scholarly journals Enhanced glucose metabolism through activation of HIF-1α covers the energy demand in a rat embryonic heart primordium after heartbeat initiation

2022 ◽  
Vol 12 (1) ◽  
Author(s):  
Tatsuya Sato ◽  
Nobutoshi Ichise ◽  
Takeshi Kobayashi ◽  
Hiroyori Fusagawa ◽  
Hiroya Yamazaki ◽  
...  
Keyword(s):  
Pentose Phosphate Pathway ◽  
Energy Demand ◽  
Glucose Transporter ◽  
Hypoxia Inducible Factor ◽  
Atp Synthesis ◽  
Pentose Phosphate ◽  
Metabolome Analysis ◽  
Nucleotide Biosynthesis ◽  
Metabolic Characteristics ◽  
Before And After

AbstractThe initiation of heartbeat is an essential step in cardiogenesis in the heart primordium, but it remains unclear how intracellular metabolism responds to increased energy demands after heartbeat initiation. In this study, embryos in Wistar rats at embryonic day 10, at which heartbeat begins in rats, were divided into two groups by the heart primordium before and after heartbeat initiation and their metabolic characteristics were assessed. Metabolome analysis revealed that increased levels of ATP, a main product of glucose catabolism, and reduced glutathione, a by-product of the pentose phosphate pathway, were the major determinants in the heart primordium after heartbeat initiation. Glycolytic capacity and ATP synthesis-linked mitochondrial respiration were significantly increased, but subunits in complexes of mitochondrial oxidative phosphorylation were not upregulated in the heart primordium after heartbeat initiation. Hypoxia-inducible factor (HIF)-1α was activated and a glucose transporter and rate-limiting enzymes of the glycolytic and pentose phosphate pathways, which are HIF-1α-downstream targets, were upregulated in the heart primordium after heartbeat initiation. These results suggest that the HIF-1α-mediated enhancement of glycolysis with activation of the pentose phosphate pathway, potentially leading to antioxidant defense and nucleotide biosynthesis, covers the increased energy demand in the beating and developing heart primordium.

scholarly journals RIP140 inhibits glycolysis-dependent proliferation of cancer cells by regulating transcriptional crosstalk between hypoxia induced factor and p53

2020 ◽  
Author(s):  
Valentin Jacquier ◽  
Delphine Gitenay ◽  
Samuel Fritsch ◽  
Laetitia K. Linares ◽  
Sandrine Bonnet ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cancer Cells ◽  
Pentose Phosphate Pathway ◽  
Glucose Transporter ◽  
Hypoxia Inducible Factor ◽  
Pentose Phosphate ◽  
Cancer Cell Proliferation ◽  
Glycolytic Intermediates ◽  
Glucose 6 Phosphate Dehydrogenase ◽  
Block Cell Proliferation

AbstractCancer cells with uncontrolled proliferation preferentially depend on glycolysis to grow, even in the presence of oxygen. Cancer cell proliferation is sustained by the production of glycolytic intermediates, which are diverted into the pentose phosphate pathway. The transcriptional co-regulator RIP140 represses the activity of transcription factors that drive cell proliferation and metabolism, especially glycolysis. However, it is still unknown whether RIP140 is involved in cancer-associated glycolysis deregulation, and whether this involvement could impact tumor cell proliferation. Here we use cell proliferation and metabolic assays to demonstrate that RIP140-deficiency causes a glycolysis-dependent increase in breast tumor growth. RIP140 inhibits the expression of the glucose transporter GLUT3 and of the Glucose-6-Phosphate Dehydrogenase G6PD, the first enzyme of the pentose phosphate pathway. RIP140 thus impacts both this pathway and glycolysis to block cell proliferation. We further demonstrate that RIP140 and p53 jointly inhibit the transcription of the GLUT3 promoter, induced by the hypoxia inducible factor HIF-2α. Overall, our data establish RIP140 as a critical modulator of the p53/HIF cross-talk that controls cancer glycolysis.

scholarly journals Activity of Energy and Carbohydrate Metabolism Enzymes in the Juvenile Pink Salmon Oncorhynchus gorbuscha (Walb.) during the Transition from Freshwater to a Marine Environment

2021 ◽  
Vol 48 (5) ◽  
pp. 546-554
Author(s):  
M. V. Churova ◽  
N. S. Shulgina ◽  
M. Yu. Krupnova ◽  
D. A. Efremov ◽  
N. N. Nemova
Keyword(s):  
Carbohydrate Metabolism ◽  
Marine Environment ◽  
Pentose Phosphate Pathway ◽  
Anaerobic Metabolism ◽  
Pink Salmon ◽  
Atp Synthesis ◽  
Pentose Phosphate ◽  
Oncorhynchus Gorbuscha ◽  
Biochemical Adaptation ◽  
Metabolism Enzymes

Abstract Biochemical adaptations of energy metabolism and some pathways of glucose oxidation during a change in salinity of the environment in larvae and smolts of the pink salmon Oncorhynchus gorbuscha (Walb.) inhabiting the White Sea were studied. We assayed the activity of energy and carbohydrate metabolism enzymes (cytochrome c oxidase (COХ), lactate dehydrogenase (LDH), glucose-6-phosphate dehydrogenase (G6PDH), 1-glycerophosphate dehydrogenase (1-GPDH), and aldolase) in pink salmon larvae in a short-term aquarium experiment and in pink salmon smolts in a long-term cage experiment simulating the transition of juveniles from freshwater to a marine environment. A decrease in the activity of COX, LDH, 1‑GPDH, and aldolase already in the first hour after the transfer of larvae to seawater was shown. Smolts kept in the estuary and in the sea had low levels of activity of 1-GPDH and aldolase in comparison with individuals from the river. Most likely, in the salmon juveniles studied, there was a redistribution of carbohydrates between the reactions of aerobic and anaerobic metabolism in favor of anaerobic ATP synthesis. No changes in the enzyme activity of the pentose phosphate pathway, G-6-PDH, were found in either larvae or smolts compared with the individuals kept in freshwater. Maintenance of the required levels of anaerobic metabolism and of the pentose phosphate pathway is probably one of the mechanisms of biochemical adaptation of pink salmon to changes in salinity.

scholarly journals Dehydroepiandrosterone Inhibits Glucose Flux Through the Pentose Phosphate Pathway in Human and Mouse Endometrial Stromal Cells, Preventing Decidualization and Implantation

2011 ◽  
Vol 25 (8) ◽  
pp. 1444-1455 ◽  
Author(s):  
Antonina I. Frolova ◽  
Kathleen O'Neill ◽  
Kelle H. Moley
Keyword(s):  
Stromal Cells ◽  
Pentose Phosphate Pathway ◽  
Glucose Transporter ◽  
Polycystic Ovary ◽  
Pentose Phosphate ◽  
Reproductive Age ◽  
Endometrial Stromal Cells ◽  
Glucose Transporter 1 ◽  
Decidual Cells

Endometrial stromal cells (ESC) must undergo a hormone-driven differentiation to form decidual cells as a requirement of proper embryo implantation. Recent studies from our laboratory have demonstrated that decidualizing cells require glucose transporter 1 expression and an increase in glucose use to complete this step. The present study focuses on the glucose-dependent molecular and metabolic pathways, which are required by ESC for decidualization. Inhibition of glycolysis had no effect on decidualization. However, blockade of the pentose phosphate pathway (PPP) with pharmacologic inhibitors 6-aminonicotinamide or dehydroepiandrosterone (DHEA), and short hairpin RNA-mediated knockdown of glucose-6-phosphate dehydrogenase, the rate-limiting step in the PPP, both led to strong decreases in decidual marker expression in vitro and decreased decidualization in vivo. Additionally, the studies demonstrate that inhibition is due, at least in part, to ribose-5-phosphate depletion, because exogenous nucleoside administration restored decidualization in these cells. The finding that PPP inhibition prevents decidualization of ESC is novel and clinically important, because DHEA is an endogenous hormone produced by the adrenal glands and elevated in a high proportion of women who have polycystic ovary syndrome, the most common endocrinopathy in reproductive age women. Together, this data suggest a mechanistic link between increased DHEA levels, use of glucose via the PPP, and pregnancy loss.

scholarly journals Mitochondria Contribute to NADPH Generation in Mouse Rod Photoreceptors

2013 ◽  
Vol 289 (3) ◽  
pp. 1519-1528 ◽  
Author(s):  
Leopold Adler ◽  
Chunhe Chen ◽  
Yiannis Koutalos
Keyword(s):  
Single Cell ◽  
Pentose Phosphate Pathway ◽  
Metabolic Pathways ◽  
Cell Function ◽  
Primary Source ◽  
Atp Synthesis ◽  
Pentose Phosphate ◽  
Cell Type ◽  
Rod Photoreceptors ◽  
Substrate Concentrations

NADPH is the primary source of reducing equivalents in the cytosol. Its major source is considered to be the pentose phosphate pathway, but cytosolic NADP+-dependent dehydrogenases using intermediates of mitochondrial pathways for substrates have been known to contribute. Photoreceptors, a nonproliferating cell type, provide a unique model for measuring the functional utilization of NADPH at the single cell level. In these cells, NADPH availability can be monitored from the reduction of the all-trans-retinal generated by light to all-trans-retinol using single cell fluorescence imaging. We have used mouse rod photoreceptors to investigate the generation of NADPH by different metabolic pathways. In the absence of extracellular metabolic substrates, NADPH generation was severely compromised. Extracellular glutamine supported NADPH generation to levels comparable to those of glucose, but pyruvate and lactate were relatively ineffective. At low extracellular substrate concentrations, partial inhibition of ATP synthesis lowered, whereas suppression of ATP consumption augmented NADPH availability. Blocking pyruvate transport into mitochondria decreased NADPH availability, and addition of glutamine restored it. Our findings demonstrate that in a nonproliferating cell type, mitochondria-linked pathways can generate substantial amounts of NADPH and do so even when the pentose phosphate pathway is operational. Competing demands for ATP and NADPH at low metabolic substrate concentrations indicate a vulnerability to nutrient shortages. By supporting substantial NADPH generation, mitochondria provide alternative metabolic pathways that may support cell function and maintain viability under transient nutrient shortages. Such pathways may play an important role in protecting against retinal degeneration.

scholarly journals The plastidial pentose phosphate pathway is essential for postglobular embryo development in Arabidopsis

2019 ◽  
Vol 116 (30) ◽  
pp. 15297-15306 ◽  
Author(s):  
Vasilios M. E. Andriotis ◽  
Alison M. Smith
Keyword(s):  
Embryo Development ◽  
Pentose Phosphate Pathway ◽  
Aromatic Amino Acids ◽  
Endosperm Development ◽  
Pentose Phosphate ◽  
Purine Nucleotide ◽  
Purine Nucleotides ◽  
Nucleotide Biosynthesis ◽  
Stage Of Development ◽  
Globular Stage

Large numbers of genes essential for embryogenesis in Arabidopsis encode enzymes of plastidial metabolism. Disruption of many of these genes results in embryo arrest at the globular stage of development. However, the cause of lethality is obscure. We examined the role of the plastidial oxidative pentose phosphate pathway (OPPP) in embryo development. In nonphotosynthetic plastids the OPPP produces reductant and metabolic intermediates for central biosynthetic processes. Embryos with defects in various steps in the oxidative part of the OPPP had cell division defects and arrested at the globular stage, revealing an absolute requirement for the production via these steps of ribulose-5-phosphate. In the nonoxidative part of the OPPP, ribulose-5-phosphate is converted to ribose-5-phosphate (R5P)—required for purine nucleotide and histidine synthesis—and subsequently to erythrose-4-phosphate, which is required for synthesis of aromatic amino acids. We show that embryo development through the globular stage specifically requires synthesis of R5P rather than erythrose-4-phosphate. Either a failure to convert ribulose-5-phosphate to R5P or a block in purine nucleotide biosynthesis beyond R5P perturbs normal patterning of the embryo, disrupts endosperm development, and causes early developmental arrest. We suggest that seed abortion in mutants unable to synthesize R5P via the oxidative part of the OPPP stems from a lack of substrate for synthesis of purine nucleotides, and hence nucleic acids. Our results show that the plastidial OPPP is essential for normal developmental progression as well as for growth in the embryo.

scholarly journals Comprehensive Analysis of 13C6 Glucose Fate in the Hypoxia-Tolerant Blind Mole Rat Skin Fibroblasts

Metabolites ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 734
Author(s):  
Dmitry Miskevich ◽  
Anastasia Chaban ◽  
Maria Dronina ◽  
Ifat Abramovich ◽  
Eyal Gottlieb ◽  
...  
Keyword(s):  
Pentose Phosphate Pathway ◽  
Hypoxia Inducible Factor ◽  
Lactate Production ◽  
Tca Cycle ◽  
Pentose Phosphate ◽  
Adaptation To Hypoxia ◽  
Rat Skin ◽  
Terrestrial Mammals ◽  
Mole Rat ◽  
Cytosolic Domain

The bioenergetics of the vast majority of terrestrial mammals evolved to consuming glucose (Glc) for energy production under regular atmosphere (about 21% oxygen). However, some vertebrate species, such as aquatic turtles, seals, naked mole rat, and blind mole rat, Spalax, have adjusted their homeostasis to continuous function under severe hypoxic environment. The exploration of hypoxia-tolerant species metabolic strategies provides a better understanding of the adaptation to hypoxia. In this study, we compared Glc homeostasis in primary Spalax and rat skin cells under normoxic and hypoxic conditions. We used the targeted-metabolomics approach, utilizing liquid chromatography and mass spectrometry (LC-MS) to track the fate of heavy Glc carbons (13C6 Glc), as well as other methodologies to assist the interpretation of the metabolic landscape, such as bioenergetics profiling, Western blotting, and gene expression analysis. The metabolic profile was recorded under steady-state (after 24 h) of the experiment. Glc-originated carbons were unequally distributed between the cytosolic and mitochondrial domains in Spalax cells compared to the rat. The cytosolic domain is dominant apparently due to the hypoxia-inducible factor-1 alpha (HIF-1α) mastering, since its level is higher under normoxia and hypoxia in Spalax cells. Consumed Glc in Spalax cells is utilized for the pentose phosphate pathway maintaining the NADPH pool, and is finally harbored as glutathione (GSH) and UDP-GlcNAc. The cytosolic domain in Spalax cells works in the semi-uncoupled mode that limits the consumed Glc-derived carbons flux to the tricarboxylic acid (TCA) cycle and reduces pyruvate delivery; however, it maintains the NAD+ pool via lactate dehydrogenase upregulation. Both normoxic and hypoxic mitochondrial homeostasis of Glc-originated carbons in Spalax are characterized by their massive cataplerotic flux along with the axis αKG→Glu→Pro→hydroxyproline (HPro). The product of collagen degradation, HPro, as well as free Pro are apparently involved in the bioenergetics of Spalax under both normoxia and hypoxia. The upregulation of 2-hydroxyglutarate production detected in Spalax cells may be involved in modulating the levels of HIF-1α. Collectively, these data suggest that Spalax cells utilize similar metabolic frame for both normoxia and hypoxia, where glucose metabolism is switched from oxidative pathways (conversion of pyruvate to Acetyl-CoA and further TCA cycle processes) to (i) pentose phosphate pathway, (ii) lactate production, and (iii) cataplerotic pathways leading to hexosamine, GSH, and HPro production.

HIF1-α-Mediated Gene Expression Induced by Vitamin B1 Deficiency

2013 ◽  
Vol 83 (3) ◽  
pp. 188-197 ◽  
Author(s):  
Rebecca L. Sweet ◽  
Jason A. Zastre
Keyword(s):  
Gene Expression ◽  
Thiamine Deficiency ◽  
Glucose Transporter ◽  
Neuroblastoma Cell ◽  
Hypoxia Inducible Factor ◽  
Clinical Manifestations ◽  
Vitamin B1 ◽  
Low Oxygen ◽  
Glucose Transporter 1 ◽  
Metabolic Intermediates

It is well established that thiamine deficiency results in an excess of metabolic intermediates such as lactate and pyruvate, which is likely due to insufficient levels of cofactor for the function of thiamine-dependent enzymes. When in excess, both pyruvate and lactate can increase the stabilization of the hypoxia-inducible factor 1-alpha (HIF-1α) transcription factor, resulting in the trans-activation of HIF-1α regulated genes independent of low oxygen, termed pseudo-hypoxia. Therefore, the resulting dysfunction in cellular metabolism and accumulation of pyruvate and lactate during thiamine deficiency may facilitate a pseudo-hypoxic state. In order to investigate the possibility of a transcriptional relationship between hypoxia and thiamine deficiency, we measured alterations in metabolic intermediates, HIF-1α stabilization, and gene expression. We found an increase in intracellular pyruvate and extracellular lactate levels after thiamine deficiency exposure to the neuroblastoma cell line SK-N-BE. Similar to cells exposed to hypoxia, there was a corresponding increase in HIF-1α stabilization and activation of target gene expression during thiamine deficiency, including glucose transporter-1 (GLUT1), vascular endothelial growth factor (VEGF), and aldolase A. Both hypoxia and thiamine deficiency exposure resulted in an increase in the expression of the thiamine transporter SLC19A3. These results indicate thiamine deficiency induces HIF-1α-mediated gene expression similar to that observed in hypoxic stress, and may provide evidence for a central transcriptional response associated with the clinical manifestations of thiamine deficiency.

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