SLC25A46 mutations cause optic atrophy, axonal neuropathy, and cerebellar neurodegeneration

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 DESCRIPTION (provided by applicant): Mitochondria are dynamic organelles that undergo constant fusion and fission. Mutations in two mitochondrial fusion genes, MFN2 and OPA1, cause overlapping neurodegenerative phenotypes: axonal peripheral neuropathy and dominant optic atrophy, respectively. This finding underscores the importance of mitochondrial dynamics in preventing nerve degeneration. However, our understanding of the underlying genetic and pathological mechanisms is lacking. We present evidence that SLC25A46 mutations cause optic atrophy, axonal neuropathy, and other clinical features in patients with recessively inherited mutations. Using whole-exome sequencing approaches, we identified mutations in SLC25A46 in four families. Our results showed that SLC25A46 mutations are associated with mitochondrial fission and fusion (Nature Genetics, in press). In this project, we propose to study pathogenesis using a mouse model and induced pluripotent stem cell (iPSC) lines carrying SLC25A46 mutations and examine the relationship between SLC25A46 and OPA1. Firstly, we will characterize the SLC25A46 mouse model, which was created with CRISPR technology. Specifically, we will evaluate optic atrophy with vision accuracy, visually evoked potentials, morphological and fundus images analysis. We will also test peripheral neuropathies by histological analysis, motor functions, reflexes, and sensory dysfunction. Nerve conduction measures will be used to confirm peripheral neuropathy. Furthermore, we will perform mitochondrial functional tests with the target tissues. Secondly, using our created iPSC model, we will differentiate iPSC lines into retinal ganglion cells with our recently established protocol and study how SLC25A46 mutations affect the process of retinal ganglion cell differentiation. Finally, our preliminary work revealed that compound heterozygous mutations of OPA1 cause very similar phenotypes to SLC25A46 mutations. We will investigate the relationship between these two proteins both functioning in mitochondrial fusion and fission. Although based on the structure, SLC25A46 is thought to be a mitochondrial carrier, its substrate is unknown. Our future work will involve using the animal and iPSC model to identify the substrate and to elucidate the functions of SLC25A46, therefore, to develop treatment. This study will allow us to understand the pathogenesis associated with SLC25A46 mutations, thereby aiding in the development of a potential treatment.