Activation of mTORC1 and c-Jun by Prohibitin1 loss in Schwann cells may link mitochondrial dysfunction to demyelination
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 con...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2021-09-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/66278 |
| _version_ | 1818026801803296768 |
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| author | Gustavo Della-Flora Nunes Emma R Wilson Edward Hurley Bin He Bert W O'Malley Yannick Poitelon Lawrence Wrabetz M Laura Feltri |
| author_facet | Gustavo Della-Flora Nunes Emma R Wilson Edward Hurley Bin He Bert W O'Malley Yannick Poitelon Lawrence Wrabetz M Laura Feltri |
| author_sort | Gustavo Della-Flora Nunes |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-10T04:37:47Z |
| format | Article |
| id | doaj.art-bab27ff9a3d44321940e8da7640d677e |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-12-10T04:37:47Z |
| publishDate | 2021-09-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-bab27ff9a3d44321940e8da7640d677e2022-12-22T02:01:58ZengeLife Sciences Publications LtdeLife2050-084X2021-09-011010.7554/eLife.66278Activation of mTORC1 and c-Jun by Prohibitin1 loss in Schwann cells may link mitochondrial dysfunction to demyelinationGustavo Della-Flora Nunes0https://orcid.org/0000-0001-9323-3556Emma R Wilson1https://orcid.org/0000-0002-8069-0173Edward Hurley2https://orcid.org/0000-0002-1967-8933Bin He3Bert W O'Malley4Yannick Poitelon5https://orcid.org/0000-0001-9868-1569Lawrence Wrabetz6M Laura Feltri7https://orcid.org/0000-0002-2276-9182Hunter James Kelly Research Institute, University at Buffalo, Buffalo, United States; Department of Biochemistry, University at Buffalo, Buffalo, United StatesHunter James Kelly Research Institute, University at Buffalo, Buffalo, United States; Department of Biochemistry, University at Buffalo, Buffalo, United StatesHunter James Kelly Research Institute, University at Buffalo, Buffalo, United StatesImmunobiology & Transplant Science Center and Department of Surgery, Houston Methodist Hospital, Houston, United StatesDepartment of Medicine and Molecular and Cellular Biology, Baylor College of Medicine, Houston, United StatesDepartment of Neuroscience and Experimental Therapeutics, Albany Medical College, Albany, United StatesHunter James Kelly Research Institute, University at Buffalo, Buffalo, United States; Department of Biochemistry, University at Buffalo, Buffalo, United States; Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, United StatesHunter James Kelly Research Institute, University at Buffalo, Buffalo, United States; Department of Biochemistry, University at Buffalo, Buffalo, United States; Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, United StatesSchwann 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.https://elifesciences.org/articles/66278PHB1mitochondrial stress responsemechanistic target of rapamycinmyelin maintenanceschwann cellsdemyelination |
| spellingShingle | Gustavo Della-Flora Nunes Emma R Wilson Edward Hurley Bin He Bert W O'Malley Yannick Poitelon Lawrence Wrabetz M Laura Feltri Activation of mTORC1 and c-Jun by Prohibitin1 loss in Schwann cells may link mitochondrial dysfunction to demyelination eLife PHB1 mitochondrial stress response mechanistic target of rapamycin myelin maintenance schwann cells demyelination |
| title | Activation of mTORC1 and c-Jun by Prohibitin1 loss in Schwann cells may link mitochondrial dysfunction to demyelination |
| title_full | Activation of mTORC1 and c-Jun by Prohibitin1 loss in Schwann cells may link mitochondrial dysfunction to demyelination |
| title_fullStr | Activation of mTORC1 and c-Jun by Prohibitin1 loss in Schwann cells may link mitochondrial dysfunction to demyelination |
| title_full_unstemmed | Activation of mTORC1 and c-Jun by Prohibitin1 loss in Schwann cells may link mitochondrial dysfunction to demyelination |
| title_short | Activation of mTORC1 and c-Jun by Prohibitin1 loss in Schwann cells may link mitochondrial dysfunction to demyelination |
| title_sort | activation of mtorc1 and c jun by prohibitin1 loss in schwann cells may link mitochondrial dysfunction to demyelination |
| topic | PHB1 mitochondrial stress response mechanistic target of rapamycin myelin maintenance schwann cells demyelination |
| url | https://elifesciences.org/articles/66278 |
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