Lipid peroxidation increases membrane tension, Piezo1 gating, and cation permeability to execute ferroptosis

The ongoing metabolic and microbicidal pathways that support and protect cellular life generate potentially damaging reactive oxygen species (ROS). To counteract damage, cells express peroxidases, which are antioxidant enzymes that catalyze the reduction of oxidized biomolecules. Glutathione peroxidase 4 (GPX4) is the major hydroperoxidase specifically responsible for reducing lipid peroxides; this homeostatic mechanism is essential, and its inhibition causes a unique type of lytic cell death, ferroptosis. The mechanism(s) that lead to cell lysis in ferroptosis, however, are unclear. We report that the lipid peroxides formed during ferroptosis accumulate preferentially at the plasma membrane. Oxidation of surface membrane lipids increased tension on the plasma membrane and led to the activation of Piezo1 and TRP channels. Oxidized membranes thus became permeable to cations, ultimately leading to the gain of cellular Na+ and Ca2+ concomitant with loss of K+. These effects were reduced by deletion of Piezo1 and completely inhibited by blocking cation channel conductance with ruthenium red or 2-aminoethoxydiphenyl borate (2-APB). We also found that the oxidation of lipids depressed the activity of the Na+/K+-ATPase, exacerbating the dissipation of monovalent cation gradients. Preventing the changes in cation content attenuated ferroptosis. Altogether, our study establishes that increased membrane permeability to cations is a critical step in the execution of ferroptosis and identifies Piezo1, TRP channels, and the Na+/K+-ATPase as targets/effectors of this type of cell death. [Display omitted] •Lipid peroxidation increases plasma membrane tension and opens Piezo1•Piezo1 and TRP channels cooperatively promote ferroptosis by facilitating cation flux•Collapse of transmembrane cation gradients is magnified by Na+/K+-ATPase inhibition•Blocking sodium influx and/or potassium efflux suppresses ferroptosis Hirata et al. report that peroxidation of lipids increases plasma membrane tension and leads to the activation of mechanosensitive cation channels including Piezo1. Gating of these channels induces loss of K+ and gain of Na+ that promote ferroptosis. These findings demonstrate key roles of mechanosensing channels in the execution of ferroptosis.