Activation of mTORC1 and c-Jun by Prohibitin1 loss in Schwann cells may link mitochondrial dysfunction to demyelination
- SUNY Buffalo, United States
- Houston Methodist Hospital, United States
- Baylor College of Medicine, United States
- 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
Gustavo Della Flora Nunes
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
- 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
- Preprint posted: November 25, 2020 (view preprint)
- Received: January 6, 2021
- Accepted: September 13, 2021
- Accepted Manuscript published: September 14, 2021 (version 1)
- 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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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
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