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首页> 外文期刊>Human Molecular Genetics >Elucidation of separate, but collaborative functions of the rRNA methyltransferase-related human mitochondrial transcription factors B1 and B2 in mitochondrial biogenesis reveals new insight into maternally inherited deafness.
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Elucidation of separate, but collaborative functions of the rRNA methyltransferase-related human mitochondrial transcription factors B1 and B2 in mitochondrial biogenesis reveals new insight into maternally inherited deafness.

机译：rRNA甲基转移酶相关的人类线粒体转录因子B1和B2在线粒体生物发生中的单独但协同的作用的阐明揭示了对母亲遗传性耳聋的新见解。

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摘要

Mitochondrial biogenesis is controlled by signaling networks that relay information to and from the organelles. However, key mitochondrial factors that mediate such pathways and how they contribute to human disease are not understood fully. Here we demonstrate that the rRNA methyltransferase-related human mitochondrial transcription factors B1 and B2 are key downstream effectors of mitochondrial biogenesis that perform unique, yet cooperative functions. The primary function of h-mtTFB2 is mtDNA transcription and maintenance, which is independent of its rRNA methyltransferase activity, while that of h-mtTFB1 is mitochondrial 12S rRNA methylation needed for normal mitochondrial translation, metabolism and cell growth. Over-expression of h-mtTFB1 causes 12S rRNA hypermethylation, aberrant mitochondrial biogenesis and increased sorbitol-induced cell death. These phenotypes are recapitulated in cells harboring the pathogenic A1555G mtDNA mutation, implicating a deleterious rRNA methylation-dependent retrograde signal in maternally inherited deafness pathology and shedding significant insight into how h-mtTFB1 acts as a nuclear modifier of this disease.
机译：线粒体的生物发生受到信号网络的控制，该网络将信息传递到细胞器或从细胞器传递信息。但是，尚未完全了解介导此类途径的关键线粒体因子及其如何导致人类疾病。在这里，我们证明，rRNA甲基转移酶相关的人类线粒体转录因子B1和B2是线粒体生物发生的关键下游效应器，它们执行独特但协同的功能。 h-mtTFB2的主要功能是mtDNA转录和维持，这与其rRNA甲基转移酶活性无关，而h-mtTFB1的功能是正常线粒体翻译，代谢和细胞生长所需的线粒体12S rRNA甲基化。 h-mtTFB1的过度表达会导致12S rRNA甲基化过高，线粒体生物发生异常以及山梨醇诱导的细胞死亡增加。这些表型在具有致病性A1555G mtDNA突变的细胞中概括，涉及母源遗传性耳聋病理学中有害的rRNA甲基化依赖性逆行信号，并且使人们对h-mtTFB1如何充当该疾病的核修饰物失去了重要见识。

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