Iron-Induced Lipid Oxidation Alters Membrane Mechanics Favoring Permeabilization

Overview

Journal Langmuir

Publisher American Chemical Society

Specialty Chemistry

Date 2024 Nov 12

PMID 39532309

Authors

Sara Lotfipour Nasudivar

Lohans Pedrera

Ana J Garcia-Saez

Affiliations

Soon will be listed here.

Abstract

Ferroptosis is a form of regulated necrosis characterized by the iron-dependent accumulation of lipid peroxides in cell membranes. However, how lipid oxidation via iron-mediated Fenton reactions affects the biophysical properties of cellular membranes and how these changes contribute to the opening of plasma membrane pores are major questions in the field. Here, we characterized the dynamics of membrane alterations during lipid oxidation induced onsite by Fenton reactions in chemically defined model membrane systems. We find that lipid vesicle permeabilization kinetically correlates with the appearance of malondialdehyde (MDA), a product of lipid oxidation. Iron-induced lipid oxidation also alters the lateral organization of supported lipid bilayers (SLBs) with lipid phase coexistence in a time-dependent manner, reducing the lipid phase mismatch and the circularity of liquid ordered domains, which indicates a decrease in line tension at the phase boundaries. Further analysis of oxidized SLBs by force spectroscopy reveals a significant decrease in the average membrane breakthrough force upon oxidation, resulting from changes in lipid bilayer organization that make it more susceptible to permeabilization. Our findings suggest that lipid oxidation via iron-mediated Fenton-like reactions induces strong changes in membrane lipid interactions and mechanical properties leading to reduced line tension in the permeabilized state of the bilayer, which promotes membrane pore formation.

References

Shah R, Shchepinov M, Pratt D . Resolving the Role of Lipoxygenases in the Initiation and Execution of Ferroptosis. ACS Cent Sci. 2018; 4(3):387-396. PMC: 5879472. DOI: 10.1021/acscentsci.7b00589. View

Almeida P . Thermodynamics of lipid interactions in complex bilayers. Biochim Biophys Acta. 2008; 1788(1):72-85. DOI: 10.1016/j.bbamem.2008.08.007. View

Proneth B, Conrad M . Ferroptosis and necroinflammation, a yet poorly explored link. Cell Death Differ. 2018; 26(1):14-24. PMC: 6294786. DOI: 10.1038/s41418-018-0173-9. View

Mertins O, Bacellar I, Thalmann F, Marques C, Baptista M, Itri R . Physical damage on giant vesicles membrane as a result of methylene blue photoirradiation. Biophys J. 2014; 106(1):162-71. PMC: 3907217. DOI: 10.1016/j.bpj.2013.11.4457. View

Ytzhak S, Weitman H, Ehrenberg B . The effect of lipid composition on the permeability of fluorescent markers from photosensitized membranes. Photochem Photobiol. 2013; 89(3):619-24. DOI: 10.1111/php.12035. View

Davies S, Guo L . Lipid peroxidation generates biologically active phospholipids including oxidatively N-modified phospholipids. Chem Phys Lipids. 2014; 181:1-33. PMC: 4075969. DOI: 10.1016/j.chemphyslip.2014.03.002. View

Brameshuber M, Sevcsik E, Rossboth B, Manner C, Deigner H, Peksel B . Oxidized Phospholipids Inhibit the Formation of Cholesterol-Dependent Plasma Membrane Nanoplatforms. Biophys J. 2016; 110(1):205-13. PMC: 4805878. DOI: 10.1016/j.bpj.2015.11.018. View

Boonnoy P, Jarerattanachat V, Karttunen M, Wong-Ekkabut J . Bilayer Deformation, Pores, and Micellation Induced by Oxidized Lipids. J Phys Chem Lett. 2015; 6(24):4884-8. DOI: 10.1021/acs.jpclett.5b02405. View

Riske K, Sudbrack T, Archilha N, Uchoa A, Schroder A, Marques C . Giant vesicles under oxidative stress induced by a membrane-anchored photosensitizer. Biophys J. 2009; 97(5):1362-70. PMC: 2749755. DOI: 10.1016/j.bpj.2009.06.023. View

10.

Runas K, Malmstadt N . Low levels of lipid oxidation radically increase the passive permeability of lipid bilayers. Soft Matter. 2014; 11(3):499-505. PMC: 4477792. DOI: 10.1039/c4sm01478b. View

11.

Megli F, Russo L . Different oxidized phospholipid molecules unequally affect bilayer packing. Biochim Biophys Acta. 2007; 1778(1):143-52. DOI: 10.1016/j.bbamem.2007.09.014. View

12.

Khandelia H, Loubet B, Olzynska A, Jurkiewicz P, Hof M . Pairing of cholesterol with oxidized phospholipid species in lipid bilayers. Soft Matter. 2014; 10(4):639-47. DOI: 10.1039/c3sm52310a. View

13.

Tero R, Yamashita R, Hashizume H, Suda Y, Takikawa H, Hori M . Nanopore formation process in artificial cell membrane induced by plasma-generated reactive oxygen species. Arch Biochem Biophys. 2016; 605:26-33. DOI: 10.1016/j.abb.2016.05.014. View

14.

Goni F, Alonso A, Bagatolli L, Brown R, Marsh D, Prieto M . Phase diagrams of lipid mixtures relevant to the study of membrane rafts. Biochim Biophys Acta. 2008; 1781(11-12):665-84. PMC: 2600854. DOI: 10.1016/j.bbalip.2008.09.002. View

15.

Shahidi F, Zhong Y . Lipid oxidation and improving the oxidative stability. Chem Soc Rev. 2010; 39(11):4067-79. DOI: 10.1039/b922183m. View

16.

Siani P, de Souza R, Dias L, Itri R, Khandelia H . An overview of molecular dynamics simulations of oxidized lipid systems, with a comparison of ELBA and MARTINI force fields for coarse grained lipid simulations. Biochim Biophys Acta. 2016; 1858(10):2498-2511. DOI: 10.1016/j.bbamem.2016.03.031. View

17.

Jacob R, Mason R . Lipid peroxidation induces cholesterol domain formation in model membranes. J Biol Chem. 2005; 280(47):39380-7. DOI: 10.1074/jbc.M507587200. View

18.

Weber G, Charitat T, Baptista M, Uchoa A, Pavani C, Junqueira H . Lipid oxidation induces structural changes in biomimetic membranes. Soft Matter. 2014; 10(24):4241-7. DOI: 10.1039/c3sm52740a. View

19.

Doll S, Proneth B, Tyurina Y, Panzilius E, Kobayashi S, Ingold I . ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat Chem Biol. 2016; 13(1):91-98. PMC: 5610546. DOI: 10.1038/nchembio.2239. View

20.

Scanavachi G, Coutinho A, Fedorov A, Prieto M, Melo A, Itri R . Lipid Hydroperoxide Compromises the Membrane Structure Organization and Softens Bending Rigidity. Langmuir. 2021; 37(33):9952-9963. DOI: 10.1021/acs.langmuir.1c00830. View