes' sizes all significantly decreased in both subcutaneous and visceral adipose tissue (the proportion of adipocytes with diameters larger than 100 μm in eWAT and ingWAT decreased by 16.83% and 11.96%, respectively. < 0.05). Succinate significantly enhanced lipolysis in adipose tissue (eWAT: , and ; ingWAT: and ; < 0.05), whereas the expression of lipogenesis-related genes remained unchanged ( > 0.05). Succinate supplementation also enhanced the activity of BAT by stimulating the expression of and ( < 0.05). Our results reported that succinate has a potential beneficial effect on obesity pathogenesis but cannot efficiently decrease bodyweight.
PubMed: 38231706
DOI: 10.3390/foods12234285 -
Frontiers in Immunology 2024Immune cell activation triggers signaling cascades leading to transcriptional reprogramming, but also strongly impacts on the cell's metabolic activity to provide energy... (Review)
Review
Immune cell activation triggers signaling cascades leading to transcriptional reprogramming, but also strongly impacts on the cell's metabolic activity to provide energy and biomolecules for inflammatory and proliferative responses. Macrophages activated by microbial pathogen-associated molecular patterns and cytokines upregulate expression of the enzyme ACOD1 that generates the immune-metabolite itaconate by decarboxylation of the TCA cycle metabolite cis-aconitate. Itaconate has anti-microbial as well as immunomodulatory activities, which makes it attractive as endogenous effector metabolite fighting infection and restraining inflammation. Here, we first summarize the pathways and stimuli inducing ACOD1 expression in macrophages. The focus of the review then lies on the mechanisms by which itaconate, and its synthetic derivatives and endogenous isomers, modulate immune cell signaling and metabolic pathways. Multiple targets have been revealed, from inhibition of enzymes to the post-translational modification of many proteins at cysteine or lysine residues. The modulation of signaling proteins like STING, SYK, JAK1, RIPK3 and KEAP1, transcription regulators (e.g. Tet2, TFEB) and inflammasome components (NLRP3, GSDMD) provides a biochemical basis for the immune-regulatory effects of the ACOD1-itaconate pathway. While the field has intensely studied control of macrophages by itaconate in infection and inflammation models, neutrophils have now entered the scene as producers and cellular targets of itaconate. Furthermore, regulation of adaptive immune responses by endogenous itaconate, as well as by exogenously added itaconate and derivatives, can be mediated by direct and indirect effects on T cells and antigen-presenting cells, respectively. Taken together, research in ACOD1-itaconate to date has revealed its relevance in diverse immune cell signaling pathways, which now provides opportunities for potential therapeutic or preventive manipulation of host defense and inflammation.
Topics: Humans; Kelch-Like ECH-Associated Protein 1; NF-E2-Related Factor 2; Signal Transduction; Inflammation; Succinates
PubMed: 38487538
DOI: 10.3389/fimmu.2024.1352165 -
Redox Biology Nov 2023The NDUFS4 knockout (KO) mouse phenotype resembles the human Complex I deficiency Leigh Syndrome. The irreversible succination of protein thiols by fumarate is increased...
The NDUFS4 knockout (KO) mouse phenotype resembles the human Complex I deficiency Leigh Syndrome. The irreversible succination of protein thiols by fumarate is increased in select regions of the NDUFS4 KO brain affected by neurodegeneration. We report that dihydrolipoyllysine-residue succinyltransferase (DLST), a component of the α-ketoglutarate dehydrogenase complex (KGDHC) of the tricarboxylic acid (TCA) cycle, is succinated in the affected regions of the NDUFS4 KO brain. Succination of DLST reduced KGDHC activity in the brainstem (BS) and olfactory bulb (OB) of KO mice. The defective production of KGDHC derived succinyl-CoA resulted in decreased mitochondrial substrate level phosphorylation (SLP), further aggravating the existing oxidative phosphorylation (OXPHOS) ATP deficit. Protein succinylation, an acylation modification that requires succinyl-CoA, was reduced in the KO mice. Modeling succination of a cysteine in the spatial vicinity of the DLST active site or introduction of succinomimetic mutations recapitulates these metabolic deficits. Our data demonstrate that the biochemical deficit extends beyond impaired Complex I assembly and OXPHOS deficiency, functionally impairing select components of the TCA cycle to drive metabolic perturbations in affected neurons.
Topics: Mice; Animals; Humans; Ketoglutarate Dehydrogenase Complex; Citric Acid Cycle; Mitochondria; Mice, Knockout; Oxidative Phosphorylation; Adenosine Triphosphate
PubMed: 37883842
DOI: 10.1016/j.redox.2023.102932 -
Cells Nov 2023The TCA cycle intermediate metabolite 'succinate' has been proposed as an inflammatory mediator, influencing autoimmunity and allergic reactions, through ligation to its...
The TCA cycle intermediate metabolite 'succinate' has been proposed as an inflammatory mediator, influencing autoimmunity and allergic reactions, through ligation to its sensing receptor SUCNR1/GPR91. Whether GPR91-mediated signalling influences the chronic inflammatory process of atherosclerosis has never been investigated. The examination of publicly available datasets revealed that the gene is expressed in human atherosclerotic plaques, especially in vascular smooth muscle cells. Using GPR91 knockout () and wildtype (WT) littermates, made hyperlipidaemic with the overexpression of the gain-of-function mutated and Western diet feeding, we showed that the full ablation of GPR91 did not accelerate atherosclerosis-lesions in the aortic arch 2.18 ± 0.48% vs. 1.64 ± 0.31%, and in the aortic roots 10.06 ± 0.91% vs. 10.67 ± 1.53% for and WT mice, respectively. In line with this, no differences between groups were observed for macrophage and T-cell infiltration in the plaque, as well as the polarization towards M1- or M2-like macrophages in the aorta, spleen and liver of and WT control mice. In conclusion, our study indicates that the global ablation of GPR91 signalling does not influence vascular inflammation or atherogenesis.
Topics: Animals; Humans; Mice; Atherosclerosis; Inflammation; Plaque, Atherosclerotic; Proprotein Convertase 9; Receptors, G-Protein-Coupled
PubMed: 37947659
DOI: 10.3390/cells12212580 -
Skeletal Muscle Sep 2023Duchenne muscular dystrophy (DMD) is a severe form of muscular dystrophy without an effective treatment, caused by mutations in the DMD gene, leading to the absence of...
BACKGROUND
Duchenne muscular dystrophy (DMD) is a severe form of muscular dystrophy without an effective treatment, caused by mutations in the DMD gene, leading to the absence of dystrophin. DMD results in muscle weakness, loss of ambulation, and death at an early age. Metabolomics studies in mdx mice, the most used model for DMD, reveal changes in metabolites associated with muscle degeneration and aging. In DMD, the tongue muscles exhibit unique behavior, initially showing partial protection against inflammation but later experiencing fibrosis and loss of muscle fibers. Certain metabolites and proteins, like TNF-α and TGF-β, are potential biomarkers for dystrophic muscle characterization.
METHODS
To investigate disease progression and aging, we utilized young (1 month old) and old (21-25 months old) mdx and wild-type tongue muscles. Metabolite changes were analyzed using 1H nuclear magnetic resonance, while TNF-α and TGF-β were assessed using Western blotting to examine inflammation and fibrosis. Morphometric analysis was conducted to assess the extent of myofiber damage between groups.
RESULTS
The histological analysis of the mid-belly tongue showed no differences between groups. No differences were found between the concentrations of metabolites from wild-type or mdx whole tongues of the same age. The metabolites alanine, methionine, and 3-methylhistidine were higher, and taurine and glycerol were lower in young tongues in both wild type and mdx (p < 0.001). The metabolites glycine (p < 0.001) and glutamic acid (p = 0.0018) were different only in the mdx groups, being higher in young mdx mice. Acetic acid, phosphocreatine, isoleucine, succinic acid, creatine, and the proteins TNF-α and TGF-β had no difference in the analysis between groups (p > 0.05).
CONCLUSIONS
Surprisingly, histological, metabolite, and protein analysis reveal that the tongue of old mdx remains partially spared from the severe myonecrosis observed in other muscles. The metabolites alanine, methionine, 3-methylhistidine, taurine, and glycerol may be effective for specific assessments, although their use for disease progression monitoring should be cautious due to age-related changes in the tongue muscle. Acetic acid, phosphocreatine, isoleucine, succinate, creatine, TNF-α, and TGF-β do not vary with aging and remain constant in spared muscles, suggesting their potential as specific biomarkers for DMD progression independent of aging.
Topics: Mice; Animals; Muscular Dystrophy, Duchenne; Tumor Necrosis Factor-alpha; Creatine; Mice, Inbred mdx; Phosphocreatine; Glycerol; Isoleucine; Muscle Fibers, Skeletal; Methionine; Racemethionine; Acetic Acid; Alanine; Disease Progression
PubMed: 37705069
DOI: 10.1186/s13395-023-00325-z -
Journal of Virology Oct 2023Itaconate derivates, as well as the naturally produced metabolite, have been proposed as antivirals against influenza virus. Here, the mechanism behind the antiviral...
Itaconate derivates, as well as the naturally produced metabolite, have been proposed as antivirals against influenza virus. Here, the mechanism behind the antiviral effects of exogenous 4-octyl itaconate (4-OI), a derivative of itaconate, against the influenza A virus replication is demonstrated. The data indicate that 4-OI targets the cysteine at position 528 of the CRM1 protein, resulting in inhibition of the nuclear export of viral ribonucleoprotein complexes in a similar manner as previously described for other selective inhibitors of nuclear export. These results postulate a mechanism not observed before for this immuno-metabolite derivative. This knowledge is helpful for the development of derivatives of 4-OI as potential antiviral and anti-inflammatory therapeutics.
Topics: Humans; Active Transport, Cell Nucleus; Antiviral Agents; Influenza, Human; Nuclear Proteins; Virus Replication; Succinates; Exportin 1 Protein
PubMed: 37823646
DOI: 10.1128/jvi.01325-23