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Misregulation of mitochondria–lysosome contact dynamics in Charcot–Marie–Tooth Type 2B disease Rab7 mutant sensory peripheral neurons
Inter-organelle contact sites between mitochondria and lysosomes mediate the crosstalk and bidirectional regulation of their dynamics in health and disease. However, mitochondria–lysosome contact sites and their misregulation have not been investigated in peripheral sensory neurons. Charcot–Marie–To...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Academy of Sciences
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10622892/ https://www.ncbi.nlm.nih.gov/pubmed/37878717 http://dx.doi.org/10.1073/pnas.2313010120 |
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author | Wong, Yvette C. Jayaraj, Nirupa D. Belton, Tayler B. Shum, George C. Ball, Hannah E. Ren, Dongjun Tadenev, Abigail L. D. Krainc, Dimitri Burgess, Robert W. Menichella, Daniela M. |
author_facet | Wong, Yvette C. Jayaraj, Nirupa D. Belton, Tayler B. Shum, George C. Ball, Hannah E. Ren, Dongjun Tadenev, Abigail L. D. Krainc, Dimitri Burgess, Robert W. Menichella, Daniela M. |
author_sort | Wong, Yvette C. |
collection | PubMed |
description | Inter-organelle contact sites between mitochondria and lysosomes mediate the crosstalk and bidirectional regulation of their dynamics in health and disease. However, mitochondria–lysosome contact sites and their misregulation have not been investigated in peripheral sensory neurons. Charcot–Marie–Tooth type 2B disease is an autosomal dominant axonal neuropathy affecting peripheral sensory neurons caused by mutations in the GTPase Rab7. Using live super-resolution and confocal time-lapse microscopy, we showed that mitochondria–lysosome contact sites dynamically form in the soma and axons of peripheral sensory neurons. Interestingly, Charcot–Marie–Tooth type 2B mutant Rab7 led to prolonged mitochondria–lysosome contact site tethering preferentially in the axons of peripheral sensory neurons, due to impaired Rab7 GTP hydrolysis–mediated contact site untethering. We further generated a Charcot–Marie–Tooth type 2B mutant Rab7 knock-in mouse model which exhibited prolonged axonal mitochondria–lysosome contact site tethering and defective downstream axonal mitochondrial dynamics due to impaired Rab7 GTP hydrolysis as well as fragmented mitochondria in the axon of the sciatic nerve. Importantly, mutant Rab7 mice further demonstrated preferential sensory behavioral abnormalities and neuropathy, highlighting an important role for mutant Rab7 in driving degeneration of peripheral sensory neurons. Together, this study identifies an important role for mitochondria–lysosome contact sites in the pathogenesis of peripheral neuropathy. |
format | Online Article Text |
id | pubmed-10622892 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
spelling | pubmed-106228922023-11-04 Misregulation of mitochondria–lysosome contact dynamics in Charcot–Marie–Tooth Type 2B disease Rab7 mutant sensory peripheral neurons Wong, Yvette C. Jayaraj, Nirupa D. Belton, Tayler B. Shum, George C. Ball, Hannah E. Ren, Dongjun Tadenev, Abigail L. D. Krainc, Dimitri Burgess, Robert W. Menichella, Daniela M. Proc Natl Acad Sci U S A Biological Sciences Inter-organelle contact sites between mitochondria and lysosomes mediate the crosstalk and bidirectional regulation of their dynamics in health and disease. However, mitochondria–lysosome contact sites and their misregulation have not been investigated in peripheral sensory neurons. Charcot–Marie–Tooth type 2B disease is an autosomal dominant axonal neuropathy affecting peripheral sensory neurons caused by mutations in the GTPase Rab7. Using live super-resolution and confocal time-lapse microscopy, we showed that mitochondria–lysosome contact sites dynamically form in the soma and axons of peripheral sensory neurons. Interestingly, Charcot–Marie–Tooth type 2B mutant Rab7 led to prolonged mitochondria–lysosome contact site tethering preferentially in the axons of peripheral sensory neurons, due to impaired Rab7 GTP hydrolysis–mediated contact site untethering. We further generated a Charcot–Marie–Tooth type 2B mutant Rab7 knock-in mouse model which exhibited prolonged axonal mitochondria–lysosome contact site tethering and defective downstream axonal mitochondrial dynamics due to impaired Rab7 GTP hydrolysis as well as fragmented mitochondria in the axon of the sciatic nerve. Importantly, mutant Rab7 mice further demonstrated preferential sensory behavioral abnormalities and neuropathy, highlighting an important role for mutant Rab7 in driving degeneration of peripheral sensory neurons. Together, this study identifies an important role for mitochondria–lysosome contact sites in the pathogenesis of peripheral neuropathy. National Academy of Sciences 2023-10-25 2023-10-31 /pmc/articles/PMC10622892/ /pubmed/37878717 http://dx.doi.org/10.1073/pnas.2313010120 Text en Copyright © 2023 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) . |
spellingShingle | Biological Sciences Wong, Yvette C. Jayaraj, Nirupa D. Belton, Tayler B. Shum, George C. Ball, Hannah E. Ren, Dongjun Tadenev, Abigail L. D. Krainc, Dimitri Burgess, Robert W. Menichella, Daniela M. Misregulation of mitochondria–lysosome contact dynamics in Charcot–Marie–Tooth Type 2B disease Rab7 mutant sensory peripheral neurons |
title | Misregulation of mitochondria–lysosome contact dynamics in Charcot–Marie–Tooth Type 2B disease Rab7 mutant sensory peripheral neurons |
title_full | Misregulation of mitochondria–lysosome contact dynamics in Charcot–Marie–Tooth Type 2B disease Rab7 mutant sensory peripheral neurons |
title_fullStr | Misregulation of mitochondria–lysosome contact dynamics in Charcot–Marie–Tooth Type 2B disease Rab7 mutant sensory peripheral neurons |
title_full_unstemmed | Misregulation of mitochondria–lysosome contact dynamics in Charcot–Marie–Tooth Type 2B disease Rab7 mutant sensory peripheral neurons |
title_short | Misregulation of mitochondria–lysosome contact dynamics in Charcot–Marie–Tooth Type 2B disease Rab7 mutant sensory peripheral neurons |
title_sort | misregulation of mitochondria–lysosome contact dynamics in charcot–marie–tooth type 2b disease rab7 mutant sensory peripheral neurons |
topic | Biological Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10622892/ https://www.ncbi.nlm.nih.gov/pubmed/37878717 http://dx.doi.org/10.1073/pnas.2313010120 |
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