Whether glucose is predominantly metabolized via oxidative phosphorylation or glycolysis differs between quiescent versus proliferating cells, including tumor cells. However, how glucose metabolism is coordinated with cell cycle in mammalian cells remains elusive. Here, we report that mammalian cells predominantly utilize the tricarboxylic acid (TCA) cycle in G1 phase, but prefer glycolysis in S phase. Mechanistically, coupling cell cycle with metabolism is largely achieved by timely destruction of IDH1/2, key TCA cycle enzymes, in a Skp2-dependent manner. As such, depleting SKP2 abolishes cell cycle-dependent fluctuation of IDH1 protein abundance, leading to reduced glycolysis in S phase. Furthermore, elevated Skp2 abundance in prostate cancer cells destabilizes IDH1 to favor glycolysis and subsequent tumorigenesis. Therefore, our study reveals a mechanistic link between two cancer hallmarks, aberrant cell cycle and addiction to glycolysis, and provides the underlying mechanism for the coupling of metabolic fluctuation with periodic cell cycle in mammalian cells.

葡萄糖主要通过氧化磷酸化还是糖酵解代谢在静止细胞与增殖细胞（包括肿瘤细胞）之间有所不同。然而，哺乳动物细胞中葡萄糖代谢如何与细胞周期协调仍然难以捉摸。在这里，我们报告哺乳动物细胞在 G1 期主要利用三羧酸 (TCA) 循环，但在 S 期更喜欢糖酵解。从机制上讲，细胞周期与代谢的耦合主要是通过以 Skp2 依赖性方式及时破坏关键 TCA 循环酶 IDH1/2 来实现的。因此，耗尽SKP2消除细胞周期依赖的 IDH1 蛋白丰度波动，导致 S 期糖酵解减少。此外，前列腺癌细胞中升高的 Skp2 丰度使 IDH1 不稳定，有利于糖酵解和随后的肿瘤发生。因此，我们的研究揭示了两个癌症标志、异常细胞周期和糖酵解成瘾之间的机制联系，并为哺乳动物细胞中代谢波动与周期性细胞周期的耦合提供了潜在机制。