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J. Biol. Chem., Vol. 275, Issue 25, 19198-19209, June 23, 2000
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From the Division of Biology, California Institute of Technology,
Pasadena, California 91125
The pathogenetic mechanism of the mitochondrial
tRNALeu(UUR) A3243G transition associated with the
mitochondrial myopathy, encephalopathy, lactic acidosis, and
stroke-like episodes (MELAS) syndrome has been investigated in
transmitochondrial cell lines constructed by transfer of mutant
mitochondrial DNA (mtDNA)-carrying mitochondria from three genetically
unrelated MELAS patients or of isogenic wild-type mtDNA-carrying
organelles into human mtDNA-less cells. An in vivo
footprinting analysis of the mtDNA segment within the tRNALeu(UUR) gene that binds the transcription termination
factor failed to reveal any difference in occupancy of sites or
qualitative interaction with the protein between mutant and wild-type
mtDNAs. Cell lines nearly homoplasmic for the mutation exhibited a
strong (70-75%) reduction in the level of aminoacylated
tRNALeu(UUR) and a decrease in mitochondrial protein
synthesis rate. The latter, however, did not show any significant
correlation between synthesis defect of the individual polypeptides and
number or proportion of UUR codons in their mRNAs, suggesting that
another step, other than elongation, may be affected. Sedimentation
analysis in sucrose gradient showed a reduction in size of the
mitochondrial polysomes, while the distribution of the two rRNA
components and of the mRNAs revealed decreased association of
mRNA with ribosomes and, in the most affected cell line, pronounced
degradation of the mRNA associated with slowly sedimenting
structures. Therefore, several lines of evidence indicate that the
protein synthesis defect in A3243G MELAS mutation-carrying cells is
mainly due to a reduced association of mRNA with ribosomes,
possibly as a consequence of the tRNALeu(UUR)
aminoacylation defect.
The Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis, and
Stroke-like Episode Syndrome-associated Human Mitochondrial
tRNALeu(UUR) Mutation Causes Aminoacylation Deficiency and
Concomitant Reduced Association of mRNA with Ribosomes*
,
*
This work was supported by National Institutes of Health
Grant GM-11726 (to G. A.).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.
To whom correspondence should be addressed. Tel.: 626-395-4958;
Fax: 626-449-0756; chomyn@seqaxp.bio.caltech.edu.
§
Present address: Dept. di Bioquímica y Biología
Molecular y Celular, Universidad de Zaragoza, Miguel Servet, 177, 50013 Zaragoza, Spain.
¶
Present address: Centro de Biología Molecular y
Celular, Universidad Miguel Hernández, C/Monóvar s/n (Pol.
Ind. Carrús) E-03206 Elche (Alicante), Spain.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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