核修饰基因MTO2/TRMU调控酵母P~R_(454)突变相关的氨基糖苷类抗生素敏感性及其机制
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摘要
线粒体12S rRNA基因A1555G突变是引起母系遗传性非综合症耳聋的重要原因,但是仅有A1555G突变不足以导致耳聋,耳聋表型的形成还与核修饰基因、环境因子、线粒体基因组单体型等多种因素相关。当前研究大多集中在分析环境因子或核基因等单一因素对A1555G突变的影响,而多个因素之间的协同作用机制尚不清楚。本论文以酿酒酵母为模式生物,综合分析了核修饰基因MT02/TRMU,线粒体PR454突变(与人A1555G突变同源)与氨基糖苷类抗生素三者之间的相互作用。
本实验室前期工作发现,在携带A1555G突变的淋巴细胞中,核修饰基因TRMU的G28T突变(A10S)能显著抑制细胞对氨基糖苷类抗生素的敏感性。本论文利用携带线粒体15SrRNAPR454突变的酿酒酵母菌株,构建了MT02基因(与人TRMU基因同源)敲除模型,并分析了氨基糖苷类抗生素对携带PR454突变酵母菌株的影响以及核修饰基因MT02的作用。研究发现MT02基因敲除能显著抑制携带PR454突变酵母菌株对氨基糖苷类抗生素的敏感性,并深入分析了形成这一表型的机制。通过检测线粒体呼吸速率、线粒体膜电位、酵母菌株的抗生素摄入量、抗生素抗性基因表达以及能量代谢等指标,发现经抗生素处理后,携带PR454突变的酵母菌株的线粒体功能被抑制,但是MT02基因敲除使携PR454突变酵母菌株中糖酵解的关键调控基因已糖激酶、磷酸果糖激酶、丙酮酸脱氢酶的表达水平显著上调,这一变化降低了酿酒酵母对线粒体功能的依赖性,并使菌株对抗生素的敏感性下降。
将人TRMUcDNA转化至同时携带线粒体PR454突变与MT02基因敲除的酿酒酵母mto2(PR)菌株中进行异源表达,结果显示TRMU基因能在酵母线粒体中特异性表达,并不同程度地恢复该菌株的线粒体功能。研究发现,与TRMU野生型转化菌株相比,TRMU A1OS突变型转化菌株对氨基糖苷类抗生素的敏感性更低,而且TRMU A1OS突变型转化菌株的线粒体功能几乎不受抗生素影响。
本论文发现核修饰基因MTO2/TRMU能够调控线粒体PR454(A1555G)突变相关的氨基糖苷类抗生素敏感性,并系统研究了其分子机制。研究结果为阐明人TRMU基因调控A1555G突变相关的抗生素敏感性提供了借鉴,并可为研究核基因、线粒体基因、环境因素三者之间的相互作用提供参考。
Mitochondrial DNA (mtDNA) mutation is one of the most important factors leading to sensorineural hearing loss. Mitochondrial12S rRNA A1555G mutation is associated with both aminoglycoside-induced and non-syndromic deafness. However, the phenotypic expression of population carrying A1555G mutation is often found to be pleiotropic, ranging from severe deafness to normal hearing. This indicates that modifier factors including nuclear genes, mitochondrial haplotype and ototoxic drugs could affect the phenotypic manifestation of A1555G mutation. Using yeast Saccharomyces cerevisiae as a model system, we investigated the crosstalk among mitochondrial PR454mutation (corresponding to human A1555G mutation), nuclear modifier MTO2/TRMU and aminoglycosides, as well as their combined effects on mitochondrial and cellular function.
Our previous work found that G28T mutation (A1OS) in TRMU gene could suppress aminoglycoside antibiotic sensitivity in lymphocytes carrying mitochondrial A1555G mutation. Yeast model was constructed by deleting TRMU homolog MT02gene from a strain carrying mitochondrial15S rRNA PR454mutation. We analyzed the effects of aminoglycosides on yeast carrying PR454mutation, and the role of nuclear modifier MTO2was also investigated. Phenotypic expression indicated that deletion of nuclear gene MT02suppressed aminoglycoside antibiotic sensitivity in-yeast carrying PR454mutation, and the underlying molecular mechanism was further analyzed. Biochemical function of cell and mitochondria including respiratory rate, mitochondrial membrane potential, antibiotic intake, expression level of drug resistance gene and energy metabolism were tested. Results showed that mitochondrial function in PR454mutant was impaired by aminoglycosides. Noticeably, deletion of MTO2from PR454mutant strain enhanced the expression levels of HXK2, PFK1and PYK1which regulating the glycolytic pathway. We proposed this independence of mitochondrial function and accelerated glycolysis made this strain less sensitive to aminoglycosides.
Yeast strains expressing human TRMU gene were obtained by transforming TRMU cDNA into mto2(PR). Human TRMU gene was specifically expressed in yeast mitochondria, and trmu could be functionally complementary with yeast mto2p. Interestingly, yeast transformed with TRMU A1OS mutant cDNA was less sensitive to neomycin when compared with the TRMU wild-type transformant. However, functional analysis showed the mechanism that TRMU gene regulating neomycin sensitivity was different from yeast MTO2, and mitochondrial dysfunction had not been observed in yeast transformed with TRMU AlOS mutant cDNA. We also analyzed this difference and suggested a potential model to explain the phenomenon.
Current study discovered a novel function of MT02/TRMU gene in regulating aminoglycoside sensitivity caused by mitochondrial (A1555G) mutation, and the crosstalk among nuclear modifier gene, mtDNA mutation and environmental factors was elucidated. Meanwhile, these results provided new insights for the study of human nuclear modifier TRMU.
本实验室前期工作发现,在携带A1555G突变的淋巴细胞中,核修饰基因TRMU的G28T突变(A10S)能显著抑制细胞对氨基糖苷类抗生素的敏感性。本论文利用携带线粒体15SrRNAPR454突变的酿酒酵母菌株,构建了MT02基因(与人TRMU基因同源)敲除模型,并分析了氨基糖苷类抗生素对携带PR454突变酵母菌株的影响以及核修饰基因MT02的作用。研究发现MT02基因敲除能显著抑制携带PR454突变酵母菌株对氨基糖苷类抗生素的敏感性,并深入分析了形成这一表型的机制。通过检测线粒体呼吸速率、线粒体膜电位、酵母菌株的抗生素摄入量、抗生素抗性基因表达以及能量代谢等指标,发现经抗生素处理后,携带PR454突变的酵母菌株的线粒体功能被抑制,但是MT02基因敲除使携PR454突变酵母菌株中糖酵解的关键调控基因已糖激酶、磷酸果糖激酶、丙酮酸脱氢酶的表达水平显著上调,这一变化降低了酿酒酵母对线粒体功能的依赖性,并使菌株对抗生素的敏感性下降。
将人TRMUcDNA转化至同时携带线粒体PR454突变与MT02基因敲除的酿酒酵母mto2(PR)菌株中进行异源表达,结果显示TRMU基因能在酵母线粒体中特异性表达,并不同程度地恢复该菌株的线粒体功能。研究发现,与TRMU野生型转化菌株相比,TRMU A1OS突变型转化菌株对氨基糖苷类抗生素的敏感性更低,而且TRMU A1OS突变型转化菌株的线粒体功能几乎不受抗生素影响。
本论文发现核修饰基因MTO2/TRMU能够调控线粒体PR454(A1555G)突变相关的氨基糖苷类抗生素敏感性,并系统研究了其分子机制。研究结果为阐明人TRMU基因调控A1555G突变相关的抗生素敏感性提供了借鉴,并可为研究核基因、线粒体基因、环境因素三者之间的相互作用提供参考。
Mitochondrial DNA (mtDNA) mutation is one of the most important factors leading to sensorineural hearing loss. Mitochondrial12S rRNA A1555G mutation is associated with both aminoglycoside-induced and non-syndromic deafness. However, the phenotypic expression of population carrying A1555G mutation is often found to be pleiotropic, ranging from severe deafness to normal hearing. This indicates that modifier factors including nuclear genes, mitochondrial haplotype and ototoxic drugs could affect the phenotypic manifestation of A1555G mutation. Using yeast Saccharomyces cerevisiae as a model system, we investigated the crosstalk among mitochondrial PR454mutation (corresponding to human A1555G mutation), nuclear modifier MTO2/TRMU and aminoglycosides, as well as their combined effects on mitochondrial and cellular function.
Our previous work found that G28T mutation (A1OS) in TRMU gene could suppress aminoglycoside antibiotic sensitivity in lymphocytes carrying mitochondrial A1555G mutation. Yeast model was constructed by deleting TRMU homolog MT02gene from a strain carrying mitochondrial15S rRNA PR454mutation. We analyzed the effects of aminoglycosides on yeast carrying PR454mutation, and the role of nuclear modifier MTO2was also investigated. Phenotypic expression indicated that deletion of nuclear gene MT02suppressed aminoglycoside antibiotic sensitivity in-yeast carrying PR454mutation, and the underlying molecular mechanism was further analyzed. Biochemical function of cell and mitochondria including respiratory rate, mitochondrial membrane potential, antibiotic intake, expression level of drug resistance gene and energy metabolism were tested. Results showed that mitochondrial function in PR454mutant was impaired by aminoglycosides. Noticeably, deletion of MTO2from PR454mutant strain enhanced the expression levels of HXK2, PFK1and PYK1which regulating the glycolytic pathway. We proposed this independence of mitochondrial function and accelerated glycolysis made this strain less sensitive to aminoglycosides.
Yeast strains expressing human TRMU gene were obtained by transforming TRMU cDNA into mto2(PR). Human TRMU gene was specifically expressed in yeast mitochondria, and trmu could be functionally complementary with yeast mto2p. Interestingly, yeast transformed with TRMU A1OS mutant cDNA was less sensitive to neomycin when compared with the TRMU wild-type transformant. However, functional analysis showed the mechanism that TRMU gene regulating neomycin sensitivity was different from yeast MTO2, and mitochondrial dysfunction had not been observed in yeast transformed with TRMU AlOS mutant cDNA. We also analyzed this difference and suggested a potential model to explain the phenomenon.
Current study discovered a novel function of MT02/TRMU gene in regulating aminoglycoside sensitivity caused by mitochondrial (A1555G) mutation, and the crosstalk among nuclear modifier gene, mtDNA mutation and environmental factors was elucidated. Meanwhile, these results provided new insights for the study of human nuclear modifier TRMU.
引文
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