Separation of metabolic supply and demand: aerobic glycolysis as a normal physiological response to fluctuating energetic demands in the membrane.
Separation of metabolic supply and demand: aerobic glycolysis as a normal physiological response to fluctuating energetic demands in the membrane.
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DOI：
10.1186/2049-3002-2-7
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发表时间：
2014
影响因子：
5.9
通讯作者：
Gatenby RA
中科院分区：
文献类型：
--
作者：
Epstein T;Xu L;Gillies RJ;Gatenby RA
癌细胞和各种正常细胞表现出有氧糖酵解，即在正常氧气浓度下高速率的葡萄糖发酵，也被称为华宝效应。这种代谢被认为是异常的，因为它违反了细胞能量产生的标准模型，该模型假设葡萄糖代谢主要由氧浓度控制，因此，发酵糖酵解是缺氧时期的紧急后备。尽管对有氧糖酵解的起源提出了几种假说，但其在癌症和正常细胞中的生物学基础仍不清楚。我们在不同的正常和肿瘤细胞系中检测了膜活性扰动后葡萄糖代谢的变化，发现抑制或激活细胞膜上的泵分别导致糖酵解的减少或增加，而氧化磷酸化保持不变。计算模拟表明，这些发现与正常生理细胞代谢的新模型是一致的，在该模型中，有效的线粒体氧化磷酸化主要为大分子合成提供慢性能量需求，而糖酵解是主要支持膜泵的快速能量需求所必需的。一个特定的模型预测，糖酵解途径中产生ATP的酶的空间分布必须主要定位在细胞膜附近，而线粒体应该主要分布在核周。这些预测在实验上得到了证实。我们的结果表明，糖酵解代谢在常氧条件下通过响应快速的能量需求而发挥关键的生理功能，这种需求主要来自于膜运输活动，即使在有氧的情况下也是如此。这支持了一种新的葡萄糖代谢模型，其中糖酵解和氧化磷酸化提供不同类型的能量需求。细胞利用高效但反应缓慢的有氧代谢来满足基线、稳定的能量需求和糖酵解代谢，这种代谢效率低但可以迅速增加三磷酸腺苷(ATP)的产生，以满足主要来自膜运输活动的短期能量需求。在这个模型中，癌细胞的Warburg效应和有氧糖酵解的起源通常代表了一种正常的生理功能，这是因为细胞分裂、生长和迁移所需的膜转运蛋白活动的能量需求增加。
Cancer cells, and a variety of normal cells, exhibit aerobic glycolysis, high rates of glucose fermentation in the presence of normal oxygen concentrations, also known as the Warburg effect. This metabolism is considered abnormal because it violates the standard model of cellular energy production that assumes glucose metabolism is predominantly governed by oxygen concentrations and, therefore, fermentative glycolysis is an emergency back-up for periods of hypoxia. Though several hypotheses have been proposed for the origin of aerobic glycolysis, its biological basis in cancer and normal cells is still not well understood. We examined changes in glucose metabolism following perturbations in membrane activity in different normal and tumor cell lines and found that inhibition or activation of pumps on the cell membrane led to reduction or increase in glycolysis, respectively, while oxidative phosphorylation remained unchanged. Computational simulations demonstrated that these findings are consistent with a new model of normal physiological cellular metabolism in which efficient mitochondrial oxidative phosphorylation supplies chronic energy demand primarily for macromolecule synthesis and glycolysis is necessary to supply rapid energy demands primarily to support membrane pumps. A specific model prediction was that the spatial distribution of ATP-producing enzymes in the glycolytic pathway must be primarily localized adjacent to the cell membrane, while mitochondria should be predominantly peri-nuclear. The predictions were confirmed experimentally. Our results show that glycolytic metabolism serves a critical physiological function under normoxic conditions by responding to rapid energetic demand, mainly from membrane transport activities, even in the presence of oxygen. This supports a new model for glucose metabolism in which glycolysis and oxidative phosphorylation supply different types of energy demand. Cells use efficient but slow-responding aerobic metabolism to meet baseline, steady energy demand and glycolytic metabolism, which is inefficient but can rapidly increase adenosine triphosphate (ATP) production, to meet short-timescale energy demands, mainly from membrane transport activities. In this model, the origin of the Warburg effect in cancer cells and aerobic glycolysis in general represents a normal physiological function due to enhanced energy demand for membrane transporters activity required for cell division, growth, and migration.