Cell jamming transition is regulated by mitochondrial pyruvate transport and endocytosis [UK5099]

However, the cellular programs that drive these transitions and regulate collective behavior remain unclear. Using a controlled crowding model integrated with live-cell imaging and time-resolved multi-omics, we demonstrate that epithelial crowding triggers early metabolic changes characterized by increased mitochondrial pyruvate anaplerosis that precedes the jamming transition.

Functional inhibition of mitochondrial pyruvate import is sufficient to sustain collective cell motility, impeding jamming transition in crowded cells. This unjammed state is driven by enhanced cytoskeletal remodeling and requires RhoA-myosin II activity. Mechanistically, we show that elevated cytoskeletal signaling promotes macropinocytic uptake, which serves as a required feedback loop to maintain motility.