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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...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2023
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.
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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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