UCP2 regulates energy metabolism and differentiation potential of human pluripotent stem cells

Authors

  • Jin Zhang,

    1. Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA, USA
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  • Ivan Khvorostov,

    1. Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA, USA
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  • Jason S Hong,

    1. Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA, USA
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  • Yavuz Oktay,

    1. Department of Chemistry and Biochemistry, University of California, Los Angeles, CA, USA
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  • Laurent Vergnes,

    1. Department of Human Genetics, University of California, Los Angeles, CA, USA
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  • Esther Nuebel,

    1. Department of Chemistry and Biochemistry, University of California, Los Angeles, CA, USA
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  • Paulin N Wahjudi,

    1. Department of Pediatrics, LA Biomedical Research Institute, Torrance, CA, USA
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  • Kiyoko Setoguchi,

    1. Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA, USA
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  • Geng Wang,

    1. Department of Chemistry and Biochemistry, University of California, Los Angeles, CA, USA
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  • Anna Do,

    1. Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA, USA
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  • Hea-Jin Jung,

    1. Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA, USA
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  • J Michael McCaffery,

    1. Department of Biology, Integrated Imaging Center, Johns Hopkins University, Baltimore, MD, USA
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  • Irwin J Kurland,

    1. Department of Medicine, Stable Isotopes and Metabolomics Core Facility, Albert Einstein College of Medicine Diabetes Center, Bronx, NY, USA
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  • Karen Reue,

    1. Department of Human Genetics, University of California, Los Angeles, CA, USA
    2. Molecular Biology Institute, University of California, Los Angeles, CA, USA
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  • Wai-Nang P Lee,

    1. Department of Pediatrics, LA Biomedical Research Institute, Torrance, CA, USA
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  • Carla M Koehler,

    Corresponding author
    1. Department of Chemistry and Biochemistry, University of California, Los Angeles, CA, USA
    2. Molecular Biology Institute, University of California, Los Angeles, CA, USA
    • Corresponding authors: Department of Chemistry and Biochemistry, University of California, Los Angeles, 607 Charles E. Young Drive East, Los Angeles, CA 90095, USA. Tel.: +1 310 794 4834; Fax: +1 310 206 4038; E-mail: koehlerc@chem.ucla.eduDepartment of Pathology and Laboratory Medicine, University of California, Los Angeles, 675 Charles E. Young Drive South, Los Angeles, CA 90095, USA. Tel.: +1 310 206 6754; Fax: +1 310 267 0382; E-mail: mteitell@mednet.ucla.edu

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  • Michael A Teitell

    Corresponding author
    1. Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA, USA
    2. Molecular Biology Institute, University of California, Los Angeles, CA, USA
    3. Broad Stem Cell Research Center, Jonsson Comprehensive Cancer Center, Center for Cell Control, and California NanoSystems Institute, University of California, Los Angeles, CA, USA
    • Corresponding authors: Department of Chemistry and Biochemistry, University of California, Los Angeles, 607 Charles E. Young Drive East, Los Angeles, CA 90095, USA. Tel.: +1 310 794 4834; Fax: +1 310 206 4038; E-mail: koehlerc@chem.ucla.eduDepartment of Pathology and Laboratory Medicine, University of California, Los Angeles, 675 Charles E. Young Drive South, Los Angeles, CA 90095, USA. Tel.: +1 310 206 6754; Fax: +1 310 267 0382; E-mail: mteitell@mednet.ucla.edu

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Errata

This article is corrected by:

  1. Errata: UCP2 regulates energy metabolism and differentiation potential of human pluripotent stem cells Volume 35, Issue 8, 899, Article first published online: 15 April 2016

  • There is a Have you seen? (December 2011) associated with this Article.

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 O2 at maximal capacity. Despite this, ATP generation in hPSCs is mainly by glycolysis and ATP is consumed by the F1F0 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.

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