Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Instituto de Investigación Hospital 12 de Octubre, Spain.
Biochem J. 2012 Jun 1;444(2):249-59. doi: 10.1042/BJ20111829.
Reprogramming of energetic metabolism is a phenotypic trait of cancer in which mitochondrial dysfunction represents a key event in tumour progression. In the present study, we show that the acquisition of the tumour-promoting phenotype in colon cancer HCT116 cells treated with oligomycin to inhibit ATP synthase is exerted by repression of the synthesis of nuclear-encoded mitochondrial proteins in a process that is regulated at the level of translation. Remarkably, the synthesis of glycolytic proteins is not affected in this situation. Changes in translational control of mitochondrial proteins are signalled by the activation of AMPK (AMP-activated protein kinase) and the GCN2 (general control non-derepressible 2) kinase, leading also to the activation of autophagy. Changes in the bioenergetic function of mitochondria are mimicked by the activation of AMPK and the silencing of ATF4 (activating transcription factor 4). These findings emphasize the relevance of translational control for normal mitochondrial function and for the progression of cancer. Moreover, they demonstrate that glycolysis and oxidative phosphorylation are controlled at different levels of gene expression, offering the cell a mechanistic safeguard strategy for metabolic adaptation under stressful conditions.
能量代谢的重编程是癌症的表型特征，其中线粒体功能障碍代表肿瘤进展中的一个关键事件。在本研究中，我们表明，在用寡霉素抑制 ATP 合酶处理的结肠癌细胞 HCT116 中获得促进肿瘤的表型是通过核编码的线粒体蛋白合成的抑制来实现的，这一过程在翻译水平受到调节。值得注意的是，在这种情况下，糖酵解蛋白的合成不受影响。线粒体蛋白翻译控制的变化由 AMPK（AMP 激活的蛋白激酶）和 GCN2（一般控制不可抑制 2）激酶的激活所发出信号，这也导致自噬的激活。线粒体生物能量功能的变化通过 AMPK 的激活和 ATF4（激活转录因子 4）的沉默来模拟。这些发现强调了翻译控制对正常线粒体功能和癌症进展的相关性。此外，它们表明糖酵解和氧化磷酸化在基因表达的不同水平上受到控制，为细胞在应激条件下提供了一种代谢适应的机制性保障策略。
