Universität zu Köln

Röck, Bernhard (2025). Ferroptosis spreads to neighboring cells via plasma membrane contacts. PhD thesis, Universität zu Köln.

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Abstract

Ferroptosis is a regulated cell death modality dependent on iron and characterized by excessive lipid peroxidation, which is affiliated with the spread of necrosis in diseased tissue by undetermined mechanisms. Through the exploitation of the temporal and spatial properties of a novel optogenetic approach that triggers ferroptosis by degrading the anti-ferroptotic enzyme GPX4, we showed that lipid peroxidation and ferroptotic cell death can spread to neighboring cells via their closely connected plasma membranes. We found that ferroptosis propagation depends on the proximity of cells that can be entirely halted by either disrupting α-catenin-dependent intercellular junctions or chelating extracellular iron. Strikingly, linking cells through a lipid bilayer or enhancing the contact area between adjacent cells facilitates ferroptosis spread. We uncovered that iron-dependent lipid peroxidation could be transmitted between directly contacting liposomes, revealing the involvement of a physicochemical mechanism. Our findings indicate that iron-dependent lipid peroxidation propagation occurs across adjacent plasma membranes of neighboring cells, contributing to ferroptotic cell death and subsequent necrosis spread in diseased tissues.