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Rab5 and Alsin regulate stress-activated cytoprotective signaling on mitochondria

  1. FoSheng Hsu
  2. Stephanie Spannl
  3. Charles Ferguson
  4. Anthony A Hyman
  5. Robert G Parton
  6. Marino Zerial  Is a corresponding author
  1. Max Planck Institute of Molecular Cell Biology and Genetics, Germany
  2. University of Queensland, Australia
Research Article
  • Cited 15
  • Views 3,872
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Cite this article as: eLife 2018;7:e32282 doi: 10.7554/eLife.32282

Abstract

Mitochondrial stress response is essential for cell survival, and damaged mitochondria are a hallmark of neurodegenerative diseases. Thus, it is fundamental to understand how mitochondria relay information within the cell. Here, by investigating mitochondrial-endosomal contact sites we made the surprising observation that the small GTPase Rab5 translocates from early endosomes to mitochondria upon oxidative stress. This process is reversible and accompanied by an increase in Rab5-positive endosomes in contact with mitochondria. Interestingly, activation of Rab5 on mitochondria depends on the Rab5-GEF ALS2/Alsin, encoded by a gene mutated in amyotrophic lateral sclerosis (ALS). Alsin-deficient human induced pluripotent stem cell-derived spinal motor neurons are defective in relocating Rab5 to mitochondria and display increased susceptibility to oxidative stress. These findings define a novel pathway whereby Alsin catalyzes the assembly of the Rab5 endocytic machinery on mitochondria. Defects in stress-sensing by endosomes could be crucial for mitochondrial quality control during the onset of ALS.

Article and author information

Author details

  1. FoSheng Hsu

    Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
    Competing interests
    No competing interests declared.
  2. Stephanie Spannl

    Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
    Competing interests
    No competing interests declared.
  3. Charles Ferguson

    Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia
    Competing interests
    No competing interests declared.
  4. Anthony A Hyman

    Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
    Competing interests
    Anthony A Hyman, Reviewing editor, eLife.
  5. Robert G Parton

    Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7494-5248
  6. Marino Zerial

    Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
    For correspondence
    zerial@mpi-cbg.de
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7490-4235

Funding

Human Frontier Science Program

  • FoSheng Hsu

Max-Planck-Gesellschaft (Open-access funding)

  • Marino Zerial

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Margaret S. Robinson, University of Cambridge, United Kingdom

Publication history

  1. Received: September 25, 2017
  2. Accepted: February 20, 2018
  3. Accepted Manuscript published: February 22, 2018 (version 1)
  4. Version of Record published: March 12, 2018 (version 2)
  5. Version of Record updated: August 7, 2018 (version 3)

Copyright

© 2018, Hsu 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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