Longevity & AgingPhysical Compression Kills Cells via Ferroptosis Triggered by Mitochondrial Collapse
When cells are squeezed into tight spaces, the nucleus deforms and triggers a cascade ending in ferroptosis—a regulated, iron-dependent form of cell death. Scientists used microfabricated PDMS pillars and microsphere spacers to confine HeLa and HT1080 cells to 3 µm height, observing that confinement—not hypoxia or nutrient deprivation—caused death. The nucleus acted as a mechanosensor, activating Drp1-driven mitochondrial fragmentation, mitochondrial ROS accumulation, and translocation of cPLA2 to mitochondria. cPLA2 generated arachidonic acid, which combined with mitochondrial ROS to drive lipid peroxidation and ferroptosis. Ferroptosis inhibitors (Ferrostatin-1, Liproxstatin-1, DFOM) significantly rescued cells. Osteoarthritis patient samples showed matching signatures—mitochondrial cPLA2 localization and elevated ROS—linking mechanical overload in disease to this death pathway.
