Identification of essential sites of lipid peroxidation in ferroptosis

Ferroptosis, an iron-dependent form of cell death driven by lipid peroxidation, provides a potential treatment avenue for drug-resistant cancers and may play a role in the pathology of some degenerative diseases. Identifying the subcellular membranes essential for ferroptosis and the sequence of the...

Full description

Saved in:

Bibliographic Details
Published in	Nature chemical biology Vol. 19; no. 6; pp. 719 - 730
Main Authors	von Krusenstiern, A. Nikolai, Robson, Ryan N., Qian, Naixin, Qiu, Baiyu, Hu, Fanghao, Reznik, Eduard, Smith, Nailah, Zandkarimi, Fereshteh, Estes, Verna M., Dupont, Marcel, Hirschhorn, Tal, Shchepinov, Mikhail S., Min, Wei, Woerpel, K. A., Stockwell, Brent R.
Format	Journal Article
Language	English
Published	New York Nature Publishing Group US 01.06.2023 Nature Publishing Group
Subjects	631/80/82 631/92/96 Apoptosis Biochemical Engineering Biochemistry Bioorganic Chemistry Cell Biology Cell Death Cell Membrane - metabolism Chemistry Chemistry and Materials Science Chemistry/Food Science Drug resistance Endoplasmic reticulum Ferroptosis Iron - metabolism Lipid peroxidation Lipid Peroxidation - physiology Lipids Membranes Peroxidation Raman spectra Therapeutic applications
Online Access	Get full text
ISSN	1552-4450 1552-4469 1552-4469
DOI	10.1038/s41589-022-01249-3

Cover

More Information
Summary:	Ferroptosis, an iron-dependent form of cell death driven by lipid peroxidation, provides a potential treatment avenue for drug-resistant cancers and may play a role in the pathology of some degenerative diseases. Identifying the subcellular membranes essential for ferroptosis and the sequence of their peroxidation will illuminate drug discovery strategies and ferroptosis-relevant disease mechanisms. In this study, we employed fluorescence and stimulated Raman scattering imaging to examine the structure–activity–distribution relationship of ferroptosis-modulating compounds. We found that, although lipid peroxidation in various subcellular membranes can induce ferroptosis, the endoplasmic reticulum (ER) membrane is a key site of lipid peroxidation. Our results suggest an ordered progression model of membrane peroxidation during ferroptosis that accumulates initially in the ER membrane and later in the plasma membrane. Thus, the design of ER-targeted inhibitors and inducers of ferroptosis may be used to optimally control the dynamics of lipid peroxidation in cells undergoing ferroptosis. Ferroptosis is a lipid-peroxide-driven cell death with promising therapeutic applications. Although peroxidation of various subcellular membranes can initiate ferroptosis, the authors found that the endoplasmic reticulum is an essential site.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Author Contributions Statement A.N.K. performed all biochemical experiments with D-PUFAs. A.N.K. prepared D-PUFA samples for imaging, and F.H. and N.Q. performed SRS imaging. Relative quantification of D-PUFAs in membranes by SRS was done by N.Q. High-resolution SRS imaging samples for mitochondrial evaluation were prepared by T.H. and imaged by N.Q. Quantification of PUFA incorporation into knockdown cell lines by SRS imaging was done by F.H. A.N.K. and F.Z. designed the lipidomics experiment and prepared samples, and F.Z. performed LCMS and analysis. R.N.R. and V.M.E. synthesized the FINO2 analogs. A.N.K. performed all biochemical and confocal fluorescence experiments of FINO2 analogs. SRS imaging samples of FINO2-2 were prepared by A.N.K. and imaged by F.H. and N.Q. C11 BODIPY imaging and quantification was performed by A.N.K. and B.Q. Membrane fractionation and relative PUFA quantification by mass spectrometry was performed by E.R. and N.S. Immunofluorescence staining of ACSL4 was performed by B.Q., and western blot quantification of ACSL4 in membrane fractions was done by E.R. and N.S. BQR viability and C11 BODIPY experiments were performed by B.Q. Knockdowns of lipid processing genes and experiments with lipid synthesis inhibitors were performed by A.N.K. Plasmid design was performed by A.N.K., and cloning was done by A.N.K. and M.D. ER-phagy experiments including knockdowns, overexpressions, and evaluation were performed by A.N.K. and M.D. Experimental design and execution was overseen by W.M., K.A.W., and B.R.S. D-PUFAs and consultation were provided by M.S.S. A.N.K. drafted the manuscript with contributions and revisions by B.R.S., W.M., K.A.W., R.N.R., F.H., F.Z., N.Q., and M.S.S.
ISSN:	1552-4450 1552-4469 1552-4469
DOI:	10.1038/s41589-022-01249-3