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Nuclear Modifier MTO2 Modulates the Aminoglycoside-Sensitivity of Mitochondrial 15S rRNA C1477G Mutation in Saccharomyces cerevisiae

The phenotypic manifestations of mitochondrial DNA (mtDNA) mutations are modulated by mitochondrial DNA haplotypes, nuclear modifier genes and environmental factors. The yeast mitochondrial 15S rRNA C1477G (P(R) or P(R) (454)) mutation corresponds to the human 12S rRNA C1494T and A1555G mutations, w...

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Autores principales: He, Xiangyu, Zhu, Xiaoyu, Wang, Xuexiang, Wang, Wei, Dai, Yu, Yan, Qingfeng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3858254/
https://www.ncbi.nlm.nih.gov/pubmed/24339937
http://dx.doi.org/10.1371/journal.pone.0081490
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author He, Xiangyu
Zhu, Xiaoyu
Wang, Xuexiang
Wang, Wei
Dai, Yu
Yan, Qingfeng
author_facet He, Xiangyu
Zhu, Xiaoyu
Wang, Xuexiang
Wang, Wei
Dai, Yu
Yan, Qingfeng
author_sort He, Xiangyu
collection PubMed
description The phenotypic manifestations of mitochondrial DNA (mtDNA) mutations are modulated by mitochondrial DNA haplotypes, nuclear modifier genes and environmental factors. The yeast mitochondrial 15S rRNA C1477G (P(R) or P(R) (454)) mutation corresponds to the human 12S rRNA C1494T and A1555G mutations, which are well known as primary factors for aminoglycoside-induced nonsyndromic deafness. Here we report that the deletion of the nuclear modifier gene MTO2 suppressed the aminoglycoside-sensitivity of mitochondrial 15S rRNA C1477G mutation in Saccharomyces cerevisiae. First, the strain with a single mtDNA C1477G mutation exhibited hypersensitivity to neomycin. Functional assays indicated that the steady-state transcription level of mitochondrial DNA, the mitochondrial respiratory rate, and the membrane potential decreased significantly after neomycin treatment. The impaired mitochondria could not produce sufficient energy to maintain cell viability. Second, when the mto2 null and the mitochondrial C1477G mutations co-existed (mto2(P(R))), the oxygen consumption rate in the double mutant decreased markedly compared to that of the control strains (MTO2(P(S)), mto2(P(S)) and MTO2(P(R))). The expression levels of the key glycolytic genes HXK2, PFK1 and PYK1 in the mto2(P(R)) strain were stimulated by neomycin and up-regulated by 89%, 112% and 55%, respectively. The enhanced glycolysis compensated for the respiratory energy deficits, and could be inhibited by the glycolytic enzyme inhibitor. Our findings in yeast will provide a new insight into the pathogenesis of human deafness.
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spelling pubmed-38582542013-12-11 Nuclear Modifier MTO2 Modulates the Aminoglycoside-Sensitivity of Mitochondrial 15S rRNA C1477G Mutation in Saccharomyces cerevisiae He, Xiangyu Zhu, Xiaoyu Wang, Xuexiang Wang, Wei Dai, Yu Yan, Qingfeng PLoS One Research Article The phenotypic manifestations of mitochondrial DNA (mtDNA) mutations are modulated by mitochondrial DNA haplotypes, nuclear modifier genes and environmental factors. The yeast mitochondrial 15S rRNA C1477G (P(R) or P(R) (454)) mutation corresponds to the human 12S rRNA C1494T and A1555G mutations, which are well known as primary factors for aminoglycoside-induced nonsyndromic deafness. Here we report that the deletion of the nuclear modifier gene MTO2 suppressed the aminoglycoside-sensitivity of mitochondrial 15S rRNA C1477G mutation in Saccharomyces cerevisiae. First, the strain with a single mtDNA C1477G mutation exhibited hypersensitivity to neomycin. Functional assays indicated that the steady-state transcription level of mitochondrial DNA, the mitochondrial respiratory rate, and the membrane potential decreased significantly after neomycin treatment. The impaired mitochondria could not produce sufficient energy to maintain cell viability. Second, when the mto2 null and the mitochondrial C1477G mutations co-existed (mto2(P(R))), the oxygen consumption rate in the double mutant decreased markedly compared to that of the control strains (MTO2(P(S)), mto2(P(S)) and MTO2(P(R))). The expression levels of the key glycolytic genes HXK2, PFK1 and PYK1 in the mto2(P(R)) strain were stimulated by neomycin and up-regulated by 89%, 112% and 55%, respectively. The enhanced glycolysis compensated for the respiratory energy deficits, and could be inhibited by the glycolytic enzyme inhibitor. Our findings in yeast will provide a new insight into the pathogenesis of human deafness. Public Library of Science 2013-12-10 /pmc/articles/PMC3858254/ /pubmed/24339937 http://dx.doi.org/10.1371/journal.pone.0081490 Text en © 2013 He et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
He, Xiangyu
Zhu, Xiaoyu
Wang, Xuexiang
Wang, Wei
Dai, Yu
Yan, Qingfeng
Nuclear Modifier MTO2 Modulates the Aminoglycoside-Sensitivity of Mitochondrial 15S rRNA C1477G Mutation in Saccharomyces cerevisiae
title Nuclear Modifier MTO2 Modulates the Aminoglycoside-Sensitivity of Mitochondrial 15S rRNA C1477G Mutation in Saccharomyces cerevisiae
title_full Nuclear Modifier MTO2 Modulates the Aminoglycoside-Sensitivity of Mitochondrial 15S rRNA C1477G Mutation in Saccharomyces cerevisiae
title_fullStr Nuclear Modifier MTO2 Modulates the Aminoglycoside-Sensitivity of Mitochondrial 15S rRNA C1477G Mutation in Saccharomyces cerevisiae
title_full_unstemmed Nuclear Modifier MTO2 Modulates the Aminoglycoside-Sensitivity of Mitochondrial 15S rRNA C1477G Mutation in Saccharomyces cerevisiae
title_short Nuclear Modifier MTO2 Modulates the Aminoglycoside-Sensitivity of Mitochondrial 15S rRNA C1477G Mutation in Saccharomyces cerevisiae
title_sort nuclear modifier mto2 modulates the aminoglycoside-sensitivity of mitochondrial 15s rrna c1477g mutation in saccharomyces cerevisiae
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3858254/
https://www.ncbi.nlm.nih.gov/pubmed/24339937
http://dx.doi.org/10.1371/journal.pone.0081490
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