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

Jin Zhang, Ivan Khvorostov, Jason S. Hong, Yavuz Oktay, Laurent Vergnes, Esther Nuebel, Paulin N. Wahjudi, Kiyoko Setoguchi, Geng Wang, Anna Do, Hea Jin Jung, J. Michael McCaffery, Irwin J. Kurland, Karen Reue, Wai Nang P. Lee, Carla M. Koehler, Michael A. Teitell

Research output: Contribution to journalArticle

294 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)4860-4873
Number of pages14
JournalEMBO Journal
Volume30
Issue number24
DOIs
Publication statusPublished - Dec 14 2011

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Keywords

  • differentiation
  • metabolism
  • mitochondria
  • stem cell

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this

Zhang, J., Khvorostov, I., Hong, J. S., Oktay, Y., Vergnes, L., Nuebel, E., ... Teitell, M. A. (2011). UCP2 regulates energy metabolism and differentiation potential of human pluripotent stem cells. EMBO Journal, 30(24), 4860-4873. https://doi.org/10.1038/emboj.2011.401