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Respiration and Growth Defects in Transmitochondrial Cell Lines Carrying the 11778 Mutation Associated with Leber’s Hereditary Optic Neuropathy

Hofhaus, Götz and Johns, Donald R. and Hurko, Orest and Attardi, Giuseppe and Chomyn, Anne (1996) Respiration and Growth Defects in Transmitochondrial Cell Lines Carrying the 11778 Mutation Associated with Leber’s Hereditary Optic Neuropathy. Journal of Biological Chemistry, 271 (22). pp. 13155-13161. ISSN 0021-9258.

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Mitochondrial DNA from two genetically unrelated patients carrying the mutation at position 11778 that causes Leber's hereditary optic neuropathy has been transferred with mitochondria into human mtDNA-less 0206 cells. As analyzed in several transmitochondrial cell lines thus obtained, the mutation, which is in the gene encoding subunit ND4 of the respiratory chain NADH dehydrogenase (ND), did not affect the synthesis, size, or stability of ND4, nor its incorporation into the enzyme complex. However, NADH dehydrogenase-dependent respiration, as measured in digitonin-permeabilized cells, was specifically decreased by approximately 40% in cells carrying the mutation. This decrease, which was significant at the 99.99% confidence level, was correlated with a significantly reduced ability of the mutant cells to grow in a medium containing galactose instead of glucose, indicating a clear impairment in their oxidative phosphorylation capacity. On the contrary, no decrease in rotenone-sensitive NADH dehydrogenase activity, using a water-soluble ubiquinone analogue as electron acceptor, was detected in disrupted mitochondrial membranes. This is the first cellular model exhibiting in a foreign nuclear background mitochondrial DNA-linked biochemical defects underlying the optic neuropathy phenotype.

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Additional Information:©1996 by The American Society for Biochemistry and Molecular Biology, Inc. Received for publication, February 6, 1996. We are grateful to Dr. Neil R. Miller of the Wilmer Institute, Johns Hopkins Medical Institutions, for providing clinical information and access to the LHON patients. We are grateful also to Dr. Youssef Hatefi and members of the Attardi laboratory for helpful discussion. We thank Susan T. Lai, Benneta Keeley, and Arger Drew for excellent technical assistance. This work was supported by National Institutes of Health Grants GM 11726 (to G. A.), Grant EY 10864 (to D.R.J.), Grant AR NS 38231 (to O. H.), and by the Kennedy/Hopkins NICHD Mental Retardation Research Center Core Grant HD 24061. The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Issue or Number:22
Record Number:CaltechAUTHORS:HOFjbc96
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:3739
Deposited By: Lindsay Cleary
Deposited On:10 Jul 2006
Last Modified:02 Oct 2019 23:06

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