Molecular crowding defines a common origin for the Warburg effect in proliferating cells and the lactate threshold in muscle physiology.
Molecular crowding defines a common origin for the Warburg effect in proliferating cells and the lactate threshold in muscle physiology.
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DOI：
10.1371/journal.pone.0019538
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发表时间：
2011-04-29
期刊：
影响因子：
3.7
通讯作者：
Oltvai ZN
中科院分区：
文献类型：
--
作者：
Vazquez A;Oltvai ZN
有氧糖酵解是一种看似浪费的ATP生产模式，在快速增殖的哺乳动物细胞和高度活跃的收缩肌肉中都可以看到，但在这些广泛不同的系统中是否存在共同的起源尚不清楚。为了研究这个问题，在这里，我们开发了一个模型，结合了代谢酶和线粒体的溶剂容量约束，占其占用的体积密度，同时假设葡萄糖和/或脂肪酸的利用率的人类中央代谢。该模型表明，有氧糖酵解的激活在快速增殖的细胞和重度收缩的肌肉中均高于阈值代谢率，因为它提供比线粒体氧化磷酸化更高的单位体积密度ATP产率。在肌肉生理学的情况下，该模型还预测，在乳酸转换之前，脂肪酸氧化增加，达到最大值，然后随着葡萄糖利用率的增加而降低到零，与经验证据一致。这些结果进一步证实了一个更大规模的模型，包括生物合成的主要细胞生物质成分。更大规模的模型还预测，在增殖细胞中，乳酸开关伴随着β-氨基分解的激活，这是瓦尔堡效应的另一个显著特征。总之，细胞内的分子拥挤是一个基本的限制细胞代谢的快速增殖和非增殖细胞与高代谢的需求。代谢通量平衡模型的这一约束的添加可以解释在稳态条件下哺乳动物细胞代谢的几个观察结果。
Aerobic glycolysis is a seemingly wasteful mode of ATP production that is seen both in rapidly proliferating mammalian cells and highly active contracting muscles, but whether there is a common origin for its presence in these widely different systems is unknown. To study this issue, here we develop a model of human central metabolism that incorporates a solvent capacity constraint of metabolic enzymes and mitochondria, accounting for their occupied volume densities, while assuming glucose and/or fatty acid utilization. The model demonstrates that activation of aerobic glycolysis is favored above a threshold metabolic rate in both rapidly proliferating cells and heavily contracting muscles, because it provides higher ATP yield per volume density than mitochondrial oxidative phosphorylation. In the case of muscle physiology, the model also predicts that before the lactate switch, fatty acid oxidation increases, reaches a maximum, and then decreases to zero with concomitant increase in glucose utilization, in agreement with the empirical evidence. These results are further corroborated by a larger scale model, including biosynthesis of major cell biomass components. The larger scale model also predicts that in proliferating cells the lactate switch is accompanied by activation of glutaminolysis, another distinctive feature of the Warburg effect. In conclusion, intracellular molecular crowding is a fundamental constraint for cell metabolism in both rapidly proliferating- and non-proliferating cells with high metabolic demand. Addition of this constraint to metabolic flux balance models can explain several observations of mammalian cell metabolism under steady state conditions.
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影响因子：
5.5
作者：
Blomstrand, E;Radegran, G;Saltin, B
通讯作者：
Saltin, B
DOI：
10.1098/rspb.1924.0048
发表时间：
1924-12-01
期刊：
PROCEEDINGS OF THE ROYAL SOCIETY OF LONDON SERIES B-CONTAINING PAPERS OF A BIOLOGICAL CHARACTER
影响因子：
--
作者：
Hill, AV;Long, CNH;Lupton, H
通讯作者：
Lupton, H
影响因子：
3.3
作者：
Hogan, MC
通讯作者：
Hogan, MC
影响因子：
3
作者：
Schellenberger J;Park JO;Conrad TM;Palsson BØ
通讯作者：
Palsson BØ
影响因子：
5.5
作者：
Conley, KE;Kushmerick, MJ;Jubrias, SA
通讯作者：
Jubrias, SA