Drosophilamodel to clarify the pathological significance of OPA1 in autosomal dominant optic atrophy

Autosomal dominant optic atrophy (DOA) is a progressive form of blindness caused by degeneration of retinal ganglion cells and their axons, mainly caused by mutations in the OPA1 mitochondrial dynaminlikeGTPase (OPA1) gene.OPA1encodes a dynamin-like GTPase present in the mitochondrial inner membrane. When associated with OPA1 mutations, DOA can present not only ocular symptoms but also multi-organ symptoms (DOA plus). DOA plus often results from point mutations in the GTPase domain, which are assumed to have dominant negative effects. However, the presence of mutations in the GTPase domain does not always result in DOA plus. Therefore, an experimental system to distinguish between DOA and DOA plus is needed. In this study, we found that loss-of-function mutations of thedOPA1gene inDrosophilacan imitate the pathology of optic nerve degeneration observed in DOA. We successfully rescued this degeneration by expressing the humanOPA1(hOPA1) gene, indicating thathOPA1is functionally interchangeable withdOPA1in the fly system. However, mutations previously identified did not ameliorate thedOPA1deficiency phenotype. By expressing both WT and DOA plus mutanthOPA1forms in the optic nerve ofdOPA1mutants, we observed that DOA plus mutations suppressed the rescue, facilitating the distinction between loss-of-function and dominant negative mutations inhOPA1. This fly model aids in distinguishing DOA from DOA plus and guides initialhOPA1mutation treatment strategies.