Loss of SLC25A46 causes neurodegeneration by affecting mitochondrial dynamics and energy production in mice

Recently, we identified biallelic mutations of SLC25A46 in patients withmultiple neuropathies. Functional studies revealed that SLC25A46may play an important role in mitochondrial dynamics bymediating mitochondrial fission. However, the cellular basis and pathogenic mechanismof the SLC25A46-related neuropathies are not fully understood. Thus, we generated a Slc25a46 knock-outmouse model. Mice lacking SLC25A46 displayed severe ataxia, mainly caused by degeneration of Purkinje cells. Increased numbers of small, unmyelinated and degenerated optic nerves as well as loss of retinal ganglion cells indicated optic atrophy. Compound muscle action potentials in peripheral nerves showed peripheral neuropathy associated with degeneration and demyelination in axons. Mutant cerebellar neurons have largemitochondria, which exhibit abnormal distribution and transport. Biochemically mutant mice showed impaired electron transport chain activity and accumulated autophagymarkers. Our results suggest that loss of SLC25A46 causes degeneration in neurons by affectingmitochondrial dynamics and energy production.