Mitochondrial Complex I decrease is responsible for bioenergetic dysfunction in K-ras transformed cells
Mitochondrial Complex I decrease is responsible for bioenergetic dysfunction in K-ras transformed cells
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DOI：
10.1016/j.bbabio.2009.11.006
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发表时间：
2010-02-01
影响因子：
4.3
通讯作者：
Lenaz, Giorgio
中科院分区：
文献类型：
--
作者：
Baracca, Alessandra;Chiaradonna, Ferdinando;Lenaz, Giorgio
许多癌细胞的特征是糖酵解速率高和有氧呼吸速率降低，其机制仍然是不清楚的。在这里，我们调查的下调氧化磷酸化（OXPHOS）在K-ras转化的小鼠成纤维细胞相比，对照对应物转录分析显示，在两个细胞系中的几个OXPHOS核基因的不同表达水平。特别地，在指数生长期，大多数编码复合物I的蛋白质的基因在转化细胞中以较低水平表达。一致地，在转化细胞中发现复合物I含量显著降低。此外，NAD依赖性呼吸和ATP合成的分析表明，复合物I活性在肿瘤细胞的线粒体中的强烈降低，这是通过酶氧化还原活性的直接测定证实的。在方差，琥珀酸依赖性呼吸和ATP合成没有显着影响。总之，我们的结果提供了新的见解，即在K-ras转化细胞中观察到的呼吸减少是特别由于复合物I活性降低。(C)2009 Elsevier B. V.保留所有权利。
Many cancer cells are characterized by high rate of glycolysis and reduced rate of aerobic respiration, whose mechanism is still elusive. Here we investigate the down-regulation of oxidative phosphorylation (OXPHOS) in K-ras transformed mouse fibroblasts as compared to a control counterpart Transcriptional analysis showed different expression levels of several OXPHOS nuclear genes in the two cell lines. In particular, during the exponential growth phase most genes encoding proteins of Complex I were expressed at lower levels in transformed cells. Consistently, a significant decrease of Complex I content was found in transformed cells. Moreover, analysis of NAD-dependent respiration and ATP synthesis indicated a strong decrease of Complex I activity in the mitochondria from neoplastic cells, that was confirmed by direct assay of the enzyme redox activity. At variance, succinate-dependent respiration and ATP synthesis were not significantly affected. Taken together, our results provide the new insight that the reduction of respiration observed in K-ras transformed cells is specifically due to a Complex I activity decrease. (C) 2009 Elsevier B.V. All rights reserved.