Mutant mitochondrial helicase Twinkle causes multiple mtDNA deletions and a late-onset mitochondrial disease in mice
Mutant mitochondrial helicase Twinkle causes multiple mtDNA deletions and a late-onset mitochondrial disease in mice
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DOI：
10.1073/pnas.0505551102
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发表时间：
2005-12-06
影响因子：
11.1
通讯作者：
Suomalainen, A
中科院分区：
文献类型：
--
作者：
Tyynismaa, H;Mjosund, KP;Suomalainen, A
线粒体DNA(MtDNA)维持缺陷近来被认为与遗传性神经退行性疾病、肌肉疾病和衰老过程有关。Flinkle是一种核编码的mtDNA解旋酶，其显性突变导致成人起病的进行性眼外肌瘫痪(PEO)伴多个mtDNA缺失。我们已经产生了表达带有PEO患者突变的小鼠Twinkle的转基因小鼠。多个mtDNA缺失在这些小鼠的组织中积累，导致进行性呼吸功能障碍和慢性迟发性线粒体疾病，从1岁开始。小鼠的肌肉忠实地复制了PEO患者的所有关键组织学、遗传学和生化特征。此外，这些小鼠在不同的神经元群体中存在进行性的细胞色素c氧化酶缺陷。然而，这些“缺失”小鼠并没有表现出过早衰老，这表明mtDNA缺失的微妙积累和进行性呼吸链功能障碍不足以加速衰老。该模型对于成人发病的线粒体疾病的治疗开发和测试是一个有价值的工具。
Defects of mitochondrial DNA (mtDNA) maintenance have recently been associated with inherited neurodegenerative and muscle diseases and the aging process. Twinkle is a nuclear-encoded mtDNA helicase, dominant mutations of which cause adult-onset progressive external ophthalmoplegia (PEO) with multiple mtDNA deletions. We have generated transgenic mice expressing mouse Twinkle with PEO patient mutations. Multiple mtDNA deletions accumulate in the tissues of these mice, resulting in progressive respiratory dysfunction and chronic late-onset mitochondrial disease starting at 1 year of age. The muscles of the mice faithfully replicate all of the key histological, genetic, and biochemical features of PEO patients. Furthermore, the mice have progressive deficiency of cytochrome c oxidase in distinct neuronal populations. These "deletor" mice do not, however, show premature aging, indicating that subtle accumulation of mtDNA deletions and progressive respiratory chain dysfunction are not sufficient to accelerate aging. This model is a valuable tool for therapy development and testing for adult-onset mitochondrial disorders.