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Complementation of mutant and wild-type human mitochondrial DNAs coexisting since the mutation event and lack of complementation of DNAs introduced separately into a cell within distinct organelles

Yoneda, Makoto and Miyatake, Tadashi and Attardi, Giuseppe (1994) Complementation of mutant and wild-type human mitochondrial DNAs coexisting since the mutation event and lack of complementation of DNAs introduced separately into a cell within distinct organelles. Molecular and Cellular Biology, 14 (4). pp. 2699-2712. ISSN 0270-7306. http://resolver.caltech.edu/CaltechAUTHORS:YONmcb94

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Abstract

The rules that govern complementation of mutant and wild-type mitochondrial genomes in human cells were investigated under different experimental conditions. Among mitochondrial transformants derived from an individual affected by the MERRF (myoclonus epilepsy associated with ragged red fibers) encephalomyopathy and carrying in heteroplasmic form the mitochondrial tRNA(Lys) mutation associated with that syndrome, normal protein synthesis and respiration was observed when the wild-type mitochondrial DNA exceeded 10% of the total complement. In these transformants, the protective effect of wild-type mitochondrial DNA was shown to involve interactions of the mutant and wild-type gene products. Very different results were obtained in experiments in which two mitochondrial DNAs carrying nonallelic disease-causing mutations were sequentially introduced within distinct organelles into the same human mitochondrial DNA-less (rho 0) cell. In transformants exhibiting different ratios of the two genomes, no evidence of cooperation between their products was observed, even 3 months after the introduction of the second mutation. These results pointed to the phenotypic independence of the two genomes. A similar conclusion was reached in experiments in which mitochondria carrying a chloramphenicol resistance-inducing mitochondrial DNA mutation were introduced into chloramphenicol-sensitive cells. A plausible interpretation of the different results obtained in the latter two sets of experiments, compared with the complementation behavior observed in the heteroplasmic MERRF transformants, is that in the latter, the mutant and wild-type genomes coexisted in the same organelles from the time of the mutation. This would imply that the way in which mitochondrial DNA is sorted among different organelles plays a fundamental role in determining the oxidative-phosphorylation phenotype in mammalian cells. These results have significant implications for mitochondrial genetics and for studies on the transmission and therapy of mitochondrial DNA-linked diseases.


Item Type:Article
Additional Information:Copyright © 1994 by the American Society for Microbiology. Received 29 November 1993/Accepted 12 January 1994 These investigations were supported by National Institutes of Health grant GM-11726 to G.A., Muscular Dystrophy Association grant 37826 to G.A. and Anne Chomyn, and a Gosney Fellowship and a Human Frontier Science Program Fellowship to M.Y. We are very grateful to A. Chomyn for providing clone pT72. The technical assistance of A. Drew, B. Keeley, and L. Tefo is gratefully acknowledged.
Record Number:CaltechAUTHORS:YONmcb94
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:YONmcb94
Alternative URL:http://mcb.asm.org/cgi/content/abstract/14/4/2699
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:5480
Collection:CaltechAUTHORS
Deposited By: Archive Administrator
Deposited On:19 Oct 2006
Last Modified:26 Dec 2012 09:12

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