Inherited optic neuropathies: working on mitochondrial bioenergetics and dynamics to discover new therapeutic strategies

Inherited optic neuropathies are neurodegenerative disorders characterized by mitochondrial dysfunctions. Leber’s Hereditary Optic Neuropathy (LHON) and Dominant Optic Atrophy (DOA) are caused by mutations in respiratory complex I (CI) core subunits and OPA1 mutations, respectively and there is no established cure. For LHON the only approved drug is idebenone but its antioxidant effects depend on its reduced form feeding electrons to CIII. NAD(P)H-quinone dehydrogenase (NQO1), an inducible cytosolic enzyme, is involved in the antioxidant response through reduction of quinones, though clear evidence about its role is still lacking. DOA is caused by mutations in OPA1 gene encoding a mitochondrial GTPase involved in mitochondrial functions. First, we show that in LHON cellular models overexpressing NQO1, idebenone treatment rescues rotenone-sensitive mitochondrial respiration and ATP synthesis, as well as reducing ROS production. This demonstrates NQO1 supports oxidative phosphorylation bypassing CI and directly transfers electrons to CIII via the NQO1-idebenone-CIII pathway. Indeed, only patient-derived fibroblasts expressing NQO1 are able to maintain respiration. Finally, treatment with NQO1 inducer dimethyl fumarate allows mitochondrial respiration in the presence of idebenone, demonstrating the correlation between NQO1 expression and the efficacy of idebenone. Subsequently, we aim to validate FDA-approved molecules, “OPA1 rescuing molecules” (ORMs), able to rescue the mitochondrial dysfunctions induced by OPA1 mutations. Here, we show the testing of six selected compounds in Opa1-ablated mouse embryonic fibroblasts (MEFs) expressing the human OPA1 isoform1 bearing the R445H and D603H mutations. Some of these molecules ameliorate the bioenergetics and/or the mitochondrial morphology, depending on the mutation. ORM14 is the most effective compound showing both energy and morphology rescuing in the final validation on patient-derived fibroblasts. Our results permit the translation into clinic of the biochemical findings on the role of NQO1 for LHON treatment, as well as “drug repurposing” for DOA.