Glucose is necessary for stabilization of hypoxia-inducible factor-1α under hypoxia: Contribution of the pentose phosphate pathway to this stabilization

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.

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

10.1101/2020.07.30.228759 ◽

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.

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

Metabolites ◽

10.3390/metabo11110734 ◽

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.

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