Mitochondria dysfunction in Charcot Marie Tooth 2B Peripheral Sensory Neuropathy

Abstract

Rab7 GTPase regulates mitochondrial morphology and function. Missense mutation(s) of Rab7 underlies the pathogenesis of Charcot Marie Tooth 2B (CMT2B) peripheral neuropathy. Herein, we investigate how mitochondrial morphology and function are impacted by the CMT2B associated Rab7V162M mutation. In contrast to recent studies of using heterologous overexpression systems, our results demonstrate significant mitochondrial fragmentation in both human CMT2B patient fibroblasts and CMT2B embryonic fibroblasts (MEFs). Primary cultured E18 dorsal root ganglion (DRG) sensory neurons also show mitochondrial fragmentation and altered axonal mitochondrial movement. In addition, we demonstrate that inhibitors to either the mitochondrial fission protein Drp1 or to the nucleotide binding to Rab7 normalize the mitochondrial deficits in both MEFs and E18 cultured DRG neurons. Our study reveals, for the first time, that expression of CMT2B Rab7 mutation at the physiological level enhances Drp1 activity to promote mitochondrial fission, potentially underlying selective vulnerability of peripheral sensory neurons in CMT2B pathogenesis.

Hitting the mark: Localization of mRNA and biomolecular condensates in health and disease

“…C. Yoon et al, 2012). Moreover, it was recently discovered that CMT2B RAB7A mutation increases activity of the mitochondrial fission protein DRP1, causing mitochondrial fragmentation, suggesting targeting of mitochondrial fragmentation as a possible therapeutic strategy (Gu et al, 2022).…”

“…These changes in axonal transport are correlated with decreased protein translation, mitochondrial function, and axon viability (Cioni et al, 2019; B. C. Yoon et al, 2012). Moreover, it was recently discovered that CMT2B RAB7A mutation increases activity of the mitochondrial fission protein DRP1, causing mitochondrial fragmentation, suggesting targeting of mitochondrial fragmentation as a possible therapeutic strategy (Gu et al, 2022).…”

Regulation of Endosomal Trafficking by Rab7 and Its Effectors in Neurons: Clues from Charcot–Marie–Tooth 2B Disease

“…Nevertheless, the impacts on Rab7 endosome motility in CMT2B are debated. With the advent of newly developed transgenic models [ 26 ], advances in in vivo imaging, and increasing availability of patient-derived iPSCs, better studies can be carried out to more definitively elucidate the impacts on Rab7 and TrkA motility in relevant heterozygote models and relevant cell types. Side-by-side comparisons of all mutants in these most physiologic models, particularly in microfluidic devices to separate distal axon and somatic signaling effects, will help clear up the discrepancies between previous overexpressed in vitro studies and in vivo studies and determine the impact and differences between mutants for axonal traffic.…”

“…Rab7 is ubiquitously expressed, and Rab7 knockout mice are early embryonically lethal [ 25 ]. CMT2B mutations in Rab7 are compatible with life and have minimal effects on mouse body weight and survival [ 26 ]. Instead, they preferentially impact peripheral neurons versus other neuronal or non-neuronal cell types and are, thus, thought to be mild hypo- or hypermorphs.…”

Role of the Intermediate Filament Protein Peripherin in Health and Disease

“…Moreover, in CMT2B cells, alterations in the late endocytic pathway and mitochondria have been found recently [ 124 , 125 ]. Considering that among peripherin interactors there are molecules regulating not only membrane traffic but also several mitochondrial proteins [ 76 ], these pathological phenotypes could be related to alterations in peripherin assembly.…”