Heteroplasmic mutations of the mitochondrial genome cause paradoxical effects on mitochondrial functions.
Heteroplasmic mutations of the mitochondrial genome cause paradoxical effects on mitochondrial functions.
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线粒体基因组的异质突变对线粒体功能产生矛盾的影响。
DOI：
10.1096/fj.12-206532
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发表时间：
2012
期刊：
影响因子：
--
通讯作者：
Huang,Taosheng
中科院分区：
文献类型：
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作者：
Zhang,Chengkang;Huang,VincentH;Simon,Mariella;Sharma,LokendraK;Fan,Weiwei;Haas,Richard;Wallace,DouglasC;Bai,Yidong;Huang,Taosheng
线粒体基因组（mtDNA）突变导致高度可变的临床特征，其发病机制尚未完全了解。在这项研究中，我们分析了异源mtDNA突变C4936 T（p.T156I）的ND 2的复合体I和同质mtDNA突变A9181 G（p.S219G）的复合体V的ATP酶6。利用胞质杂交技术，我们发现，在高糖培养基中，培养的细胞主要依赖于无氧糖酵解的能量，C4936 T突变抑制细胞生长的50%。耗氧量和活性氧的产生也分别减少了60%和75%。由于受试者也患有结膜癌，我们进一步测试了C4936 T突变是否与肿瘤形成相关。在锚定依赖性生长试验中，我们发现只有具有高水平C4936 T突变的细胞形成集落。相反，当细胞在半乳糖培养基中生长时，细胞被迫通过氧化磷酸化产生ATP，C4936 T突变保护细胞免于可能由A9181 G突变引起的凋亡。我们的研究结果表明，mtDNA突变引起的表型可能取决于营养物质的可用性。这种基因-环境相互作用可能导致mtDNA突变引起的发病机制和临床表型的复杂性。张，C.，Huang，V.H.，西蒙，M.，夏尔马湖K.，Fan，W.，哈斯河，华莱士，D. C.的方法，Bai，Y.，（1996年），美国，Huang，T.线粒体基因组的异质性突变对线粒体功能产生矛盾的影响。
Mitochondrial genome (mtDNA) mutation causes highly variable clinical features, and its pathogenesis is not fully understood. In this study, we analyzed the heteroplasmic mtDNA mutation C4936T (p.T156I) in ND2 of complex I and the homoplasmic mtDNA mutation A9181G (p.S219G) in ATPase 6 of complex V. Using cybrid technology, we found that in a high-glucose medium in which cultured cells mainly depend on anaerobic glycolysis for energy, the C4936T mutation inhibited cell growth by 50%. Oxygen consumption and reactive oxygen species production were also reduced by 60 and 75%, respectively. Because the subject also had conjunctiva carcinoma, we further tested whether the C4936T mutation was associated with tumor formation. In an anchorage-dependant growth test, we found that only cells with a high level of C4936T mutation formed colonies. In contrast, when the cells grew in a galactose medium in which cells were forced to generate ATP through oxidative phosphorylation, the C4936T mutation protected cells from apoptosis probably caused by the A9181G mutation. Our results suggest that the phenotype caused by mtDNA mutations may depend on the availability of the nutrients. This gene-environment interaction may contribute to the complexity of pathogenesis and clinical phenotypes caused by mtDNA mutation.—Zhang, C., Huang, V. H., Simon, M., Sharma, L. K., Fan, W., Haas, R., Wallace, D. C., Bai, Y., Huang, T. Heteroplasmic mutations of the mitochondrial genome cause paradoxical effects on mitochondrial functions.