Taldo1 Knockdown impaired NADPH production in CD8+ T cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE315519 | GEO | 2026/02/08
REPOSITORIES: GEO
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Project description:Transketolase (TKT) is a key enzyme in the non-oxidative pentose phosphate pathway. However, the impact of Taldo1 disruption on CD8+ T cell differentiation and function remains undefined. Here, we found that knockdown of Taldo1 in CD8+ T cells impairs NADPH production, causes ribose-5-phosphate accumulation, elevates oxidative stress, reduces lipid synthesis, induces mitochondrial dysfunction, and compromises effector cell proliferation, cytokine production, and antitumor efficacy, whereas enhancing Taldo1 promotes memory T cell differentiation, persistence, and recall responses during immune challenges.
2026-02-08 | GSE315826 | GEO
Project description:Oxidative stress modulates carcinogenesis in the liver; however, direct evidence for metabolic control of oxidative stress during pathogenesis, particularly, of progression from cirrhosis to hepatocellular carcinoma (HCC), has been lacking. Deficiency of transaldolase (TAL), a ratelimiting enzyme of the non-oxidative branch of the pentose phosphate pathway (PPP), elicits growth restriction, and predisposes to cirrhosis and HCC in mice and humans. Here, we show that mitochondrial oxidative stress and disease progression from cirrhosis to HCC and acetaminophen-induced liver necrosis are critically dependent on NADPH depletion by aldose reductase (AR), while this enzyme protects from carbon trapping in the PPP and stunted growth in TAL deficiency. Both TAL and AR are confined to the cytosol, however, their inactivation distorts NADPH production and mitochondrial oxidative stress into opposite directions.
2023-01-13 | GSE217133 | GEO
Project description:Cancer cells heavily rely on nicotinamide adenine dinucleotide phosphate (NADPH) to counteract oxidative stress and facilitate reductive biosynthesis. One crucial route for NADPH production operates through the oxidative pentose phosphate pathway, with a pivotal step at glucose-6-phosphate dehydrogenase (G6PD). This study delves into the repercussions of G6PD ablation on the development of lung tumors driven by the KRAS oncogene and deficient in LKB1 (KL). The research involved comparing the growth of KL lung tumors with or without G6PD, revealing a significant inhibition of KL lung tumor growth upon G6PD loss. Subsequently, RNA-seq analysis was employed to identify the alterations in gene expression following G6PD deletion, providing insights into the underlying mechanisms.
2024-01-23 | GSE253613 | 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:Reactive oxygen species (ROS) production is a conserved immune response, primarily mediated in Arabidopsis by the respiratory burst oxidase homolog D (RBOHD), a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase associated with the plasma membrane. A rapid increase in NADPH is necessary to fuel RBOHD proteins and hence maintain ROS production. However, the molecular mechanism underlying the NADPH generation for fueling RBOHD remains unclear. In this study, we isolated a new mutant allele of flagellin-insensitive 4 (FIN4), encoding the first enzyme in de novo NAD biosynthesis. fin4 mutants show reduced NADPH levels and impaired ROS production. However, FIN4 and other genes involved in the NAD- and NADPH-generating pathways are not highly upregulated upon elicitor treatment. Therefore, we hypothesized that a cytosolic NADP-linked dehydrogenase might be post-transcriptionally activated to keep the NADPH supply close to RBOHD. RPM1-INDUCED PROTEIN KINASE (RIPK), a receptor-like cytoplasmic kinase, regulates broad-spectrum ROS signaling in plant immunity. We then isolated the proteins associated with RIPK and identified NADP-malic enzyme 2 (NADP-ME2), an NADPH-generating enzyme. Compared with wild-type plants, nadp-me2 mutants display decreased NADP-ME activity, lower NADPH levels, as well as reduced ROS production in response to immune elicitors. Furthermore, we found that RIPK can directly phosphorylate NADP-ME2 and enhance its activity in vitro. The phosphorylation of NADP-ME2 S371 residue contributes to ROS production upon immune elicitor treatment and the susceptibility to the necrotrophic bacterium, Pectobacterium carotovorum. Overall, our study suggests that RIPK activates NADP-ME2 to rapidly increase cytosolic NADPH, hence fueling RBOHD to sustain ROS production in plant immunity.
2022-03-10 | GSE198017 | GEO
Project description:Exposure to oxygen and light generates photooxidative stress by the bacteriochlorophyll a mediated formation of singlet oxygen (1O2) in the facultative photosynthetic bacterium Rhodobacter sphaeroides. We have identified SorY as an sRNA, which is induced under several stress conditions and confers increased resistance against 1O2. SorY by direct interaction decreases the levels of takP mRNA, encoding a TRAP-T transporter. A takP mutant shows higher resistance to 1O2 than the wild type, which is no longer affected by SorY. We present a model in which SorY reduces the metabolite flux into the TCA cycle by reducing malate import through TakP. It was previously shown that oxidative stress in bacteria leads to switch from glycolysis to the pentose phosphate cycle and to reduced activity of the tricaboxylic acid cycle. As a consequence the production of the prooxidant NADH is reduced and production of the protective NADPH is enhanced. In R. sphaeroides enzymes for glycolysis, pentose phosphate pathway, EntnerM-bM-^@M-^SDoudoroff pathway and gluconeogenesis are induced in response to 1O2 by the alternative sigma factor RpoHII. The same is true for the sRNA SorY. By limiting malate import SorY thus contributes to the balance of the metabolic fluxes under photooxidative stress conditions. This assigns a so far unknown function to an sRNA in oxidative stress response. RNA samples collected from a control strain harbouring an empty vector (2.4.1pBBR) and of the SorY overexpressing strain (2.4.1pBBRSorYi) after 10 min of 1O2 stress were analyzed by two-color microarrays
2014-11-18 | E-GEOD-63328 | biostudies-arrayexpress
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:Exposure to oxygen and light generates photooxidative stress by the bacteriochlorophyll a mediated formation of singlet oxygen (1O2) in the facultative photosynthetic bacterium Rhodobacter sphaeroides. We have identified SorY as an sRNA, which is induced under several stress conditions and confers increased resistance against 1O2. SorY by direct interaction decreases the levels of takP mRNA, encoding a TRAP-T transporter. A takP mutant shows higher resistance to 1O2 than the wild type, which is no longer affected by SorY. We present a model in which SorY reduces the metabolite flux into the TCA cycle by reducing malate import through TakP. It was previously shown that oxidative stress in bacteria leads to switch from glycolysis to the pentose phosphate cycle and to reduced activity of the tricaboxylic acid cycle. As a consequence the production of the prooxidant NADH is reduced and production of the protective NADPH is enhanced. In R. sphaeroides enzymes for glycolysis, pentose phosphate pathway, Entner–Doudoroff pathway and gluconeogenesis are induced in response to 1O2 by the alternative sigma factor RpoHII. The same is true for the sRNA SorY. By limiting malate import SorY thus contributes to the balance of the metabolic fluxes under photooxidative stress conditions. This assigns a so far unknown function to an sRNA in oxidative stress response.
2014-11-18 | GSE63328 | GEO
Project description:Brief summary: Analysis of gene expression in endothelial cells upon contact-inhibition. With this experiments we aimed to identify genes that are associated with the induction of cellular quiescence. Abstract from the associated publication: In contrast to the growing insight in the metabolic reprogramming underlying the angiogenic switch, little is known about the metabolic changes accompanying the quiescence of endothelial cells (ECs). Nonetheless, when dysfunctional, quiescent ECs (QECs) contribute to multiple diseases. Here, we report that QECs are not hypometabolic, but upregulate fatty acid β-oxidation (FAO), not for energy or biomass production, but for redox homeostasis. Hence, inhibition of CPT1a, a rate-controlling step of fatty acid breakdown, promotes a pro-thrombotic and pro-inflammatory signature of QECs by increasing oxidative stress. EC-specific genetic loss similarly elevates oxidative stress in vivo. Compared to proliferating ECs (PECs), QECs switch on a broad “vasculoprotective” metabolic program, involving (i) NAPDH production by the oxidative pentose phosphate pathway (oxPPP) and nicotinamide nucleotide transhydrogenase (NNT), and (ii) prostacyclin synthesis. Molecularly, pro-quiescent Notch signaling elevates FAO by upregulating CPT1a gene transcription. Thus, QECs switch on vasculoprotective metabolic reactions to ensure vascular health.
2018-10-24 | GSE89174 | GEO
Project description:Cellular redox control is maintained by generation of reactive oxygen/nitrogen species balanced by activation of antioxidative pathways. Disruption of redox balance leads to oxidative stress, a central causative event in numerous diseases including heart failure. Redox control in the heart exposed to hemodynamic stress, however, remains to be fully elucidated. Here, we show that production of cardiomyocyte NADPH (nicotinamide adenine dinucleotide phosphate), a key factor in redox regulation, is decreased in pressure overload-induced heart failure. As a consequence, the level of reduced glutathione is downregulated, a change associated with cardiac cell death, fibrosis, and cardiomyopathy. We report that the pentose phosphate pathway (PPP) and mitochondrial serine/glycine/folate metabolic signaling, two major NADPH-generating pathways in the cytosol and mitochondria, respectively, are induced in the heart by pressure overload. We identify ATF4 (activating transcriptional factor 4) as an upstream transcription factor controlling the expression of multiple enzymes in these two pathways. Consistent with this, joint pathway analysis (JPA) of transcriptomic and metabolomic data reveals that ATF4 preferably controls oxidative stress and redox-related pathways. Overexpression of ATF4 in cardiomyocytes in culture leads to a significant increase in NADPH-producing enzymes whereas silencing of ATF4 decreases their expression. Further, stable isotope tracer experiments reveal that ATF4 overexpression in vitro strongly augments metabolic flux within these two pathways. In vivo, cardiomyocyte-specific deletion of ATF4 exacerbates cardiomyopathy in the setting of pressure overload and accelerates the development of heart failure, attributable, at least in part, to an inability to increase the expression of NADPH-generating enzymes. Taken together, our findings reveal that ATF4 plays a critical role in cardiac homeostasis under conditions of hemodynamic stress by governing both cytosolic and mitochondrial production of NADPH.
2022-05-16 | GSE187005 | GEO