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

ABSTRACT: Mammalian cells entering the cell cycle favor glycolysis to rapidly generate ATP and produce the biosynthetic intermediates required for rapid biomass accumulation. Simultaneously, the ubiquitin ligase Anaphase-Promoting Complex/Cyclosome (APC/C)-Cdh1 remains active, allowing origin licensing and blocking premature DNA replication. Paradoxically, glycolysis is reduced by APC/CCdh1 through the degradation of key glycolytic enzymes, 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 favoring glycolysis. Upon mitogen stimulation, rapid mTOR-mediated phosphorylation of the APC/C adapter protein Cdh1 at the N-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 favoring 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.

INSTRUMENT(S): TSQ Quantiva

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Steven D. Cappell

PROVIDER: MSV000098175 | MassIVE | Thu Jun 12 12:30:00 BST 2025

REPOSITORIES: MassIVE

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