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

• DOI: 10.1073/pnas.2313010120
• Publication Date: 2023-10-25T18:02:48Z
• Authors: Yvette C. Wong; Nirupa D. Jayaraj; Tayler B. Belton; George C. Shum; Hannah E. Ball; Dongjun Ren; Abigail L. D. Tad...; Dimitri Krainc; Robert W. Burgess; Daniela M. Menich...
• Keywords: 570; Sensory Receptor Cells; 610; rab7 GTP-Binding Proteins; Biological Sciences; SS1; Mitochondria; Mice; rab GTP-Binding Proteins; Charcot-Marie-Tooth Disease; Mutation; Animals; Guanosine Triphosphate; Lysosomes; JMG

Inter-organelle contact sites between mitochondria and lysosomes mediate the crosstalk bidirectional regulation of their dynamics in health disease. However, mitochondria–lysosome misregulation have not been investigated peripheral sensory neurons. Charcot–Marie–Tooth type 2B disease is an autosomal dominant axonal neuropathy affecting neurons caused by mutations GTPase Rab7. Using live super-resolution confocal time-lapse microscopy, we showed that dynamically form soma axons Interestingly, mutant Rab7 led to prolonged site tethering preferentially neurons, due impaired GTP hydrolysis–mediated untethering. We further generated a knock-in mouse model which exhibited defective downstream mitochondrial hydrolysis as well fragmented axon sciatic nerve. Importantly, mice demonstrated preferential behavioral abnormalities neuropathy, highlighting important role for driving degeneration Together, this study identifies pathogenesis neuropathy.