Suppression of a mitochondrial tRNA gene mutation phenotype associated with changes in the nuclear background

Huiling Hao, Lawrence E. Morrison, Carlos T Moraes

Research output: Contribution to journalArticle

53 Citations (Scopus)

Abstract

We previously have characterized a pathogenic mtDNA mutation in the tRNA(Asn) gene. This mutation (G5703A) was associated with a severe mitochondrial protein synthesis defect and a reduction in steady-state levels of tRNA(Asn). We now show that, although transmitochondrial cybrids harboring homoplasmic levels of the mutation do not survive in galactose medium, several galactose-resistant clones could be obtained. These cell lines had restored oxidative phosphorylation function and 2-fold higher steady-state levels of tRNA(Asn) when compared with the parental mutant cell line. The revertant lines contained apparently homoplasmic levels of the mutation and no other detectable alteration in the tRNA(Asn) gene. To investigate the origin of the suppression, we transferred mtDNA from the revertants (143B/206 TK-) to a different nuclear background (143B/207 TK-, 8AG(r)). These new transmitochondrial cybrids became defective once again in oxidative phosphorylation and regained galactose sensitivity. However, galactose-resistant clones could also be obtained by growing the 8AG(r) transmitochondrial cybrids under selection. Because the original rate of reversion was higher than that expected by a classic second site nuclear mutation, and because of the aneuploid features of these cell lines, we searched for the presence of chromosomal alterations that could be associated with the revertant phenotype. These studies, however, did not reveal any gross changes. Our results suggest that modulation of the dosage or expression of unknown nuclear-coded factor(s) can compensate for a pathogenic mitochondrial tRNA gene mutation, suggesting new strategies for therapeutic intervention.

Original languageEnglish
Pages (from-to)1117-1124
Number of pages8
JournalHuman Molecular Genetics
Volume8
Issue number6
DOIs
StatePublished - Jun 9 1999

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Mitochondrial Genes
RNA, Transfer, Asn
Transfer RNA
Phenotype
Galactose
Mutation
Oxidative Phosphorylation
Mitochondrial DNA
Cell Line
Clone Cells
Mitochondrial Proteins
Aneuploidy
Genes

ASJC Scopus subject areas

  • Genetics

Cite this

Suppression of a mitochondrial tRNA gene mutation phenotype associated with changes in the nuclear background. / Hao, Huiling; Morrison, Lawrence E.; Moraes, Carlos T.

In: Human Molecular Genetics, Vol. 8, No. 6, 09.06.1999, p. 1117-1124.

Research output: Contribution to journalArticle

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