title: Distinct profiles of human embryonic stem cell metabolism and mitochondria identified by oxygen.
abstract: Oxygen is a powerful regulator of cell function and embryonic development. It has previously been determined that oxygen regulates human embryonic stem (hES) cell glycolytic and amino acid metabolism, but the effects on mitochondria are as yet unknown. Two hES cell lines (MEL1, MEL2) were analyzed to determine the role of 5% (physiological) and 20% (atmospheric) oxygen in regulating mitochondrial activity. In response to extended physiological oxygen culture, MEL2 hES cells displayed reduced mtDNA content, mitochondrial mass and expression of metabolic genes TFAM, NRF1, PPARa and MT-ND4. Furthermore, MEL2 hES cell glucose consumption, lactate production and amino acid turnover were elevated under physiological oxygen. In stark contrast, MEL1 hES cell amino acid and carbohydrate use and mitochondrial function were relatively unaltered in response to oxygen. Furthermore, differentiation kinetics were delayed in the MEL1 hES cell line following BMP4 treatment. Here we report the first incidence of metabolic dysfunction in a hES cell population, defined as a failure to respond to oxygen concentration through the modulation of metabolism, demonstrating that hES cells can be perturbed during culture despite exhibiting the defining characteristics of pluripotent cells. Collectively, these data reveal a central role for oxygen in the regulation of hES cell metabolism and mitochondrial function, whereby physiological oxygen promotes glucose flux and suppresses mitochondrial biogenesis and gene expression.
authors.affiliation: School of BiosciencesUniversity of Melbourne, Parkville 3010, Victoria, AustraliaMenzies Institute of Medical ResearchUniversity of Tasmania, Hobart 7000, Tasmania, Australia.
authors.forename: Jarmon G
authors.initials: JG
authors.lastname: Lees
authors.affiliation: School of BiosciencesUniversity of Melbourne, Parkville 3010, Victoria, AustraliaMenzies Institute of Medical ResearchUniversity of Tasmania, Hobart 7000, Tasmania, Australia School of BiosciencesUniversity of Melbourne, Parkville 3010, Victoria, AustraliaMenzies Institute of Medical ResearchUniversity of Tasmania, Hobart 7000, Tasmania, Australia.
authors.forename: Joy
authors.initials: J
authors.lastname: Rathjen
authors.affiliation: School of BiosciencesUniversity of Melbourne, Parkville 3010, Victoria, AustraliaMenzies Institute of Medical ResearchUniversity of Tasmania, Hobart 7000, Tasmania, Australia.
authors.forename: John R
authors.initials: JR
authors.lastname: Sheedy
authors.affiliation: School of BiosciencesUniversity of Melbourne, Parkville 3010, Victoria, AustraliaMenzies Institute of Medical ResearchUniversity of Tasmania, Hobart 7000, Tasmania, Australia.
authors.forename: David K
authors.initials: DK
authors.lastname: Gardner
authors.affiliation: School of BiosciencesUniversity of Melbourne, Parkville 3010, Victoria, AustraliaMenzies Institute of Medical ResearchUniversity of Tasmania, Hobart 7000, Tasmania, Australia ajharvey@unimelb.edu.au.
authors.forename: Alexandra J
authors.initials: AJ
authors.lastname: Harvey
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000596:Amino Acids / Q000378:metabolism; D050260:Carbohydrate Metabolism / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D004272:DNA, Mitochondrial / Q000096:biosynthesis; D005947:Glucose / Q000378:metabolism; D000066449:Human Embryonic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D019344:Lactic Acid / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D010100:Oxygen / Q000494:pharmacology*; D039904:Pluripotent Stem Cells / Q000187:drug effects
chemical_list: D000596:Amino Acids; D004272:DNA, Mitochondrial; D019344:Lactic Acid; D000255:Adenosine Triphosphate; D005947:Glucose; D010100:Oxygen