Enhanced Glycolysis through Suppression of APC/C by mTOR Activity

In a groundbreaking study, a research team led by Matthias Peter has uncovered a critical and transient regulatory mechanism that links cell cycle progression with metabolic reprogramming during proliferation. The findings, published in Nature (2025), reveal the role of the Anaphase-Promoting Complex/Cyclosome (APC/C) and its co-activator CDH1 in coordinating cell cycle entry and metabolic reprogramming.

The central finding of the study is the transient accumulation of PFKFB3, a critical glycolytic activator, whose protein stability hinges on APC/C activity. This metabolic switch ensures that energy and biosynthetic needs are met precisely at the moment cells commit to division. The latest research demonstrates that APC/C inactivation is not merely a consequence of cell cycle progression, but a proactive switch to reshape the cell's metabolic framework.

The study shows that transient APC/C inactivation induced by mTOR-dependent phosphorylation of CDH1 orchestrates a metabolic switch to glycolysis. Transient APC/C inactivation allows for a sharp and timely burst in PFKFB3 levels, elevating glycolytic flux to meet the heightened biosynthetic and energetic demands during early cell cycle re-entry.

The implications of this discovery extend far beyond basic cell biology, offering novel insights into how disruptions in metabolic regulation can impact diseases characterized by uncontrolled proliferation, including cancer. The Warburg effect - a phenomenon where cancer cells exhibit elevated glycolysis even in oxygen-rich conditions - mirrors the metabolic switch observed in the study, suggesting potential links between APC/C regulation and cancer.

The expression of the CDH1(T129A) mutant, which enforces continuous APC/C activation, was found to profoundly inhibit CDK2 activation, a key driver of cell cycle progression. This finding further supports the role of APC/C in regulating cell cycle entry and proliferation.

The research employs genetic and pharmacological tools, live-cell imaging, and single-cell resolution to dissect temporal dynamics of cell cycle entry decisions. The work integrates nutrient sensing/metabolic regulation and cell cycle control into a coherent framework, explaining how proliferative cues translate into metabolic remodeling necessary for successful cell division.

This research prompts a reevaluation of APC/C's traditional perception solely as a mitotic regulator, positioning it as a critical integrator of metabolism and cell cycle machinery. The findings deepen our understanding of cellular proliferation and lay the groundwork for innovative therapeutic strategies targeting metabolic vulnerabilities linked to cell cycle dysregulation.

Image credits: AI Generated

References: Paul, D., Bolhuis, D.L., Yan, H. et al. Transient APC/C inactivation by mTOR boosts glycolysis during cell cycle entry. Nature (2025). https://doi.org/10.1038/s41586-025-09328-w