Mutations in the UGO1-like protein SLC25A46 cause an optic atrophy spectrum disorder

Dominant optic atrophy (DOA)(1,2) and axonal peripheral neuropathy (Charcot-Marie-Tooth Type 2 or CMT2)(3) are hereditary neurodegenerative disorders most commonly caused by mutations in the canonical mitochondrial fusion genes OPA1 and MFN2, respectively(4). In yeast, homologs of OPA1(Mgm1) and MFN2(Fzo1) work in concert with Ugo1(5,6), which has no human equivalent to date(7). By whole exome sequencing patients with optic atrophy and CMT2, we identified four families with recessive mutations in SLC25A46. We demonstrate that SLC25A46, like Ugo1, is a modified carrier protein that has been recruited to the outer mitochondrial membrane and interacts with the inner membrane remodeling protein, mitofilin(Fcj1). Loss-of-function in cultured cells and in zebrafish unexpectedly leads to increased mitochondrial connectivity, while severely affecting the development and maintenance of neurons in the fish. The discovery of SLC25A46 strengthens the genetic overlap between optic atrophy and CMT2, while exemplifying a novel class of modified solute transporters linked to mitochondrial dynamics.