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G Cortopassi, L Cavelier, M McGrogan, M-L Savontaus, A Wong; Differentiation-Specific Effects of LHON Mutations Introduced into Neuronal NT2 Cells . Invest. Ophthalmol. Vis. Sci. 2002;43(13):906.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Inheritance of one of three primary mutations at positions 11778, 3460, or 14484 of the mitochondrial genome in subunits of Complex I causes Leber's Hereditary Optic Neuropathy (LHON), a specific degeneration of the optic nerve, resulting in bilateral blindness. It is unclear why inheritance of a systemic mitochondrial mutation would result in a specific neurodegeneration, and previous studies examining the pathophysiological mechanism of LHON have used non-neural cells. Method: In an attempt to address the neural-specific phenotype of the LHON genotype, we have created cybrids using a neuronal precursor cell line, Ntera 2/D1 (NT2), containing mitochondria from patient lymphoblasts bearing the most common LHON mutation (11778) and the most severe LHON mutation (3460). Results: The undifferentiated LHON-NT2 mutant cells were no different from the parental cell control in terms of mtDNA/nDNA ratio, mitochondrial membrane potential, reactive oxygen species (ROS) production, or the ability to reduce Alamar blue. However, differentiation of the cells to the neuronal phenotype resulted in significant increases in ROS production in the LHON-NT2 neurons vs. controls, which is abolished by rotenone, a specific inhibitor of Complex I. Conclusion: We infer that the LHON genotype requires a differentiated neuronal environment in order to exert the phenotype of increased mitochondrial ROS, and suggest that the LHON degenerative phenotype may be the result of a increase in mitochondrial superoxide which is caused by the LHON mutations, which is possibly mediated through neuron-specific alterations in Complex I structure.
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