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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Genetic Analysis Of Interactions With Eukaryotic Rrna Identify The Mitoribosome As Target In Aminoglycoside Ototoxicity
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Genetic Analysis Of Interactions With Eukaryotic Rrna Identify The Mitoribosome As Target In Aminoglycoside Ototoxicity

机译：与真核生物Rna相互作用的遗传分析确定了Mitoribosome作为目标的氨基糖苷耳毒性。

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摘要

Aminoglycoside ototoxicity has been related to a surprisingly large number of cellular structures and metabolic pathways. The finding that patients with mutations in mitochondrial rRNA are hypersus-ceptible to aminoglycoside-induced hearing loss has indicated a possible role for mitochondrial protein synthesis. To study the molecular interaction of aminoglycosides with eukaryotic ribo-somes, we made use of the observation that the drug binding site is a distinct domain defined by the small subunit rRNA, and investigated drug susceptibility of bacterial hybrid ribosomes carrying various alleles of the eukaryotic decoding site. Compared to hybrid ribosomes with the A site of human cytosolic ribosomes, susceptibility of mitochondrial hybrid ribosomes to various aminoglycosides correlated with the relative cochleotoxicity of these drugs. Sequence alterations that correspond to the mitochondrial deafness mutations A1555G and C1494T increased drug-binding and rendered the ribosomal decoding site hypersusceptible to aminoglycoside-induced mistranslation and inhibition of protein synthesis. Our results provide experimental support for aminoglycoside-induced dysfunction of the mitochondrial ribosome. We propose a pathogenic mechanism in which interference of aminoglycosides with mitochondrial protein synthesis exacerbates the drugs' cochlear toxicity, playing a key role in sporadic dose dependent and genetically inherited, aminoglycoside-induced deafness.
机译：氨基糖苷的耳毒性已与数量众多的细胞结构和代谢途径有关。线粒体rRNA突变的患者对氨基糖苷类引起的听力丧失高度敏感，这一发现表明线粒体蛋白合成可能具有作用。为了研究氨基糖苷类与真核生物核糖体的分子相互作用，我们利用以下观察结果：药物结合位点是由小亚基rRNA定义的独特结构域，并研究了携带各种真核生物解码等位基因的细菌杂合核糖体的药物敏感性。现场。与具有人胞质核糖体A位点的杂合核糖体相比，线粒体杂合核糖体对各种氨基糖苷的敏感性与这些药物的相对耳蜗毒性相关。对应于线粒体耳聋突变A1555G和C1494T的序列改变增加了药物结合，并使核糖体解码位点对氨基糖苷诱导的错误翻译和蛋白质合成的抑制作用高度敏感。我们的结果为氨基糖苷诱导的线粒体核糖体功能障碍提供了实验支持。我们提出了一种致病机制，其中氨基糖苷对线粒体蛋白合成的干扰加剧了药物的耳蜗毒性，在偶发的剂量依赖性和遗传遗传的氨基糖苷引起的耳聋中起关键作用。

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