glycolysis Dotaz Zobrazit nápovědu
Macrophage-mediated phagocytosis and cytokine production represent the front lines of resistance to bacterial invaders. A key feature of this pro-inflammatory response in mammals is the complex remodeling of cellular metabolism towards aerobic glycolysis. Although the function of bactericidal macrophages is highly conserved, the metabolic remodeling of insect macrophages remains poorly understood. Here, we used adults of the fruit fly Drosophila melanogaster to investigate the metabolic changes that occur in macrophages during the acute and resolution phases of Streptococcus-induced sepsis. Our studies revealed that orthologs of Hypoxia inducible factor 1α (HIF1α) and Lactate dehydrogenase (LDH) are required for macrophage activation, their bactericidal function, and resistance to infection, thus documenting the conservation of this cellular response between insects and mammals. Further, we show that macrophages employing aerobic glycolysis induce changes in systemic metabolism that are necessary to meet the biosynthetic and energetic demands of their function and resistance to bacterial infection.
- Klíčová slova
- D. melanogaster, HIF1α, Warburg effect, aerobic glycolysis, bacterial infection, immunology, immunometabolism, inflammation, polarization of macrophages,
- MeSH
- aerobióza MeSH
- Drosophila imunologie MeSH
- glykolýza * MeSH
- makrofágy imunologie metabolismus MeSH
- Streptococcus imunologie MeSH
- streptokokové infekce imunologie MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
The establishment of the mitochondrion is seen as a transformational step in the origin of eukaryotes. With the mitochondrion came bioenergetic freedom to explore novel evolutionary space leading to the eukaryotic radiation known today. The tight integration of the bacterial endosymbiont with its archaeal host was accompanied by a massive endosymbiotic gene transfer resulting in a small mitochondrial genome which is just a ghost of the original incoming bacterial genome. This endosymbiotic gene transfer resulted in the loss of many genes, both from the bacterial symbiont as well the archaeal host. Loss of genes encoding redundant functions resulted in a replacement of the bulk of the host's metabolism for those originating from the endosymbiont. Glycolysis is one such metabolic pathway in which the original archaeal enzymes have been replaced by bacterial enzymes from the endosymbiont. Glycolysis is a major catabolic pathway that provides cellular energy from the breakdown of glucose. The glycolytic pathway of eukaryotes appears to be bacterial in origin, and in well-studied model eukaryotes it takes place in the cytosol. In contrast, here we demonstrate that the latter stages of glycolysis take place in the mitochondria of stramenopiles, a diverse and ecologically important lineage of eukaryotes. Although our work is based on a limited sample of stramenopiles, it leaves open the possibility that the mitochondrial targeting of glycolytic enzymes in stramenopiles might represent the ancestral state for eukaryotes.
- MeSH
- biologická evoluce MeSH
- Blastocystis cytologie enzymologie genetika metabolismus MeSH
- energetický metabolismus MeSH
- genom mitochondriální MeSH
- glykolýza * MeSH
- mitochondrie genetika metabolismus MeSH
- rozsivky cytologie enzymologie genetika metabolismus MeSH
- symbióza MeSH
- transformace genetická MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Nutrient or energy deprivation, especially glucose restriction, is a promising anticancer therapeutic approach. However, establishing a precise and potent deprivation strategy remains a formidable task. The Golgi morphology is crucial in maintaining the function of transport proteins (such as GLUT1) driving glycolysis. Thus, in this study, we present a "Golgi-customized Trojan horse" based on tellurium loaded with apigenin (4',5,7-trihydroxyflavone) and human serum albumin, which was able to induce GLUT1 plasma membrane localization disturbance via Golgi dispersal leading to the inhibition of tumor glycolysis. Diamond-shaped delivery system can efficiently penetrate into cells as a gift like Trojan horse, which decomposes into tellurite induced by intrinsically high H2O2 and GSH levels. Consequently, tellurite acts as released warriors causing up to 3.8-fold increase in Golgi apparatus area due to the down-regulation of GOLPH3. Further, this affects GLUT1 membrane localization and glucose transport disturbance. Simultaneously, apigenin hinders ongoing glycolysis and causes significant decrease in ATP level. Collectively, our "Golgi-customized Trojan horse" demonstrates a potent antitumor activity because of its capability to deprive energy resources of cancer cells. This study not only expands the applications of tellurium-based nanomaterials in the biomedicine but also provides insights into glycolysis restriction for anticancer therapy.
- Klíčová slova
- Apigenin, GLUT1 disturbance, Glycolysis inhibition, Golgi dispersal, Tellurite,
- MeSH
- apigenin * aplikace a dávkování farmakologie MeSH
- buněčná membrána * metabolismus účinky léků MeSH
- glukosa metabolismus MeSH
- glykolýza * účinky léků MeSH
- Golgiho aparát * metabolismus účinky léků MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- nádory farmakoterapie metabolismus patologie MeSH
- přenašeč glukosy typ 1 * metabolismus MeSH
- protinádorové látky aplikace a dávkování farmakologie MeSH
- telur * aplikace a dávkování MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- apigenin * MeSH
- glukosa MeSH
- přenašeč glukosy typ 1 * MeSH
- protinádorové látky MeSH
- SLC2A1 protein, human MeSH Prohlížeč
- telur * MeSH
Aerobic glycolysis is a prominent feature of cancer. Here, we reported that miR-19a-3p promotes aerobic glycolysis in ovarian cancer cells SKVO3 and ES-2 by increased production of ATP, lactic acid, extracellular acidification (ECAR), and increased expression of PKM2, LDHA, GLUT1 and GLUT3. Further study showed that over-expression of IGFBP3, the target of miR-19a-3p, decreases aerobic glycolysis in ovarian cancer cells, while knockdown of IGFBP3 expression increases aerobic glycolysis. The rescue assay suggested that miR-19a-3p promotes aerobic glycolysis in ovarian cancer cells through targeting IGFBP3. Moreover, over-expression of miR-19a-3p or silencing of IGFBP3 expression promoted activation of AKT, which is important for aerobic glycolysis in cancer cells, indicating that miR-19a-3p promotes aerobic glycolysis in ovarian cancer cells through the IGFBP3/PI3K/AKT pathway. This suggests that miR-19a-3p and IGFBP3 may serve as potential treatment targets of ovarian cancer.
- Klíčová slova
- IGFBP3, PI3K/AKT pathway, aerobic glycolysis, miR-19a-3p, ovarian cancer,
- MeSH
- fosfatidylinositol-3-kinasy metabolismus MeSH
- glykolýza genetika MeSH
- IGFBP-3 genetika metabolismus MeSH
- lidé MeSH
- mikro RNA * genetika metabolismus MeSH
- nádorové buněčné linie MeSH
- nádory vaječníků * genetika MeSH
- proliferace buněk MeSH
- protoonkogenní proteiny c-akt metabolismus MeSH
- regulace genové exprese u nádorů MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- fosfatidylinositol-3-kinasy MeSH
- IGFBP-3 MeSH
- IGFBP3 protein, human MeSH Prohlížeč
- mikro RNA * MeSH
- MIRN19A microRNA, human MeSH Prohlížeč
- protoonkogenní proteiny c-akt MeSH
- Klíčová slova
- Breast cancer, Cancer stem cell, Glycogenolysis, Glycolysis, HIF1a, Metabolic reprogramming,
- MeSH
- glukoneogeneze účinky léků MeSH
- glukosa analýza metabolismus MeSH
- glykogen metabolismus MeSH
- glykogenolýza * MeSH
- glykolýza * MeSH
- hypoxie buňky MeSH
- indoly farmakologie MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- nádorové kmenové buňky metabolismus MeSH
- nádorové mikroprostředí MeSH
- oxidativní fosforylace MeSH
- propanoly farmakologie MeSH
- triple-negativní karcinom prsu metabolismus patologie MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- glukosa MeSH
- glykogen MeSH
- indoly MeSH
- propanoly MeSH
- SR18292 MeSH Prohlížeč
- Klíčová slova
- ALANINE/chemistry *, BRAIN/chemistry *, CARBOHYDRATES/metabolism *, MUSCLES/chemistry *,
- MeSH
- alanin chemie MeSH
- glykolýza * MeSH
- metabolismus sacharidů * MeSH
- mozek - chemie * MeSH
- mozek * MeSH
- sacharidy * MeSH
- svaly chemie MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- alanin MeSH
- sacharidy * MeSH
- MeSH
- acidóza metabolismus MeSH
- erytrocyty * MeSH
- glukosa-6-fosfatasa metabolismus MeSH
- glykolýza fyziologie MeSH
- koncentrace vodíkových iontů * MeSH
- laktáty metabolismus MeSH
- lidé MeSH
- pyruváty metabolismus MeSH
- techniky in vitro MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- glukosa-6-fosfatasa MeSH
- laktáty MeSH
- pyruváty MeSH
The most frequent alterations in plasma amino acid concentrations in type 1 and type 2 diabetes are decreased L-serine and increased branched-chain amino acid (BCAA; valine, leucine, and isoleucine) levels. The likely cause of L-serine deficiency is decreased synthesis of 3-phosphoglycerate, the main endogenous precursor of L-serine, due to impaired glycolysis. The BCAA levels increase due to decreased supply of pyruvate and oxaloacetate from glycolysis, enhanced supply of NADH + H+ from beta-oxidation, and subsequent decrease in the flux through the citric acid cycle in muscles. These alterations decrease the supply of α-ketoglutarate for BCAA transamination and the activity of branched-chain keto acid dehydrogenase, the rate-limiting enzyme in BCAA catabolism. L-serine deficiency contributes to decreased synthesis of phospholipids and increased synthesis of deoxysphinganines, which play a role in diabetic neuropathy, impaired homocysteine disposal, and glycine deficiency. Enhanced BCAA levels contribute to increased levels of aromatic amino acids (phenylalanine, tyrosine, and tryptophan), insulin resistance, and accumulation of various metabolites, whose influence on diabetes progression is not clear. It is concluded that amino acid concentrations should be monitored in patients with diabetes, and systematic investigation is needed to examine the effects of L-serine and glycine supplementation on diabetes progression when these amino acids are decreased.
- Klíčová slova
- branched-chain amino acids, glycine, insulin resistance, serine,
- MeSH
- aminokyseliny metabolismus MeSH
- diabetes mellitus 2. typu * metabolismus MeSH
- glycin metabolismus MeSH
- glykolýza MeSH
- kyselina pyrohroznová MeSH
- lidé MeSH
- serin metabolismus MeSH
- větvené aminokyseliny metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Názvy látek
- aminokyseliny MeSH
- glycin MeSH
- kyselina pyrohroznová MeSH
- serin MeSH
- větvené aminokyseliny MeSH
Liver fibrosis is characterized by the activation of perivascular hepatic stellate cells (HSCs), the release of fibrogenic nanosized extracellular vesicles (EVs), and increased HSC glycolysis. Nevertheless, how glycolysis in HSCs coordinates fibrosis amplification through tissue zone-specific pathways remains elusive. Here, we demonstrate that HSC-specific genetic inhibition of glycolysis reduced liver fibrosis. Moreover, spatial transcriptomics revealed a fibrosis-mediated up-regulation of EV-related pathways in the liver pericentral zone, which was abrogated by glycolysis genetic inhibition. Mechanistically, glycolysis in HSCs up-regulated the expression of EV-related genes such as Ras-related protein Rab-31 (RAB31) by enhancing histone 3 lysine 9 acetylation on the promoter region, which increased EV release. Functionally, these glycolysis-dependent EVs increased fibrotic gene expression in recipient HSC. Furthermore, EVs derived from glycolysis-deficient mice abrogated liver fibrosis amplification in contrast to glycolysis-competent mouse EVs. In summary, glycolysis in HSCs amplifies liver fibrosis by promoting fibrogenic EV release in the hepatic pericentral zone, which represents a potential therapeutic target.
- MeSH
- extracelulární vezikuly * metabolismus MeSH
- glykolýza * MeSH
- jaterní cirhóza * metabolismus patologie genetika MeSH
- jaterní hvězdicovité buňky * metabolismus patologie MeSH
- játra metabolismus patologie MeSH
- lidé MeSH
- modely nemocí na zvířatech MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- Rab proteiny vázající GTP metabolismus genetika MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- Rab proteiny vázající GTP MeSH
