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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.*

Genetic variants affecting NQO1 protein levels impact the efficacy of idebenone treatment in Leber hereditary optic neuropathy.

Cell Rep. Med. 5:101383 (2024)

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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.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Lhon ; Leber Hereditary Optic Neuropathy ; Nqo1 ; Complex I ; Cybrids ; Fibroblasts ; Idebenone ; Mtdna ; Retinal Ganglion Cells; Mtdna; Cells; Mitochondria; Progression; Antioxidant; Apoptosis; Accuracy; Analogs; Epi-743; Chain

ISSN (print) / ISBN 2666-3791

e-ISSN 2666-3791

Journal Cell Reports Medicine

Quellenangaben Volume: 5, Issue: 2, Article Number: 101383

Publisher Cell Press

Publishing Place 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Neurogenomics (ING)

Grants European Commission
Associazione Luigi Comini, Onlus
Italian Ministry of Health
German Federal Ministry of Education and Research (BMBF
Bonn, Germany)
E-Rare project GENOMIT
Center for the Study of Mitochondrial Pediatric Diseases - Mariani Foun-dation