Evaluation of Mitochondrial Dysfunction and Idebenone Responsiveness in Fibroblasts from Leber’s Hereditary Optic Neuropathy (LHON) Subjects

Abstract

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.

Letter to the Editor: Retinal morphological and functional response to Idebenone therapy in Leber hereditary optic neuropathy

“…Regarding the mtDNA copy number, Giordano et al observed that symptomatic carriers have a decreased rate of mtDNA copy number [ 5 ]. Baglivo et al correlated, in their study, the amount of mtDNA and treatment response and hypothesized that in m.3460G>A variant a protective role of mitochondrial biogenesis could be considered since in m.11778G>A variant, there was no correlation between the mtDNA copy number and disease penetrance [ 6 ]. In our study, we obtained a good response to Idebenone in patient with m.3460G>A mutation and no response in patient with m.11778G>A mutation.…”