Wang H, Lemire B D, Cass C E, Weiner J H, Michalak M, Penn A M, Fliegel L
Department of Biochemistry, University of Alberta, Edmonton, Canada.
Biochim Biophys Acta. 1996 May 24;1316(1):51-9. doi: 10.1016/0925-4439(96)00015-4.
Kearns-Sayre syndrome is the most commonly diagnosed mitochondrial cytopathy and produces severe neuromuscular symptoms. The most frequent cause is a mitochondrial DNA deletion that removes a 4977-base pair segment of DNA that includes several genes encoding for respiratory chain subunits. Treatment of AIDS patients with nucleoside analogs has been reported to cause mtDNA depletion and myopathies. Here, we report that azidothymidine, dideoxyguanosine, and dideoxycytidine cause a depletion of wild-type mtDNA while increasing the levels of deleted mitochondria DNA in Kearns-Sayre syndrome fibroblasts. The result of these effects is a large increase in the relative amounts of delta mtDNA in comparison to wild type mtDNA. We found that Kearns-Sayre syndrome fibroblasts are a mixed population of cells with deleted mtDNA comprising from 0 to over 20% of the total mtDNA in individual cells. Treatment of cloned cell lines with dideoxycytidine did not result in increased levels of delta mtDNA. The results suggest that nucleoside analogs may act to increase the average delta mtDNA levels in a mixed population of cells by preferentially inhibiting the proliferation of cells with little or no delta mtDNA. This raises the possibility that modulation of deleted mtDNA levels may occur by similar mechanisms in vivo, in response to the influence of exogenous agents.
卡恩斯-塞尔综合征是最常被诊断出的线粒体细胞病，会产生严重的神经肌肉症状。最常见的病因是线粒体DNA缺失，缺失的DNA片段有4977个碱基对，其中包含几个编码呼吸链亚基的基因。据报道，用核苷类似物治疗艾滋病患者会导致线粒体DNA耗竭和肌病。在此，我们报告叠氮胸苷、双脱氧鸟苷和双脱氧胞苷会导致野生型线粒体DNA耗竭，同时增加卡恩斯-塞尔综合征成纤维细胞中缺失型线粒体DNA的水平。这些作用的结果是，与野生型线粒体DNA相比，缺失型线粒体DNA的相对量大幅增加。我们发现，卡恩斯-塞尔综合征成纤维细胞是一个混合细胞群体，其中缺失型线粒体DNA在单个细胞的总线粒体DNA中所占比例从0到超过20%不等。用双脱氧胞苷处理克隆细胞系并不会导致缺失型线粒体DNA水平升高。结果表明，核苷类似物可能通过优先抑制几乎没有或没有缺失型线粒体DNA的细胞增殖，从而使混合细胞群体中的平均缺失型线粒体DNA水平升高。这就增加了一种可能性，即在外源因素的影响下，体内可能通过类似机制调节缺失型线粒体DNA的水平。
