RNA-Sequencing of Transaldolase and Aldose Reducatase Deficiency in Mouse Liver
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE217133 | GEO | 2023/01/13
REPOSITORIES: GEO
Similar Datasets
Project description:Dynamic regulation of glucose flux between aerobic glycolysis and the pentose phosphate pathway (PPP) during epithelial-mesenchymal transition (EMT) is not well-understood. Here we show that Snail (SNAI1), a key transcriptional repressor of EMT, regulates glucose flux toward PPP, allowing cancer cell survival under metabolic stress. Mechanistically, Snail regulates glycolytic activity via repression of PFKP (phosphofructokinase, platelet), a major isoform of cancer-specific phosphofructokinase-1 (PFK-1), an enzyme involving the first rate-limiting step of glycolysis. The suppression of PFKP switches the glucose flux towards PPP, generating NADPH with increased metabolites of oxidative PPP. Functionally, dynamic regulation of PFKP significantly potentiates cancer cell survival under metabolic stress and increases metastatic capacities in vivo. Further, knockdown of PFKP rescues metabolic reprogramming and cell death induced by loss of Snail. Thus, the Snail-PFKP axis plays an important role in cancer cell survival via regulation of glucose flux between glycolysis and PPP.Dynamic regulation of glucose flux between aerobic glycolysis and the pentose phosphate pathway (PPP) during epithelial-mesenchymal transition (EMT) is not well-understood. Here we show that Snail (SNAI1), a key transcriptional repressor of EMT, regulates glucose flux toward PPP, allowing cancer cell survival under metabolic stress. Mechanistically, Snail regulates glycolytic activity via repression of PFKP (phosphofructokinase, platelet), a major isoform of cancer-specific phosphofructokinase-1 (PFK-1), an enzyme involving the first rate-limiting step of glycolysis. The suppression of PFKP switches the glucose flux towards PPP, generating NADPH with increased metabolites of oxidative PPP. Functionally, dynamic regulation of PFKP significantly potentiates cancer cell survival under metabolic stress and increases metastatic capacities in vivo. Further, knockdown of PFKP rescues metabolic reprogramming and cell death induced by loss of Snail. Thus, the Snail-PFKP axis plays an important role in cancer cell survival via regulation of glucose flux between glycolysis and PPP.
2017-11-07 | MTBLS387 | MetaboLights
Project description:We recentlly showed that everolimus, a mTORC1 inhibitor increases reactive oxygen species (ROS) levels, decreases the levels of NADPH and of glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the pentose phosphate pathway (PPP), and induces apoptosis of T-ALL cells.
2023-02-23 | GSE225751 | GEO
Project description:Electron transport chain (ETC) defects occurring from mitochondrial disease mutations compromise ATP synthesis and render cells vulnerable to nutrient and oxidative stress conditions. This bioenergetic failure is thought to underlie pathologies associated with mitochondrial diseases. However, the precise metabolic processes resulting from a defective mitochondrial ETC that compromise cell viability under stress conditions are not entirely understood. We design a whole genome gain-of-function CRISPR activation screen using human mitochondrial disease complex I (CI) mutant cells to identify genes whose increased function rescue glucose restriction-induced cell death. The top hit of the screen is the cytosolic Malic Enzyme (ME1), that is sufficient to enable survival and proliferation of CI mutant cells under nutrient stress conditions. Unexpectedly, this metabolic rescue is independent of increased ATP synthesis through glycolysis or oxidative phosphorylation, but dependent on ME1-produced NADPH and glutathione (GSH). Survival upon nutrient stress or pentose phosphate pathway (PPP) inhibition depends on compensatory NADPH production through the mitochondrial one-carbon metabolism that is severely compromised in CI mutant cells. Importantly, this defective CI-dependent decrease in mitochondrial NADPH production pathway or genetic ablation of SHMT2 causes strong inflammatory cytokine signatures associated with redox dependent induction of ASK1 and activation of stress kinases p38 and JNK. These studies find that a major defect of CI deficiencies is decreased mitochondrial one-carbon NADPH production that is associated with increased inflammation and cell death.
2021-09-09 | PXD018839 | Pride
Project description:In this study, the distribution and regulation of periplasmic and cytoplasmic carbon fluxes in Gluconobacter oxydans 621H with glucose were studied by 13C-based metabolic flux analysis (13C-MFA) in combination with transcriptomics and enzyme assays. For 13C-MFA, cells were cultivated with specifically 13C-labeled glucose and intracellular metabolites were analyzed for their labeling pattern by LC-MS. In growth phase I, 90% of the glucose was oxidized periplasmatically to gluconate and partially further oxidized to 2-ketogluconate. Of the glucose taken up by the cells, 9% was phosphorylated to glucose 6-phosphate, whereas 91% was oxidized by cytoplasmic glucose dehydrogenase to gluconate. Additional gluconate was taken up into the cells by transport. Of the cytoplasmic gluconate, 70% was oxidized to 5-ketogluconate and 30% was phosphorylated to 6-phosphogluconate. In growth phase II, 87% of gluconate was oxidized to 2-ketogluconate in the periplasm and 13% was taken up by the cells and almost completely converted to 6-phosphogluconate. Since G. oxydans lacks phosphofructokinase, glucose 6-phosphate can only be metabolized via the oxidative pentose phosphate pathway (PPP) or the Entner-Doudoroff pathway (EDP). 13C-MFA showed that 6-phosphogluconate is catabolized primarily via the oxidative PPP in both phase I and II (62% and 93%) and demonstrated a cyclic carbon flux through the oxidative PPP. The transcriptome comparison revealed an increased expression of PPP genes in growth phase II, which was supported by enzyme activity measurements and correlated with the increased PPP flux in phase II. Moreover, genes possibly related to a general stress response displayed increased expression in growth phase II. The transcriptome comparisons of G. oxydans growth phase II vs. growth phase I were repeated independently three times in biological replicates resulting in 3 hybridizations as termed by sample 1 to 3.
2013-02-13 | E-GEOD-42223 | biostudies-arrayexpress
Project description:Regulatory T cells (Tregs) are critical for maintaining immune homeostasis and preventing autoimmunity. Here, we show that the non-oxidative pentose phosphate pathway (PPP) regulates Treg function to prevent autoimmunity. Deletion of transketolase (TKT), an indispensable enzyme of non-oxidative PPP, in Tregs causes a fatal autoimmune disease in mice, with impaired Treg suppressive capability despite regular Treg numbers and normal Foxp3 expression levels. Mechanistically, reduced glycolysis and enhanced oxidative stress induced by TKT deficiency triggers excessive fatty acid and amino acid catabolism, resulting in uncontrolled oxidative phosphorylation and impaired mitochondrial fitness. Reduced -KG levels as a result of reductive TCA cycle activity leads to DNA hypermethylation, thereby limiting functional gene expression and suppressive activity of TKT-deficient Tregs. We also find that TKT levels are frequently downregulated in Tregs of patients with autoimmune disorders. Our study identifies the non-oxidative PPP as an integrator of metabolic and epigenetic processes that control Treg function.
2022-03-31 | GSE198995 | GEO
Project description:Infection with antimony resistant (SbR) but not with sentitive (SbS) Leishmania donovani (LD) gives rise to aggressive pathology and higher organ parasite load in infected patients, the cause of which is far from clear. The pentose phosphate pathway (PPP) is a key route of glucose metabolism in most organisms, providing NADPH for use as a cellular reductant and various carbohydrate intermediates used in cellular metabolism. Alteration in PPP is primary reason behind aggressive pathology and multi drug resistance in several types of carcinoma and other infectious disease model. A time kinetic study with equal inoculum of SbRLD and SbSLD promastigotes and host cells infected with equal number of SbR and SbSLD, resulted in remarkable higher growth rate in SbRLD which is also reflected in terms of their DNA content. Our result showed an activated PPP pathway in response to oxidative stress in SbRLD. Our result suggest that SbRLD have adapted to a higher nucleotide metaboism that provide them a selective survival advantage in presence of drug mediated oxidative stress and explains, in part, the cause of higher organ parasite load in SbRLD infected patients.
2020-02-04 | GSE144659 | GEO
Project description:Metabolic pathways are now considered as intrinsic virulence attributes of pathogenic bacteria and hence represent potential targets for anti-bacterial strategies. Here, we addressed the role of the pentose phosphate pathway (PPP) and its connections with other metabolic pathways in the pathophysiology of Francisella novicida. We have previously shown that this intracellular bacterial pathogen used gluconeogenesis to metabolize host-derived nutrients in the cytosolic compartment of infected macrophages. Francisella species, which lacks the oxidative branch of the PPP, are equipped with all the genes of the non-oxidative branch (i.e. tktA, tal, rpiA and rpe, encoding transketolase, transaldolase, ribose-phosphate isomerase and ribulose phosphate epimerase, respectively). The involvement of the PPP in the early stage of intracellular life cycle of F. novicida was first demonstrated with the study of PPP inactivation mutants. Indeed, inactivation of tktA, rpiA or rpe genes, severely impaired intramacrophagic multiplication during the first 24–hours. However, time-lapse video microscopy demonstrated that rpiA and rpe mutants were able to resume late intracellular bacterial multiplication. To get further insight into the links between the PPP and other metabolic networks of the bacterium, we next performed a thorough proteo-metabolomic analysis of these mutants. We show that the PPP constitutes a major bacterial metabolic hub with multiple connections with glycolysis, tricarboxylic acid cycle and other metabolic pathways, such as fatty acid degradation and sulfur metabolism. Hence, our study highlights how, by its multiple connections with other metabolic pathways, PPP is instrumental to Francisella pathogenesis and growth in its intracellular niche.
2021-07-27 | PXD023550 | Pride
Project description:Non-oxidative pentose phosphate pathway (PPP) is a crucial gatekeeper of glucose catabolism in metabolic tissues. However, its role in regulatory T cells (Tregs) remains unknown. Here we report deleting transketolase (TKT), an indispensable enzyme of non-oxidative PPP, in Tregs caused a fatal auto-immune disease in mice. TKT deletion impaired suppressive capability without disturbing Treg cell number. Mechanistically, TKT deficiency caused Treg metabolic remodeling with decreased glucose catabolism, activated fatty acid and amino acid catabolism and uncontrolled oxidative phosphorylation. Moreover, excessive ammonia from deregulated amino acid catabolism impaired mitochondrial fitness while reduced α-ketoglutarate/succinate ratio led to DNA hypermethylation, limiting functional gene expression and suppressive activity of TKT-deficient Tregs. Therefore, our study identifies non-oxidative PPP as a new pathway for controlling Treg function.
2022-03-31 | GSE172047 | GEO
Project description:Non-oxidative pentose phosphate pathway (PPP) is a crucial gatekeeper of glucose catabolism in metabolic tissues. However, its role in regulatory T cells (Tregs) remains unknown. Here we report deleting transketolase (TKT), an indispensable enzyme of non-oxidative PPP, in Tregs caused a fatal auto-immune disease in mice. TKT deletion impaired suppressive capability without disturbing Treg cell number. Mechanistically, TKT deficiency caused Treg metabolic remodeling with decreased glucose catabolism, activated fatty acid and amino acid catabolism and uncontrolled oxidative phosphorylation. Moreover, excessive ammonia from deregulated amino acid catabolism impaired mitochondrial fitness while reduced α-ketoglutarate/succinate ratio led to DNA hypermethylation, limiting functional gene expression and suppressive activity of TKT-deficient Tregs. Therefore, our study identifies non-oxidative PPP as a new pathway for controlling Treg function.
2022-03-31 | GSE171675 | GEO
Project description:In this study, the distribution and regulation of periplasmic and cytoplasmic carbon fluxes in Gluconobacter oxydans 621H with glucose were studied by 13C-based metabolic flux analysis (13C-MFA) in combination with transcriptomics and enzyme assays. For 13C-MFA, cells were cultivated with specifically 13C-labeled glucose and intracellular metabolites were analyzed for their labeling pattern by LC-MS. In growth phase I, 90% of the glucose was oxidized periplasmatically to gluconate and partially further oxidized to 2-ketogluconate. Of the glucose taken up by the cells, 9% was phosphorylated to glucose 6-phosphate, whereas 91% was oxidized by cytoplasmic glucose dehydrogenase to gluconate. Additional gluconate was taken up into the cells by transport. Of the cytoplasmic gluconate, 70% was oxidized to 5-ketogluconate and 30% was phosphorylated to 6-phosphogluconate. In growth phase II, 87% of gluconate was oxidized to 2-ketogluconate in the periplasm and 13% was taken up by the cells and almost completely converted to 6-phosphogluconate. Since G. oxydans lacks phosphofructokinase, glucose 6-phosphate can only be metabolized via the oxidative pentose phosphate pathway (PPP) or the Entner-Doudoroff pathway (EDP). 13C-MFA showed that 6-phosphogluconate is catabolized primarily via the oxidative PPP in both phase I and II (62% and 93%) and demonstrated a cyclic carbon flux through the oxidative PPP. The transcriptome comparison revealed an increased expression of PPP genes in growth phase II, which was supported by enzyme activity measurements and correlated with the increased PPP flux in phase II. Moreover, genes possibly related to a general stress response displayed increased expression in growth phase II.
2013-02-13 | GSE42223 | GEO