PLA2G6 guards placental trophoblasts against ferroptotic injury

Abstract

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-specific manner. 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.

Phospholipid peroxidation fuels ExoU phospholipase-dependent cell necrosis and supportsPseudomonas aeruginosa-driven pathology

“…Specifically, ferroptosis is thought to be a constitutively activated form of cell death that is kept under control through the activity of endogenous regulators of lipid peroxidation such as GPX4, FSP1-mediated coQ10 production, α-tocopherol (vitamin E). In addition, the host cellular calcium (Ca 2+ )-independent PLA2γ, the peroriredoxin Prdx6 PLA2 or the PLA2G6 (Ca 2+ -independent PLA2β) can cleave and remove preferentially peroxidised phospholipids, hence contributing to phospholipid peroxide detoxification (Beharier et al, 2020; Kinsey et al, 2008; van Kuijk et al, 1987; Lu et al, 2019; Miyamoto et al, 2003; Sevanian et al, 1988; Yedgar et al, 2006). The activity of those phospholipases is tightly regulated by various cellular systems (e.g.…”

“…These results suggest that, instead of promoting pathological lipid peroxidation, ExoU might actually use cellular lipid peroxidation to promote cell necrosis. To this regard, various host phospholipase A2 enzymes have been described to specifically cleave and remove peroxidised phospholipids from membranes (Beatty et al; Beharier et al, 2020; Lu et al, 2019). To address this hypothesis, we performed a redox phospholipidomic approach to determine if ExoU could interfere with the endogenous levels of peroxidised phospholipids.…”

Lipid Metabolism and Ferroptosis

“…However, the detailed mechanism how iPLA 2 remodels membrane phospholipids to suppress ferroptosis is unclear. Another study directly focused on the ability of iPLA 2 β (PLA2G6) to hydrolyze Hp-PE species, which are the main driver of ferroptosis [84]. The authors directly analyze the abundance of 15-HpETE-PE and found that 15-HpETE-PE are upregulated in PLA2G6 KO cells compared to control cells both in normal and RSL3-treated conditions [84].…”

“…Another study directly focused on the ability of iPLA 2 β (PLA2G6) to hydrolyze Hp-PE species, which are the main driver of ferroptosis [84]. The authors directly analyze the abundance of 15-HpETE-PE and found that 15-HpETE-PE are upregulated in PLA2G6 KO cells compared to control cells both in normal and RSL3-treated conditions [84]. The authors further show that PLA2G6 KO mice are more susceptible to ferroptosis induced by RSL3 and ischemia/reperfusion (I/R) than wild-type mice during pregnancy, thereby increasing fetal death rates [84].…”

RNA Network Interactions During Differentiation of Human Trophoblasts

“…We sought to hinder trophoblast differentiation using hypoxia or the addition of DMSO to the culture medium, two approaches that have led to reproducible results in our laboratory ( Nelson et al, 1999 ; Yusuf et al, 2002 ; Roh et al, 2005 ; Oh et al, 2011 ; Mouillet et al, 2013 ; Bildirici et al, 2018 ; Beharier et al, 2020 ). We used next generation sequencing technology to identify differentially expressed lncRNAs, miRNAs, and mRNAs during these processes.…”