Activation of mTORC1 and c-Jun by Prohibitin1 loss in Schwann cells may link mitochondrial dysfunction to demyelination

  1. Gustavo Della Flora Nunes
  2. Emma R Wilson  Is a corresponding author
  3. Edward Hurley  Is a corresponding author
  4. Bin He
  5. Bert W O'Malley  Is a corresponding author
  6. Yannick Poitelon  Is a corresponding author
  7. Lawrence Wrabetz  Is a corresponding author
  8. M Laura Feltri  Is a corresponding author
  1. SUNY Buffalo, United States
  2. Houston Methodist Hospital, United States
  3. Baylor College of Medicine, United States
  4. Albany Medical College, United States

Abstract

Schwann cell (SC) mitochondria are quickly emerging as an important regulator of myelin maintenance in the peripheral nervous system (PNS). However, the mechanisms underlying demyelination in the context of mitochondrial dysfunction in the PNS are incompletely understood. We recently showed that conditional ablation of the mitochondrial protein Prohibitin 1 (PHB1) in SCs causes a severe and fast progressing demyelinating peripheral neuropathy in mice, but the mechanism that causes failure of myelin maintenance remained unknown. Here, we report that mTORC1 and c-Jun are continuously activated in the absence of Phb1, likely as part of the SC response to mitochondrial damage. Moreover, we demonstrate that these pathways are involved in the demyelination process, and that inhibition of mTORC1 using rapamycin partially rescues the demyelinating pathology. Therefore, we propose that mTORC1 and c-Jun may play a critical role as executioners of demyelination in the context of perturbations to SC mitochondria.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Gustavo Della Flora Nunes

    Departments of Biochemistry, SUNY Buffalo, Buffalo, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9323-3556
  2. Emma R Wilson

    Departments of Biochemistry, SUNY Buffalo, Buffalo, United States
    For correspondence
    ewilson5@buffalo.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8069-0173
  3. Edward Hurley

    Departments of Biochemistry and Neurology, SUNY Buffalo, Buffalo, United States
    For correspondence
    edwardhu@buffalo.edu
    Competing interests
    The authors declare that no competing interests exist.
  4. Bin He

    Immunobiology & Transplant Science Center and Department of Surgery,, Houston Methodist Hospital, Houston, TX, 77030, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Bert W O'Malley

    Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States
    For correspondence
    berto@bcm.edu
    Competing interests
    The authors declare that no competing interests exist.
  6. Yannick Poitelon

    Dept of Neuroscience and Experimental Therapeutics, Albany Medical College, Albany, United States
    For correspondence
    poitely@amc.edu
    Competing interests
    The authors declare that no competing interests exist.
  7. Lawrence Wrabetz

    Neurology, SUNY Buffalo, Buffalo, United States
    For correspondence
    lwrabetz@buffalo.edu
    Competing interests
    The authors declare that no competing interests exist.
  8. M Laura Feltri

    Departments of Biochemistry and Neurology, SUNY Buffalo, Buffalo, United States
    For correspondence
    mlfeltri@buffalo.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2276-9182

Funding

National Institute of Neurological Disorders and Stroke (R01NS100464)

  • M Laura Feltri

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

Reviewing Editor

  1. Marianne E Bronner, California Institute of Technology, United States

Ethics

Animal experimentation: All animal procedures have been approved by the Institutional Animal Care and Use Committee (IACUC) of the Roswell Park Cancer Institute (Buffalo-NY, USA), and followed the guidelines stablished by the NIH's Guide for the Care and Use of Laboratory Animals and the regulations in place at the University at Buffalo (Buffalo-NY, USA).

Version history

  1. Preprint posted: November 25, 2020 (view preprint)
  2. Received: January 6, 2021
  3. Accepted: September 13, 2021
  4. Accepted Manuscript published: September 14, 2021 (version 1)
  5. Version of Record published: September 28, 2021 (version 2)

Copyright

© 2021, Della Flora Nunes 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. Gustavo Della Flora Nunes
  2. Emma R Wilson
  3. Edward Hurley
  4. Bin He
  5. Bert W O'Malley
  6. Yannick Poitelon
  7. Lawrence Wrabetz
  8. M Laura Feltri
(2021)
Activation of mTORC1 and c-Jun by Prohibitin1 loss in Schwann cells may link mitochondrial dysfunction to demyelination
eLife 10:e66278.
https://doi.org/10.7554/eLife.66278

Share this article

https://doi.org/10.7554/eLife.66278

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