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Baglivo, M.* ; Nasca, A.* ; Lamantea, E.* ; Vinci, S.* ; Spagnolo, M.* ; Marchet, S.* ; Prokisch, H. ; Catania, A.* ; Lamperti, C.* ; Ghezzi, D.*

Evaluation of mitochondrial dysfunction and idebenone responsiveness in fibroblasts from Leber's hereditary optic neuropathy (LHON) subjects.

Int. J. Mol. Sci. 24:11 (2023)

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Open Access Gold as soon as Publ. Version/Full Text is submitted to ZB.

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Leber's hereditary optic neuropathy (LHON) is a disease that affects the optical nerve, causing visual loss. The diagnosis of LHON is mostly defined by the identification of three pathogenic variants in the mitochondrial DNA. Idebenone is widely used to treat LHON patients, but only some of them are responders to treatment. In our study, we assessed the maximal respiration rate (MRR) and other respiratory parameters in eight fibroblast lines from subjects carrying LHON pathogenic variants. We measured also the effects of idebenone treatment on cell growth and mtDNA amounts. Results showed that LHON fibroblasts had significantly reduced respiratory parameters in untreated conditions, but no significant gain in MRR after idebenone supplementation. No major toxicity toward mitochondrial function and no relevant compensatory effect in terms of mtDNA quantity were found for the treatment at the tested conditions. Our findings confirmed that fibroblasts from subjects harboring LHON pathogenic variants displayed impaired respiration, regardless of the disease penetrance and severity. Testing responsiveness to idebenone treatment in cultured cells did not fully recapitulate in vivo data. The in-depth evaluation of cellular respiration in fibroblasts is a good approach to evaluating novel mtDNA variants associated with LHON but needs further evaluation as a potential biomarker for disease prognosis and treatment responsiveness.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Lhon ; Leber’s Hereditary Optic Neuropathy ; Biomarker ; Fibroblasts ; Idebenone ; Mtdna ; Responsiveness; Nqo1

ISSN (print) / ISBN 1422-0067

e-ISSN 1661-6596

Journal International Journal of Molecular Sciences

Quellenangaben Volume: 24, Issue: 16, Article Number: 11

Publisher MDPI

Publishing Place Basel

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Neurogenomics (ING)

Grants
Cell Line and DNA Bank of Genetic Movement Disorders and Mitochondrial Diseases" of the Telethon Network of Genetic Biobanks
The "Cell Line and DNA Bank of Genetic Movement Disorders and Mitochondrial Diseases" of the Telethon Network of Genetic Biobanks (GTB18001) and the EuroBioBanK Network supplied the biological specimens.