Over-expression of Tfam improves the mitochondrial disease phenotypes in a mouse model system
Over-expression of Tfam improves the mitochondrial disease phenotypes in a mouse model system
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DOI：
10.1016/j.bbrc.2010.08.143
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发表时间：
2010-10-08
影响因子：
3.1
通讯作者：
Yonekawa, Hiromichi
中科院分区：
文献类型：
--
作者：
Nishiyama, Satoshi;Shitara, Hiroshi;Yonekawa, Hiromichi
由线粒体DNA（mtDNA）突变引起的线粒体疾病的表型已被提出严格受野生型和致病突变的mtDNA的比例调节。更具体地说，认为疾病表型的发作发生在细胞由于病理性mtDNA过量而不能维持适当的线粒体功能时。已经提出了导致致病性mtDNA群体减少的疗法作为线粒体疾病的治疗方法，但这些疗法难以在实践中应用。在本报告中，我们提出了一个新的概念：即使在线粒体DNA基因型的相对比例保持不变的情况下，也可以通过增加病原细胞中野生型线粒体DNA群体的绝对拷贝数来改善线粒体疾病表型。我们已经成功地改善线粒体疾病的典型症状，在模型小鼠线的线粒体转录因子A（Tfam）的过表达，随后由mtDNA拷贝数的增加。这一新概念将导致开发一种新的线粒体疾病治疗方法。(C)2010年爱思唯尔公司All rights reserved.
The phenotypes of mitochondrial diseases caused by mutations in mitochondrial DNA (mtDNA) have been proposed to be strictly regulated by the proportion of wild-type and pathogenically mutated mtDNAs. More specifically, it is thought that the onset of the disease phenotype occurs when cells cannot maintain the proper mitochondrial function because of an over-abundance of pathological mtDNA. Therapies that cause a decrease in the pathogenic mtDNA population have been proposed as a treatment for mitochondrial diseases, but these therapies are difficult to apply in practice. In this report, we present a novel concept: to improve mitochondrial disease phenotypes via an increase in the absolute copy number of the wild-type mtDNA population in pathogenic cells even when the relative proportion of mtDNA genotypes remains unchanged. We have succeeded in ameliorating the typical symptoms of mitochondrial disease in a model mouse line by the over-expression of the mitochondrial transcription factor A (Tfam) followed by an increase of the mtDNA copy number. This new concept should lead to the development of a novel therapeutic treatment for mitochondrial diseases. (C) 2010 Elsevier Inc. All rights reserved.