PLA2G6 guards placental trophoblasts against ferroptotic injury

被引:142
作者
Beharier, Ofer [1 ]
Tyurin, Vladimir A. [2 ,3 ]
Goff, Julie P. [1 ]
Guerrero-Santoro, Jennifer [1 ]
Kajiwara, Kazuhiro [1 ]
Chu, Tianjiao [1 ]
Tyurina, Yulia Y. [1 ]
St Croix, Claudette M. [4 ]
Wallace, Callen T. [4 ]
Parry, Samuel [5 ]
Parks, W. Tony [6 ]
Kagan, Valerian E. [2 ,3 ]
Sadovsky, Yoel [1 ,7 ]
机构
[1] Univ Pittsburgh, Magee Womens Res Inst, Dept Obstet Gynecol & Reprod Sci, Pittsburgh, PA 15213 USA
[2] Univ Pittsburgh, Dept Environm & Occupat Hlth, Pittsburgh, PA 15261 USA
[3] Univ Pittsburgh, Ctr Free Rad & Antioxidant Hlth, Pittsburgh, PA 15261 USA
[4] Univ Pittsburgh, Dept Cell Biol, Pittsburgh, PA 15261 USA
[5] Univ Penn, Dept Obstet & Gynecol, Sch Med, Philadelphia, PA 19104 USA
[6] Univ Toronto, Mt Sinai Hosp, Dept Lab Med & Pathobiol, Toronto, ON M5G 1X8, Canada
[7] Univ Pittsburgh, Dept Microbiol & Mol Genet, Pittsburgh, PA 15219 USA
关键词
ferroptosis; PLA2G6; GPX4; placenta; trophoblast; ARACHIDONIC-ACID RELEASE; LIPID-PEROXIDATION; PHOSPHOLIPASE A(2); OXIDATIVE STRESS; CELL-DEATH; SIGNALING PATHWAYS; HYPOXIA; DIFFERENTIATION; PURIFICATION; IPLA(2)GAMMA;
D O I
10.1073/pnas.2009201117
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The recently identified ferroptotic cell death is characterized by excessive accumulation of hydroperoxy-arachidonoyl (C20:4)- or adrenoyl (C22:4)- phosphatidylethanolamine (Hp-PE). The selenium-dependent glutathione peroxidase 4 (GPX4) inhibits ferroptosis, converting unstable ferroptotic lipid hydroperoxides to nontoxic lipid alcohols in a tissue-specificmanner. While placental oxidative stress and lipotoxicity are hallmarks of placental dysfunction, the possible role of ferroptosis in placental dysfunction is largely unknown. We found that spontaneous preterm birth is associated with ferroptosis and that inhibition of GPX4 causes ferroptotic injury in primary human trophoblasts and during mouse pregnancy. Importantly, we uncovered a role for the phospholipase PLA2G6 (PNPLA9, iPLA2beta), known to metabolize Hp-PE to lyso-PE and oxidized fatty acid, in mitigating ferroptosis induced by GPX4 inhibition in vitro or by hypoxia/reoxygenation injury in vivo. Together, we identified ferroptosis signaling in the human and mouse placenta, established a role for PLA2G6 in attenuating trophoblastic ferroptosis, and provided mechanistic insights into the ill-defined placental lipotoxicity that may inspire PLA2G6-targeted therapeutic strategies.
引用
收藏
页码:27319 / 27328
页数:10
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