title: UCP2 regulates energy metabolism and differentiation potential of human pluripotent stem cells.
abstract: It has been assumed, based largely on morphologic evidence, that human pluripotent stem cells (hPSCs) contain underdeveloped, bioenergetically inactive mitochondria. In contrast, differentiated cells harbour a branched mitochondrial network with oxidative phosphorylation as the main energy source. A role for mitochondria in hPSC bioenergetics and in cell differentiation therefore remains uncertain. Here, we show that hPSCs have functional respiratory complexes that are able to consume O(2) at maximal capacity. Despite this, ATP generation in hPSCs is mainly by glycolysis and ATP is consumed by the F(1)F(0) ATP synthase to partially maintain hPSC mitochondrial membrane potential and cell viability. Uncoupling protein 2 (UCP2) plays a regulating role in hPSC energy metabolism by preventing mitochondrial glucose oxidation and facilitating glycolysis via a substrate shunting mechanism. With early differentiation, hPSC proliferation slows, energy metabolism decreases, and UCP2 is repressed, resulting in decreased glycolysis and maintained or increased mitochondrial glucose oxidation. Ectopic UCP2 expression perturbs this metabolic transition and impairs hPSC differentiation. Overall, hPSCs contain active mitochondria and require UCP2 repression for full differentiation potential.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhang
authors.forename: Ivan
authors.initials: I
authors.lastname: Khvorostov
authors.forename: Jason S
authors.initials: JS
authors.lastname: Hong
authors.forename: Yavuz
authors.initials: Y
authors.lastname: Oktay
authors.forename: Laurent
authors.initials: L
authors.lastname: Vergnes
authors.forename: Esther
authors.initials: E
authors.lastname: Nuebel
authors.forename: Paulin N
authors.initials: PN
authors.lastname: Wahjudi
authors.forename: Kiyoko
authors.initials: K
authors.lastname: Setoguchi
authors.forename: Geng
authors.initials: G
authors.lastname: Wang
authors.forename: Anna
authors.initials: A
authors.lastname: Do
authors.forename: Hea-Jin
authors.initials: HJ
authors.lastname: Jung
authors.forename: J Michael
authors.initials: JM
authors.lastname: McCaffery
authors.forename: Irwin J
authors.initials: IJ
authors.lastname: Kurland
authors.forename: Karen
authors.initials: K
authors.lastname: Reue
authors.forename: Wai-Nang P
authors.initials: WN
authors.lastname: Lee
authors.forename: Carla M
authors.initials: CM
authors.lastname: Koehler
authors.forename: Michael A
authors.initials: MA
authors.lastname: Teitell
mesh_terms: D000255:Adenosine Triphosphate; D002454:Cell Differentiation; D002460:Cell Line; D004734:Energy Metabolism; D006019:Glycolysis; D006801:Humans; D006868:Hydrolysis; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D010101:Oxygen Consumption; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism* / Q000648:ultrastructure; D017382:Reactive Oxygen Species / Q000378:metabolism; D000071246:Uncoupling Protein 2
chemical_list: D007473:Ion Channels; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; C000604389:UCP2 protein, human; D000071246:Uncoupling Protein 2; D000255:Adenosine Triphosphate
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