UC San Diego

Charcot-Marie-Tooth type 2B (CMT2B) is a rare inherited autosomal dominant axonal neuropathy of the peripheral sensory system. The disease is characterized by sensory loss, muscle weakness, and atrophy in the body's periphery. Genetically, CMT2B is caused by mutation(s) in Ras-related protein Rab7, a GTP-binding protein that is fundamental for regulating endocytic pathways and trafficking. Recent studies suggested that Rab7 was also associated with mitochondria structure and function. Therefore, our group is interested in studying the link between mitochondrial morphology and the degeneration of the sensory fibers in CMT2B. We generated a Rab7V162M knock-in mouse model and obtained all three genotypes: wt (+/+), heterozygote (KI/+), and homozygote (KI/KI). I cultured mouse embryonic fibroblasts (MEFs) for all genotypes and analyzed their mitochondria morphology. I found that the mitochondria in the mutant mice were fragmented, while the wild-type mitochondria were filamentous. One potential explanation is that Rab7 mutation(s) increased dynamin-related protein 1 (DRP1) activity, a critical regulator that promotes mitochondrial fission. To test this, we found that the DRP1 inhibitor, Mdivi-1, rescued excessive mitochondrial fragmentation. Furthermore, the Rab7 inhibitor, CID, also showed a rescuing effect. We thus conclude that the CMT2B mutation(s) increased the Rab7 activity, leading to enhanced DRP1 activity. As a result, the mitochondria became extremely fragmented in CMT2B.