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Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation

  1. Xinde Zheng
  2. Leah Boyer
  3. Mingji Jin
  4. Jerome Mertens
  5. Yongsung Kim
  6. Li Ma
  7. Li Ma
  8. Michael Hamm
  9. Fred H Gage
  10. Tony Hunter  Is a corresponding author
  1. Salk Institute for Biological Studies, United States
  2. Salk Institute, United States
Research Article
  • Cited 82
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Cite this article as: eLife 2016;5:e13374 doi: 10.7554/eLife.13374

Abstract

How metabolism is reprogrammed during neuronal differentiation is unknown. We found that the loss of hexokinase (HK2) and lactate dehydrogenase (LDHA) expression, together with a switch in pyruvate kinase gene splicing from PKM2 to PKM1, marks the transition from aerobic glycolysis in neural progenitor cells (NPC) to neuronal oxidative phosphorylation. The protein levels of c-MYC and N-MYC, transcriptional activators of the HK2 and LDHA genes, decrease dramatically. Constitutive expression of HK2 and LDHA during differentiation leads to neuronal cell death, indicating that the shut-off aerobic glycolysis is essential for neuronal survival. The metabolic regulators PGC-1α and ERRγ increase significantly upon neuronal differentiation to sustain the transcription of metabolic and mitochondrial genes, whose levels are unchanged compared to NPCs, revealing distinct transcriptional regulation of metabolic genes in the proliferation and post-mitotic differentiation states. Mitochondrial mass increases proportionally with neuronal mass growth, indicating an unknown mechanism linking mitochondrial biogenesis to cell size.

Article and author information

Author details

  1. Xinde Zheng

    Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Leah Boyer

    Laboratory of Genetics, Salk Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Mingji Jin

    Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Jerome Mertens

    Laboratory of Genetics, Salk Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Yongsung Kim

    Laboratory of Genetics, Salk Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Li Ma

    Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Li Ma

    Gene Expression Laboratory, Salk Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Michael Hamm

    Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Fred H Gage

    Laboratory of Genetics, Salk Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Tony Hunter

    Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, United States
    For correspondence
    hunter@salk.edu
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. Gail Mandel, Oregon Health and Science University, United States

Publication history

  1. Received: November 27, 2015
  2. Accepted: June 9, 2016
  3. Accepted Manuscript published: June 10, 2016 (version 1)
  4. Version of Record published: July 27, 2016 (version 2)

Copyright

© 2016, Zheng et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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