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On the permeability of cell membranes subjected to lipid oxidation

The formation of transient hydrophilic pores in their membranes is a well-recognized mechanism of permeabilization of cells exposed to high-intensity electric pulses. However, the formation of such pores alone is not able to explain all aspects of the so-called electroporation phenomenon. In particular, the reasons for the sustained permeability of cell membranes, which persist long after the pulses’ application, remain elusive: The complete resealing of the cell membranes takes indeed orders of magnitude longer than the time of electropore closure as reported from molecular modelling investigations. A possible alternative mechanism to explain the observed long-lived permeability of cell membranes, lipid peroxidation, has been previously suggested but the theoretical investigations of membrane lesions, containing excess amounts of hydroperoxides, have shown that the conductivities of such lesions were not high enough to reasonably explain the entire range of experimental measurements. Here, we expand on these studies and investigate the permeability of cell membrane lesions that underwent secondary oxidation. Molecular dynamics simulations and free energy calculations on lipid bilayer in different states show that such lesions provide a better model for post-pulsed permeable and conductive electropermeabilized cells. Furthermore, the results of the article are further discussed in the context of a type of cell death – ferroptosis, which is associated with lipid oxidation. Highlights The contribution of secondary lipids’ oxidation to the permeabilization of model membranes is quantitatively assessed Small patches of secondary lipids’ oxidation cause the formation of long-lived pores in lipid bilayers. The cholesterol content of membranes enhances the lifetime of the formed pores. A single pore accounts for the measured post-pulse electropermeabilization of cells. The diffusion of the secondary oxidation lipids leads, even after pores closure to the permeability of the lipid membrane. Lipid oxidation is discussed in terms of ferroptosis.