The role of mtDNA mutations in the pathogenesis of age-related hearing loss in mice carrying a mutator DNA polymerase γ
The role of mtDNA mutations in the pathogenesis of age-related hearing loss in mice carrying a mutator DNA polymerase γ
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DOI：
10.1016/j.neurobiolaging.2007.01.014
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发表时间：
2008-07
影响因子：
4.2
通讯作者：
Shinichi Someya;T. Yamasoba;G. Kujoth;T. Pugh;R. Weindruch;M. Tanokura;T. Prolla
中科院分区：
文献类型：
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作者：
Shinichi Someya;T. Yamasoba;G. Kujoth;T. Pugh;R. Weindruch;M. Tanokura;T. Prolla
线粒体DNA （mtDNA）突变可能导致衰老和与年龄相关的疾病。先前，我们报道了携带线粒体Polg DNA聚合酶突变等位基因的小鼠中mtDNA突变的积累与年龄相关性听力损失有关。为了阐明mtDNA突变在年龄相关性听力损失或老年性耳聋发病机制中的作用，我们通过比较9月龄线粒体突变小鼠和对照小鼠耳蜗组织的基因表达模式，进行了大规模的基因表达分析，以确定mtDNA突变应答基因和与mtDNA突变相关的生物过程类别。线粒体dna突变与衰老线粒体突变小鼠耳蜗能量代谢障碍、诱导细胞凋亡、细胞骨架功能障碍和听力功能障碍的转录改变相关。TUNEL染色和caspase-3免疫染色分析表明，与年龄匹配的对照组相比，线粒体突变小鼠耳蜗中凋亡标志物水平显著升高。这些观察结果支持了mtDNA突变如何影响耳蜗功能的新模型，即mtDNA突变的积累导致线粒体功能障碍，相关的能量代谢障碍，以及诱导凋亡程序。本文提供的数据首次在分子水平上对线粒体突变小鼠中年龄相关疾病的发病机制进行了全面评估，并揭示了以前未被识别的与mtDNA突变相关的生物学途径。
Mitochondrial DNA (mtDNA) mutations may contribute to aging and age-related diseases. Previously, we reported that accumulation of mtDNA mutations is associated with age-related hearing loss in mice carrying a mutator allele of the mitochondrial Polg DNA polymerase. To elucidate the role of mtDNA mutations in the pathogenesis of age-related hearing loss or presbycusis, we performed large scale gene expression analysis to identify mtDNA mutation-responsive genes and biological process categories associated with mtDNA mutations by comparing the gene expression patterns of cochlear tissues from 9-month-old mitochondrial mutator and control mice. mtDNA mutations were associated with transcriptional alterations consistent with impairment of energy metabolism, induction of apoptosis, cytoskeletal dysfunction, and hearing dysfunction in the cochlea of aged mitochondrial mutator mice. TUNEL staining and caspase-3 immunostaining analysis demonstrated that the levels of apoptotic markers were significantly increased in the cochleae of mitochondrial mutator mice compared to age-matched controls. These observations support a new model of how mtDNA mutations impact cochlear function whereby accumulation of mtDNA mutations lead to mitochondrial dysfunction, an associated impairment of energy metabolism, and the induction of an apoptotic program. The data presented here provide the first global assessment at the molecular level of the pathogenesis of age-related disease in mitochondrial mutator mice and reveal previously unrecognized biological pathways associated with mtDNA mutations.