Mutation of succinate dehydrogenase subunit C results in increased O2•-, oxidative stress, and genomic instability
Mutation of succinate dehydrogenase subunit C results in increased O2•-, oxidative stress, and genomic instability
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DOI：
10.1158/0008-5472.can-06-0833
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发表时间：
2006-08-01
期刊：
影响因子：
11.2
通讯作者：
Spitz, Douglas R.
中科院分区：
文献类型：
--
作者：
Slane, Benjamin G.;Aykin-Burns, Nukhet;Spitz, Douglas R.
编码琥珀酸脱氢酶（SDH）亚基的基因突变被认为是导致癌症和衰老的原因，但其机制尚不清楚。相对于亲本B1细胞，表达SDH亚基C（SDHC; B 9）突变的成纤维细胞显示二氢乙啶和二氯二氢荧光素（CDCFH 2）氧化增加3倍，表明O-2（中心点-）和H2 O2的稳态水平增加，谷胱甘肽/谷胱甘肽二硫化物增加（表明氧化应激），以及超氧化物歧化酶活性增加。B 9细胞还显示出与癌细胞相关的特征，包括非整倍性、葡萄糖消耗增加以及对葡萄糖剥夺诱导的细胞毒性的敏感性。野生型（WT）人SDHC在B 9细胞中的表达引起促氧化剂产生、葡萄糖消耗、对葡萄糖剥夺诱导的细胞毒性的敏感性和非整倍性以恢复到WT表型。这些数据表明，SDHC突变导致O-2（中心点-）产生增加，代谢氧化应激和基因组不稳定性，编码线粒体电子传递链蛋白的基因突变可能导致与癌细胞相关的表型变化。这些结果也允许推测，DNA损伤的基因编码的电子传递链蛋白可能会导致一个“突变表型”，通过增加稳态水平的O-2（中心点-）和H2 O2。
Mutations in genes coding for succinate dehydrogenase (SDH) subunits are believed to contribute to cancer and aging, but the mechanism for this is unclear. Hamster fibroblasts expressing a mutation in SDH subunit C (SDHC; B9) showed 3-fold increases in dihydroethidine and dichlorodihydrofluorescein (CDCFH2) oxidation indicative of increased steady-state levels of O-2(center dot-) and H2O2, increases in glutathione/glutathione disulfide (indicative of oxidative stress), as well as increases in superoxide dismutase activity, relative to parental B1 cells. B9 cells also showed characteristics associated with cancer cells, including aneuploidy, increases in glucose consumption, and sensitivity to glucose deprivation-induced cytotoxicity. Expression of wild-type (WT) human SDHC in B9 cells caused prooxidant production, glucose consumption, sensitivity to glucose deprivation-induced cytotoxicity, and aneuploidy to revert to the WT phenotype. These data show that SDHC mutations cause increased O-2(center dot-) production, metabolic oxidative stress, and genomic instability and that mutations in genes coding for mitochondrial electron transport chain proteins can contribute to phenotypic changes associated with cancer cells. These results also allow for the speculation that DNA damage to genes coding for electron transport chain proteins could result in a "mutator phenotype" by increasing steady-state levels of O-2(center dot-) and H2O2.