Strikingly High Activity of 15-Lipoxygenase Towards Di-Polyunsaturated Arachidonoyl/Adrenoyl-Phosphatidylethanolamines Generates Peroxidation Signals of Ferroptotic Cell Death

Svetlana N Samovich; Karolina Mikulska-Ruminska; Haider H Dar; Yulia Y Tyurina; Vladimir A Tyurin; Austin B Souryavong; Alexander A Kapralov; Andrew A Amoscato; Ofer Beharier; S Ananth Karumanchi; Claudette M St Croix; Xin Yang; Theodore R Holman; Andrew P VanDemark; Yoel Sadovsky; Rama K Mallampalli; Sally E Wenzel; Wei Gu; Yuri L Bunimovich; Ivet Bahar; Valerian E Kagan; Hülya Bayir

doi:10.1002/anie.202314710

Strikingly High Activity of 15-Lipoxygenase Towards Di-Polyunsaturated Arachidonoyl/Adrenoyl-Phosphatidylethanolamines Generates Peroxidation Signals of Ferroptotic Cell Death

Angew Chem Int Ed Engl. 2024 Feb 26;63(9):e202314710. doi: 10.1002/anie.202314710. Epub 2024 Jan 17.

Authors

Svetlana N Samovich^{1

2}, Karolina Mikulska-Ruminska³, Haider H Dar², Yulia Y Tyurina², Vladimir A Tyurin², Austin B Souryavong², Alexander A Kapralov², Andrew A Amoscato², Ofer Beharier⁴, S Ananth Karumanchi⁵, Claudette M St Croix⁶, Xin Yang⁷, Theodore R Holman⁸, Andrew P VanDemark⁹, Yoel Sadovsky^{10

11}, Rama K Mallampalli¹², Sally E Wenzel², Wei Gu^{7

13}, Yuri L Bunimovich¹⁴, Ivet Bahar¹⁵, Valerian E Kagan^{2

16

17

18}, Hülya Bayir^{1

2

19}

Affiliations

¹ Department of Pediatrics, Division of Critical Care and Hospital Medicine, Redox Health Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY 10032, USA.
² Department of Environmental and Occupational Health, Center for Free Radical and Antioxidant Health, School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA.
³ Institute of Physics, Faculty of Physics, Astronomy and Informatics, Nicolaus Copernicus University in Torun, Torun, PL87100, Poland.
⁴ Obstetrics and Gynecology Division, Hadassah Medical Center, Faculty of Medicine of the Hebrew University of Jerusalem, 97654, Jerusalem, Israel.
⁵ Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
⁶ Department of Cell Biology, University of Pittsburgh, Pittsburgh, PA 15260, USA.
⁷ Institute for Cancer Genetics, Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
⁸ Department of Chemistry and Biochemistry, University of California Santa Cruz, Santa Cruz, CA 95064, USA.
⁹ Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15260, USA.
¹⁰ Magee-Womens Research Institute, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA 15213, USA.
¹¹ Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, PA 15219, USA.
¹² Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA.
¹³ Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
¹⁴ Department of Dermatology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
¹⁵ Laufer Center for Physical and Quantitative Biology, Laufer Center, Z-5252, Stony Brook University, Stony Brook, NY 11794, USA.
¹⁶ Department of Radiation Oncology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
¹⁷ Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA.
¹⁸ Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
¹⁹ Department of Critical Care Medicine, Safar Center for Resuscitation Research, Children's Neuroscience Institute, Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA 15213, USA.

PMID: 38230815
PMCID: PMC11068323 (available on 2025-02-26)
DOI: 10.1002/anie.202314710

Abstract

The vast majority of membrane phospholipids (PLs) include two asymmetrically positioned fatty acyls: oxidizable polyunsaturated fatty acids (PUFA) attached predominantly at the sn2 position, and non-oxidizable saturated/monounsaturated acids (SFA/MUFA) localized at the sn1 position. The peroxidation of PUFA-PLs, particularly sn2-arachidonoyl(AA)- and sn2-adrenoyl(AdA)-containing phosphatidylethanolamines (PE), has been associated with the execution of ferroptosis, a program of regulated cell death. There is a minor subpopulation (≈1-2 mol %) of doubly PUFA-acylated phospholipids (di-PUFA-PLs) whose role in ferroptosis remains enigmatic. Here we report that 15-lipoxygenase (15LOX) exhibits unexpectedly high pro-ferroptotic peroxidation activity towards di-PUFA-PEs. We revealed that peroxidation of several molecular species of di-PUFA-PEs occurred early in ferroptosis. Ferrostatin-1, a typical ferroptosis inhibitor, effectively prevented peroxidation of di-PUFA-PEs. Furthermore, co-incubation of cells with di-AA-PE and 15LOX produced PUFA-PE peroxidation and induced ferroptotic death. The decreased contents of di-PUFA-PEs in ACSL4 KO A375 cells was associated with lower levels of di-PUFA-PE peroxidation and enhanced resistance to ferroptosis. Thus, di-PUFA-PE species are newly identified phospholipid peroxidation substrates and regulators of ferroptosis, representing a promising therapeutic target for many diseases related to ferroptotic death.

Keywords: Cell Death; Mass Spectrometry; Oxidation; Phospholipids; Redox Lipidomics.

MeSH terms

Arachidonate 15-Lipoxygenase* / metabolism
Cell Death
Fatty Acids, Unsaturated / metabolism
Lipid Peroxidation
Phosphatidylethanolamines* / metabolism
Phospholipids / metabolism

Substances

Phosphatidylethanolamines
Arachidonate 15-Lipoxygenase
Phospholipids
Fatty Acids, Unsaturated

Abstract

MeSH terms

Substances

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