Galactose-replacement unmasks the biochemical consequences of the G11778A mitochondrial DNA mutation of LHON in patient-derived fibroblasts

• Published in: Experimental cell research 2024-06, Vol.439 (1), p.114075-114075, Article 114075
• Main Authors: Pasqualotto, Bryce A., Tegeman, Carina, Frame, Ariel K., McPhedrain, Ryan, Halangoda, Kolitha, Sheldon, Claire A., Rintoul, Gordon L.
• Format: Article
• Language: English
• Subjects: ATP; Fibroblasts; Galactose; LHON; Oxidative stress; Proliferation
• ISSN: 0014-4827; 1090-2422
• DOI: 10.1016/j.yexcr.2024.114075

Leber's hereditary optic neuropathy (LHON) is a visual impairment associated with mutations of mitochondrial genes encoding elements of the electron transport chain. While much is known about the genetics of LHON, the cellular pathophysiology leading to retinal ganglion cell degeneration and subsequent vision loss is poorly understood. The impacts of the G11778A mutation of LHON on bioenergetics, redox balance and cell proliferation were examined in patient-derived fibroblasts. Replacement of glucose with galactose in the culture media reveals a deficit in the proliferation of G11778A fibroblasts, imparts a reduction in ATP biosynthesis, and a reduction in capacity to accommodate exogenous oxidative stress. While steady-state ROS levels were unaffected by the LHON mutation, cell survival was diminished in response to exogenous H2O2. •Patient-derived fibroblasts reciprocate pathological features of LHON.•G11778A mutation imparts altered fibroblast proliferation.•G11778A increases fibroblast susceptibility to ROS.•Galactose-replacement unmasks an ATP deficit in LHON fibroblasts.