PLA2G6 guards placental trophoblasts against ferroptotic injury
PLA2G6 guards placental trophoblasts against ferroptotic injury
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DOI：
10.1073/pnas.2009201117
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发表时间：
2020-11-03
影响因子：
11.1
通讯作者：
Sadovsky, Yoel
中科院分区：
文献类型：
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作者：
Beharier, Ofer;Tyurin, Vladimir A.;Sadovsky, Yoel
最近鉴定的铁凋亡细胞死亡的特征是过氧化氢花生四烯酸（C20：4）-或肾上腺素（C22：4）-磷脂酰乙醇胺（Hp-PE）的过度积累。硒依赖性谷胱甘肽过氧化物酶4（GPX 4）抑制铁凋亡，以组织特异性方式将不稳定的铁凋亡脂质氢过氧化物转化为无毒的脂质醇。虽然胎盘氧化应激和脂毒性是胎盘功能障碍的标志，但铁凋亡在胎盘功能障碍中的可能作用在很大程度上是未知的。我们发现，自发性早产与铁凋亡有关，GPX 4的抑制导致原代人滋养层细胞和小鼠妊娠期间的铁凋亡损伤。重要的是，我们发现了磷脂酶PLA 2G 6（PNPLA 9，iPLA 2 β）的作用，已知其将Hp-PE代谢为溶血-PE和氧化脂肪酸，在体外减轻由GPX 4抑制或体内缺氧/复氧损伤诱导的铁凋亡。总之，我们确定了人类和小鼠胎盘中的铁凋亡信号传导，确定了PLA 2G 6在减弱滋养层铁凋亡中的作用，并提供了对不明确的胎盘脂毒性的机制见解，这可能会激发PLA 2G 6靶向治疗策略。
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.