Mechanical confinement induces ferroptosis through mitochondrial dysfunction.

Cells in highly crowded environments are exposed to fluctuating mechanical forces. While cells can activate the cortical migration machinery to escape from undesirable compressive stress, the consequence to less motile cells and of prolonged extensive confinement is yet to be uncovered. Here, we demonstrate that nuclear deformation generated by axial confinement triggers a specific form of regulated cell death - ferroptosis. We show that axial confinement is sensed by the nucleus and results in Drp1-dependent mitochondrial fragmentation and mitochondrial ROS accumulation. Meanwhile, we detect cPLA2 translocation to mitochondria. These mitochondrial ROS accumulation and arachidonic acid production concertedly lead to lipid peroxidation and evoke ferroptosis. Interestingly, we find in osteoarthritis, a disease intimately associated with mechanical overloading and inflammation, characteristics of confinement-induced ferroptosis including mitochondrial localization of cPLA2 and high ROS. Together, our findings unveil a pivotal role of cell nucleus and mitochondria in linking mechanical confinement with cell death, highlighting the orchestration of Drp1 and cPLA2 in confinement-induced ferroptosis.