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

Svetlana N SamovichKarolina Mikulska-RuminskaHaider H DarYulia Y TyurinaVladimir A TyurinAustin B SouryavongAlexander A KapralovAndrew A AmoscatoOfer BeharierS Ananth KarumanchiClaudette M St CroixXin YangTheodore R HolmanAndrew P VanDemarkYoel SadovskyRama K MallampalliSally E WentzelWei GuYuri L BunimovichIvet BaharValerian E KaganHülya Bayır
Published in: Angewandte Chemie (International ed. in English) (2024)
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.
Keyphrases
  • cell death
  • cell cycle arrest
  • biofilm formation
  • fatty acid
  • induced apoptosis
  • pseudomonas aeruginosa
  • transcription factor
  • candida albicans
  • cystic fibrosis
  • single cell
  • oxidative stress
  • endoplasmic reticulum stress