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Abstract During morphogenesis, epithelial sheets undergo sequential folding to form three-dimensional organ structures. The resulting folds are often irreversible, ensuring that morphogenesis progresses in one direction. However, the mechanism establishing folding irreversibility remains unclear. Here, we report a mechanical property of epithelia that determines folding irreversibility. Using a mechanical assay, we demonstrate that long-term, high-curvature folding induces plastic, irreversible deformations, while short-term or low-curvature folding results in an elastic, shape-restoring response. This elastic-plastic transition occurs in a switch-like manner, with critical thresholds in folding curvature and duration. The transition is induced by F-actin accumulating into a bracket-like structure across the fold, triggered by cells sensing deformations via mechanosensitive signaling pathways, including TRPC 3/6-mediated calcium influx and ligand-independent EGFR activation. These results demonstrate that cells control epithelial folding irreversibility by detecting folding characteristics and adaptively switching between elastic and plastic responses, providing mechanical insight into the directionality of morphogenesis.

Our recent finding that free radical-induced formation of megamitochondria (MG) is followed by apoptosis has prompted us to investigate the correlation between the MG formation and the swelling of mitochondria which is considered to play a key role in early stages of apoptotic processes of the cell. Mitochondria of rat hepatocytes or RL-34 cells and those isolated from rat livers became enlarged up to three times in their diameters when they were exposed to a hypotonic medium. MG induced in the liver of rats placed on a 1% hydrazine-diet for 4—5 days or those induced in the liver of mice placed on a 2% chloramphenicol (CP)-diet for 9-10 days were endowed with a dense matrix whereas those fed with the toxic diets for longer periods of time became enlarged further and their matrix became extremely pale indicating that MG in the latter animals became swollen secondarily. The membrane potential, the content of cytochrome c and the rate of the generation of reactive oxygen species (ROS) of MG in the former animals were almost unchanged compared to those of mitochondria in control animals whereas those of MG in the latter animals became distinctly decreased. These results may suggest that free radical-induced MG possibly cause apoptosis via their secondary swelling. [ABSTRACT FROM AUTHOR]