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Alleviation of neuronal energy deficiency by mTOR inhibition as a treatment for mitochondria-related neurodegeneration

  1. Xinde Zheng
  2. Leah Boyer
  3. Mingji Jin
  4. Yongsung Kim
  5. Weiwei Fan
  6. Cedric Bardy
  7. Travis Berggren
  8. Ronald M Evans
  9. Fred H Gage
  10. Tony Hunter  Is a corresponding author
  1. Salk Institute for Biological Studies, United States
Research Article
  • Cited 42
  • Views 4,999
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Cite this article as: eLife 2016;5:e13378 doi: 10.7554/eLife.13378

Abstract

mTOR inhibition is beneficial in neurodegenerative disease models and its effects are often attributable to the modulation of autophagy and anti-apoptosis. Here, we report a neglected but important bioenergetic effect of mTOR inhibition in neurons. mTOR inhibition by rapamycin significantly preserves neuronal ATP levels, particularly when oxidative phosphorylation is impaired, such as in neurons treated with mitochondrial inhibitors, or in neurons derived from maternally inherited Leigh syndrome (MILS) patient iPS cells with ATP synthase deficiency. Rapamycin treatment significantly improves the resistance of MILS neurons to glutamate toxicity. Surprisingly, in mitochondrially defective neurons, but not neuroprogenitor cells, ribosomal S6 and S6 kinase phosphorylation increased over time, despite activation of AMPK, which is often linked to mTOR inhibition. A rapamycin-induced decrease in protein synthesis, a major energy-consuming process, may account for its ATP-saving effect. We propose that a mild reduction in protein synthesis may have the potential to treat mitochondria-related neurodegeneration.

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
    No competing interests declared.
  2. Leah Boyer

    Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, United States
    Competing interests
    No competing interests declared.
  3. Mingji Jin

    Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, Lo Jolla, United States
    Competing interests
    No competing interests declared.
  4. Yongsung Kim

    Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, United States
    Competing interests
    No competing interests declared.
  5. Weiwei Fan

    Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, United States
    Competing interests
    No competing interests declared.
  6. Cedric Bardy

    Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, United States
    Competing interests
    No competing interests declared.
  7. Travis Berggren

    Stem cell core, Salk Institute for Biological Studies, La Jolla, United States
    Competing interests
    No competing interests declared.
  8. Ronald M Evans

    Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, United States
    Competing interests
    No competing interests declared.
  9. Fred H Gage

    Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, United States
    Competing interests
    No competing interests declared.
  10. Tony Hunter

    Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, United States
    For correspondence
    hunter@salk.edu
    Competing interests
    Tony Hunter, Senior editor, eLife.

Reviewing Editor

  1. Richard D Palmiter, Howard Hughes Medical Institute, University of Washington, United States

Publication history

  1. Received: November 29, 2015
  2. Accepted: March 23, 2016
  3. Accepted Manuscript published: March 23, 2016 (version 1)
  4. Accepted Manuscript updated: March 29, 2016 (version 2)
  5. Version of Record published: April 26, 2016 (version 3)

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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