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

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, depletingSKP2abolishes 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.

Automated summary

Glucose metabolism in mammalian cells varies with different cell cycle phases, with TCA cycle being predominantly used in G1 phase and glycolysis favored in S phase. The coupling of cell cycle with metabolism is largely achieved through Skp2-mediated timely destruction of key TCA cycle enzymes IDH1/2. This mechanistic link between aberrant cell cycle and glycolysis addiction provides insights into the coupling of metabolic fluctuation with periodic cell cycle in mammalian cells.