Idebenone, the only approved treatment for Leber hereditary optic neuropathy (LHON), promotes recovery of visual function in up to 50% of patients, but we can neither predict nor understand the non-responders. Idebenone is reduced by the cytosolic NAD(P)H oxidoreductase I (NQO1) and directly shuttles electrons to respiratory complex III, bypassing complex I affected in LHON. We show here that two polymorphic variants drastically reduce NQO1 protein levels when homozygous or compound heterozygous. This hampers idebenone reduction. In its oxidized form, idebenone inhibits complex I, decreasing respiratory function in cells. By retrospectively analyzing a large cohort of idebenone-treated LHON patients, classified by their response to therapy, we show that patients with homozygous or compound heterozygous NQO1 variants have the poorest therapy response, particularly if carrying the m.3460G>A/MT-ND1 LHON mutation. These results suggest consideration of patient NQO1 genotype and mitochondrial DNA mutation in the context of idebenone therapy.
Genetic variants affecting NQO1 protein levels impact the efficacy of idebenone treatment in Leber hereditary optic neuropathy / Aleo S.J.; Del Dotto V.; Romagnoli M.; Fiorini C.; Capirossi G.; Peron C.; Maresca A.; Caporali L.; Capristo M.; Tropeano C.V.; Zanna C.; Ross-Cisneros F.N.; Sadun A.A.; Pignataro M.G.; Giordano C.; Fasano C.; Cavaliere A.; Porcelli A.M.; Tioli G.; Musiani F.; Catania A.; Lamperti C.; Marzoli S.B.; De Negri A.; Cascavilla M.L.; Battista M.; Barboni P.; Carbonelli M.; Amore G.; La Morgia C.; Smirnov D.; Vasilescu C.; Farzeen A.; Blickhaeuser B.; Prokisch H.; Priglinger C.; Livonius B.; Catarino C.B.; Klopstock T.; Tiranti V.; Carelli V.; Ghelli A.M.. - In: CELL REPORTS MEDICINE. - ISSN 2666-3791. - ELETTRONICO. - 5:2(2024), pp. 101383.1-101383.24. [10.1016/j.xcrm.2023.101383]
Genetic variants affecting NQO1 protein levels impact the efficacy of idebenone treatment in Leber hereditary optic neuropathy
Aleo S. J.Co-primo
Investigation
;Del Dotto V.Co-primo
Investigation
;Caporali L.Investigation
;Capristo M.Methodology
;Tropeano C. V.Methodology
;Zanna C.Methodology
;Fasano C.Investigation
;Porcelli A. M.Supervision
;Tioli G.Software
;Musiani F.Software
;Barboni P.Supervision
;Carbonelli M.Investigation
;La Morgia C.Investigation
;Tiranti V.Conceptualization
;Carelli V.
Penultimo
Writing – Original Draft Preparation
;Ghelli A. M.
Ultimo
Writing – Original Draft Preparation
2024
Abstract
Idebenone, the only approved treatment for Leber hereditary optic neuropathy (LHON), promotes recovery of visual function in up to 50% of patients, but we can neither predict nor understand the non-responders. Idebenone is reduced by the cytosolic NAD(P)H oxidoreductase I (NQO1) and directly shuttles electrons to respiratory complex III, bypassing complex I affected in LHON. We show here that two polymorphic variants drastically reduce NQO1 protein levels when homozygous or compound heterozygous. This hampers idebenone reduction. In its oxidized form, idebenone inhibits complex I, decreasing respiratory function in cells. By retrospectively analyzing a large cohort of idebenone-treated LHON patients, classified by their response to therapy, we show that patients with homozygous or compound heterozygous NQO1 variants have the poorest therapy response, particularly if carrying the m.3460G>A/MT-ND1 LHON mutation. These results suggest consideration of patient NQO1 genotype and mitochondrial DNA mutation in the context of idebenone therapy.| File | Dimensione | Formato | |
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2024 - Aleo - Idebenone and NQO1 - Cell reports Medicine.pdf
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