Here we address disease modeling approaches through the lens of the disease gene SLC25A46. Human recessive loss of SLC25A46 function causes a spectrum of disorders that range from optic atrophy to Charcot-Marie-Tooth type 2, Leigh syndrome, progressive myoclonic ataxia and lethal congenital pontocerebellar hypoplasia[27–32]. Here, SLC25A46 is linked to Leber hereditary optic neuropathy.