Mitochondrial elongation-mediated glucose metabolism reprogramming is essential for tumour cell survival during energy stress
Mitochondrial elongation-mediated glucose metabolism reprogramming is essential for tumour cell survival during energy stress
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DOI：
10.1038/onc.2017.98
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发表时间：
2017-08-24
期刊：
影响因子：
8
通讯作者：
Xing, J.
中科院分区：
文献类型：
--
作者：
Li, J.;Huang, Q.;Xing, J.
迄今为止，能量应激下肿瘤细胞存活的机制还不清楚。累积的证据开始揭示特定的线粒体形态通常与细胞的能量状态和存活有关。然而，线粒体在肿瘤细胞对能量应激的代谢适应中的功能作用仍有待阐明。在这项研究中，我们首先研究了肿瘤细胞中营养剥夺诱导的线粒体形态学变化及其潜在的分子机制。然后，我们系统地探讨了通过能量应激诱导的线粒体形态改变及其对肿瘤细胞存活的影响来进行葡萄糖代谢重编程。我们的研究结果表明，饥饿处理导致了显着的线粒体伸长，这主要是介导的DRP1（S637）磷酸化通过蛋白激酶A激活和随后的抑制线粒体转位的DRP1。我们进一步观察到，在能量应激条件下的肿瘤细胞表现出从糖酵解向氧化磷酸化的明显转变，这被突变体DRP1（S637A）的强制表达诱导的线粒体分裂的恢复所逆转。从机制上讲，能量应激诱导的线粒体延长促进嵴的形成和呼吸复合物的组装，以增强氧化磷酸化，这反过来又通过NAD（+）依赖性SIRT1激活对糖酵解表现出反馈抑制作用。此外，我们的数据表明，DRP1（S637）介导的能量应激下的线粒体延长是必要的肿瘤细胞的生存在体外和体内，并预测肝细胞癌患者的预后不良。总的来说，我们的研究表明，线粒体形态的重塑在肿瘤细胞通过重编程葡萄糖代谢适应能量应激中起着关键作用。
To date, mechanisms of tumour cell survival under energy stress are not well understood. Cumulative evidence is beginning to reveal that specific mitochondrial morphologies are often associated with energetic states and survival of cells. However, the functional roles of mitochondria in the metabolic adaptation of tumour cells to energy stress remain to be elucidated. In this study, we first investigated the changes in mitochondrial morphology induced by nutrition deprivation in tumour cells, and the underlying molecular mechanism. We then systematically explored glucose metabolism reprogramming by energy stress-induced alteration of mitochondrial morphology and its effect on tumour cell survival. Our results showed that starvation treatment resulted in a dramatic mitochondrial elongation, which was mainly mediated by DRP1(S637) phosphorylation through protein kinase A activation and subsequent suppression of mitochondrial translocation of DRP1. We further observed that tumour cells under an energy stress condition exhibited a clear shift from glycolysis towards oxidative phosphorylation, which was reversed by the recovery of mitochondrial fission induced by forced expression of mutant DRP1(S637A). Mechanistically, energy stress-induced mitochondrial elongation facilitated cristae formation and assembly of respiratory complexes to enhance oxidative phosphorylation, which in turn exhibited a feedback inhibitory effect on glycolysis through NAD(+)-dependent SIRT1 activation. In addition, our data indicated that DRP1(S637)-mediated mitochondrial elongation under energy stress was essential for tumour cell survival both in vitro and in vivo and predicted poor prognosis of hepatocellular carcinoma patients. Overall, our study demonstrates that remodelling of mitochondrial morphology plays a critical role in tumour cell adaptation to energy stress by reprogramming glucose metabolism.