Leber's hereditary optic neuropathy (LHON) is the maternally inherited mitochondrial disease caused by homoplasmic mutations in mitochondrial electron transport chain Complex I subunit genes. The mechanism of its incomplete penetrance is still largely unclear. In this study, we created the patient-specific human induced pluripotent stem cells (hiPSCs) from MT-ND4 mutated LHON-affected patient, asymptomatic mutation carrier and healthy control, and differentiated them into retinal ganglion cells (RGCs). We found the defective neurite outgrowth in affected RGCs, but not in the carrier RGCs which had significant expression of SNCG gene. We observed enhanced mitochondrial biogenesis in affected and carrier derived RGCs. Surprisingly, we observed increased NADH dehydrogenase enzymatic activity of Complex I in hiPSC-derived RGCs of asymptomatic carrier, but not of the affected patient. LHON mutation substantially decreased basal respiration in both affected and unaffected carrier hiPSCs, and had the same effect on spare respiratory capacity, which ensures normal function of mitochondria in conditions of increased energy demand or environmental stress. The expression of antioxidant enzyme catalase was decreased in affected and carrier patient hiPSC-derived RGCs as compared to the healthy control, which might indicate to higher oxidative stress-enriched environment in the LHON-specific RGCs. Microarray profiling demonstrated enhanced expression of cell cycle machinery and downregulation of neuronal specific genes.
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