Transient APC/C inactivation by mTOR boosts glycolysis during cell cycle entry

Debasish Paul, Derek L. Bolhuis, Hualong Yan, Sudipto Das, Xia Xu, Christina C. Abbate, Lisa M. M. Jenkins, Michael J. Emanuele, Thorkell Andresson, Jing Huang, John G. Albeck, Nicholas G. Brown and Steven D. Cappell ()
Additional contact information
Debasish Paul: National Cancer Institute
Derek L. Bolhuis: University of North Carolina
Hualong Yan: National Cancer Institute
Sudipto Das: Frederick National Laboratory for Cancer Research
Xia Xu: Frederick National Laboratory for Cancer Research
Christina C. Abbate: University of California
Lisa M. M. Jenkins: National Cancer Institute
Michael J. Emanuele: University of North Carolina
Thorkell Andresson: Frederick National Laboratory for Cancer Research
Jing Huang: National Cancer Institute
John G. Albeck: University of California
Nicholas G. Brown: University of North Carolina
Steven D. Cappell: National Cancer Institute

Nature, 2025, vol. 646, issue 8083, 198-207

Abstract: Abstract Mammalian cells entering the cell cycle favour glycolysis to rapidly generate ATP and produce the biosynthetic intermediates that are required for rapid biomass accumulation1. Simultaneously, the ubiquitin-ligase anaphase-promoting complex/cyclosome and its coactivator CDH1 (APC/CCDH1) remains active, allowing origin licensing and blocking premature DNA replication. Paradoxically, glycolysis is reduced by APC/CCDH1 through the degradation of key glycolytic enzymes2, raising the question of how cells coordinate these mutually exclusive events to ensure proper cell division. Here we show that cells resolve this paradox by transiently inactivating the APC/C during cell cycle entry, which allows a transient metabolic shift favouring glycolysis. After mitogen stimulation, rapid mTOR-mediated phosphorylation of the APC/C adapter protein CDH1 at the amino terminus causes it to partially dissociate from the APC/C. This partial inactivation of the APC/C leads to the accumulation of PFKFB3, a rate-limiting enzyme for glycolysis, promoting a metabolic shift towards glycolysis. Delayed accumulation of phosphatase activity later removes CDH1 phosphorylation, restoring full APC/C activity, and shifting cells back to favouring oxidative phosphorylation. Thus, cells coordinate the simultaneous demands of cell cycle progression and metabolism through an incoherent feedforward loop, which transiently inhibits APC/C activity to generate a pulse of glycolysis that is required for mammalian cell cycle entry.

Date: 2025
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DOI: 10.1038/s41586-025-09328-w

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