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Human Molecular Genetics, 2002, Vol. 11, No. 4 431-438
© 2002 Oxford University Press

Differentiation-specific effects of LHON mutations introduced into neuronal NT2 cells

Alice Wong, Lucia Cavelier1, Heather E. Collins-Schramm2, Michael F. Seldin2, Michael McGrogan3, Marja-Liisa Savontaus4 and Gino A. Cortopassi+

Department of Molecular Biosciences, One Shields Avenue, School of Veterinary Medicine, University of California, Davis, CA 95616, USA, 1Section of Medical Genetics, Department of Genetics and Pathology, Rudbeck Laboratories, Dag Hammarsjölds väg 20, 751 85, Uppsala, Sweden, 2Rowe Program in Human Genetics, Departments of Biological Chemistry and Medicine, One Shields Avenue, School of Medicine, University of California, Davis, CA 95616, USA, 3Layton Biosciences, 709 East Evelyn Avenue, Sunnyvale, CA 94086, USA and 4Departments of Medical Genetics and Biology, University of Turku, FIN-20500 Turku, Finland

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 has been unclear why inheritance of a systemic mitochondrial mutation would result in a specific neurodegeneration. To address the neuron-specific degenerative 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). The undifferentiated LHON-NT2 mutant cells were not significantly 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. Differentiation of NT2s resulted in a neuronal morphology and neuron-specific pattern of gene expression, and a 3-fold reduction in mtDNA/nDNA ratio in both mutant and control cells; however, the differentiation protocol yielded significantly less LHON cells than controls, by 30%, indicating either a decreased proliferative potential or increased cell death of the LHON-NT2 cells. Differentiation of the cells to the neuronal form also resulted in significant increases in ROS production in the LHON-NT2 neurons versus controls, which is abolished by rotenone, a specific inhibitor of Complex I. We infer that the LHON genotype requires a differentiated neuronal environment in order to induce increased mitochondrial ROS, which may be the cause of the reduced NT2 yield; and suggest that the LHON degenerative phenotype may be the result of an increase in mitochondrial superoxide which is caused by the LHON mutations, possibly mediated through neuron-specific alterations in Complex I structure.

+ To whom correspondence should be addressed. Tel: +1 530 754 9665; Fax: +1 530 754 9342; Email: gacortopassi@ucdavis.edu


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