Skp2 dictates cell cycle-dependent metabolic oscillation between glycolysis and TCA cycle

Jing Liu, Yunhua Peng, Le Shi, Lixin Wan, Hiroyuki Inuzuka, Jiangang Long, Jianping Guo, Jinfang Zhang, Min Yuan, Shuangxi Zhang, Xun Wang, Jing Gao, Xiangpeng Dai, Shozo Furumoto, Lijun Jia, Pier Paolo Pandolfi, John M. Asara, William G. Kaelin, Jiankang Liu, Wenyi Wei

Research output: Contribution to journalArticlepeer-review

46 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)80-93
Number of pages14
JournalCell Research
Issue number1
Publication statusPublished - 2021 Jan


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