Misregulation of mitochondria–lysosome contact dynamics in Charcot–Marie–Tooth Type 2B disease Rab7 mutant sensory peripheral neurons

Author:

Wong Yvette C.1ORCID,Jayaraj Nirupa D.1,Belton Tayler B.1,Shum George C.1ORCID,Ball Hannah E.1ORCID,Ren Dongjun1,Tadenev Abigail L. D.2ORCID,Krainc Dimitri13ORCID,Burgess Robert W.2ORCID,Menichella Daniela M.14

Affiliation:

1. Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611

2. The Jackson Laboratory, Bar Harbor, ME 04609

3. Simpson Querrey Center for Neurogenetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611

4. Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611

Abstract

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.

Funder

HHS | NIH | National Institute of Neurological Disorders and Stroke

HHS | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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