MFN1 augmentation prevents retinal degeneration in a Charcot-Marie-Tooth type 2A mouse model

Charcot-Marie-Tooth disease type 2A (CMT2A), the most common inherited peripheral axonal neuropathy, is associated with more than 100 dominant mutations, including R94Q as the most abundant mutation in the Mitofusin2 (MFN2) gene. CMT2A is characterized by progressive motor and sensory loss, color-vision defects, and progressive loss of visual acuity. We used a well-established transgenic mouse model of CMT2A with R94Q mutation on MFN2 gene (MFN2(R94Q)) to investigate the functional and morphological changes in retina. We documented extensive vision loss due to photoreceptor degeneration, retinal ganglion cell and their axonal loss, retinal secondary neuronal and synaptic alternation, and Müller cell gliosis in the retina of MFN2(R94Q) mice. Imbalanced MFN1/MFN2 ratio and dysregulated mitochondrial fusion/fission result in retinal degeneration via P62/LC3B-mediated mitophagy/autophagy in MFN2(R94Q) mice. Finally, transgenic MFN1 augmentation (MFN2(R94Q):MFN1) rescued vision and retinal morphology to wild-type level via restoring homeostasis in mitochondrial MFN1/MFN2 ratio, fusion/fission cycle, and PINK1-dependent, Parkin-independent mitophagy.