title: Neural stem/progenitor cells display a low requirement for oxidative metabolism independent of hypoxia inducible factor-1alpha expression.
abstract: Neural stem/progenitor cells (NSPCs) are multipotent cells within the embryonic and adult brain that give rise to both neuronal and glial cell lineages. Maintenance of NSPC multipotency is promoted by low oxygen tension, although the metabolic underpinnings of this trait have not been described. In this study, we investigated the metabolic state of undifferentiated NSPCs in culture, and tested their relative reliance on oxidative versus glycolytic metabolism for survival, as well as their dependence on hypoxia inducible factor-1alpha (HIF-1α) expression for maintenance of metabolic phenotype. Unlike primary neurons, NSPCs from embryonic and adult mice survived prolonged hypoxia in culture. In addition, NSPCs displayed greater susceptibility to glycolytic inhibition compared with primary neurons, even in the presence of alternative mitochondrial TCA substrates. NSPCs were also more resistant than neurons to mitochondrial cyanide toxicity, less capable of utilizing galactose as an alternative substrate to glucose, and more susceptible to pharmacological inhibition of the pentose phosphate pathway by 6-aminonicotinamide. Inducible deletion of exon 1 of the Hif1a gene improved the ability of NSPCs to utilize pyruvate during glycolytic inhibition, but did not alter other parameters of metabolism, including their ability to withstand prolonged hypoxia. Taken together, these data indicate that NSPCs have a relatively low requirement for oxidative metabolism for their survival and that hypoxic resistance is not dependent upon HIF-1α signaling.
authors: Department of Neurosciences, University of New Mexico Health Sciences Center, Albuquerque, New Mexico 87131-0001, USA.
authors: Kate M
authors: KM
authors: Candelario
authors: C William
authors: CW
authors: Shuttleworth
authors: Lee Anna
authors: LA
authors: Cunningham
mesh_terms: D015120:6-Aminonicotinamide / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics; D015687:Cell Hypoxia / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007381:Intermediate Filament Proteins / Q000172:deficiency; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D019344:Lactic Acid / Q000378:metabolism; D008164:Luminescent Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000172:deficiency; D064231:Nestin; D058953:Neural Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D010100:Oxygen / Q000378:metabolism*; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D019289:Pyruvic Acid / Q000378:metabolism; D012966:Sodium Cyanide / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007381:Intermediate Filament Proteins; D008164:Luminescent Proteins; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; C054562:yellow fluorescent protein, Bacteria; D015120:6-Aminonicotinamide; D019344:Lactic Acid; D019289:Pyruvic Acid; D007770:L-Lactate Dehydrogenase; D010751:Phosphopyruvate Hydratase; D005947:Glucose; D012966:Sodium Cyanide; D010100:Oxygen