Loss of Frataxin induces iron toxicity, sphingolipid synthesis, and Pdk1/Mef2 activation, leading to neurodegeneration

  1. Kuchuan Chen
  2. Guang Lin
  3. Nele A Haelterman
  4. Tammy Szu-Yu Ho
  5. Tongchao Li
  6. Zhihong Li
  7. Lita Duraine
  8. Brett H Graham
  9. Manish Jaiswal
  10. Shinya Yamamoto
  11. Matthew N Rasband
  12. Hugo J Bellen  Is a corresponding author
  1. Baylor College of Medicine, United States
  2. Howard Hughes Medical Institute, Baylor College of Medicine, United States

Abstract

Mutations in Frataxin (FXN) cause Friedreich's ataxia (FRDA), a recessive neurodegenerative disorder. Previous studies have proposed that loss of FXN causes mitochondrial dysfunction, which triggers elevated reactive oxygen species (ROS) and leads to the demise of neurons. Here we describe a ROS independent mechanism that contributes to neurodegeneration in fly FXN mutants. We show that loss of frataxin homolog (fh) in Drosophila leads to iron toxicity, which in turn induces sphingolipid synthesis and ectopically activates 3-phosphoinositide dependent protein kinase-1 (Pdk1) and myocyte enhancer factor-2 (Mef2). Dampening iron toxicity, inhibiting sphingolipid synthesis by Myriocin, or reducing Pdk1 or Mef2 levels, all effectively suppress neurodegeneration in fh mutants. Moreover, increasing dihydrosphingosine activates Mef2 activity through PDK1 in mammalian neuronal cell line suggesting that the mechanisms are evolutionarily conserved. Our results indicate that an iron/sphingolipid/PDk1/Mef2 pathway may play a role in FRDA.

Article and author information

Author details

  1. Kuchuan Chen

    Program in Developmental Biology, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
  2. Guang Lin

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
  3. Nele A Haelterman

    Program in Developmental Biology, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
  4. Tammy Szu-Yu Ho

    Department of Neuroscience, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
  5. Tongchao Li

    Program in Developmental Biology, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
  6. Zhihong Li

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
  7. Lita Duraine

    Howard Hughes Medical Institute, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
  8. Brett H Graham

    Program in Developmental Biology, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
  9. Manish Jaiswal

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
  10. Shinya Yamamoto

    Program in Developmental Biology, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
  11. Matthew N Rasband

    Program in Developmental Biology, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
  12. Hugo J Bellen

    Program in Developmental Biology, Baylor College of Medicine, Houston, United States
    For correspondence
    hbellen@bcm.edu
    Competing interests
    Hugo J Bellen, Reviewing editor, eLife.

Reviewing Editor

  1. J Paul Taylor, St Jude Children's Research Hospital, United States

Version history

  1. Received: March 18, 2016
  2. Accepted: June 24, 2016
  3. Accepted Manuscript published: June 25, 2016 (version 1)
  4. Version of Record published: July 21, 2016 (version 2)

Copyright

© 2016, Chen 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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  1. Kuchuan Chen
  2. Guang Lin
  3. Nele A Haelterman
  4. Tammy Szu-Yu Ho
  5. Tongchao Li
  6. Zhihong Li
  7. Lita Duraine
  8. Brett H Graham
  9. Manish Jaiswal
  10. Shinya Yamamoto
  11. Matthew N Rasband
  12. Hugo J Bellen
(2016)
Loss of Frataxin induces iron toxicity, sphingolipid synthesis, and Pdk1/Mef2 activation, leading to neurodegeneration
eLife 5:e16043.
https://doi.org/10.7554/eLife.16043

Share this article

https://doi.org/10.7554/eLife.16043

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