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| Status |
Public on Sep 27, 2020 |
| Title |
Sub-lethal stimulation of ferroptosis leads to trophoblast dysfunction |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Ferroptosis is a recently identified program of regulated cell death, defined by excessive accumulation of hydroperoxy-arachidonoyl (C20:4)- or adrenoyl (C22:4)- phosphatidyl-ethanolamine (OOH-PE). The selenium-dependent glutathione peroxidase 4 (GPX4) inhibits ferroptosis, converting unstable ferroptotic lipid hydroperoxides to non-toxic lipid alcohols. The effect of GPX4 ablation is divergent among cells and tissues, suggesting that additional regulators may guard trophoblasts against ferroptosis. While placental oxidative stress and lipotoxicity are hallmarks of placental dysfunction, the possible role of ferroptosis in placental function has not been hitherto investigated. Here we found that placental dysfunction is associated with ferroptosis, and that inhibition of GPX4 causes trophoblast injury and ferroptosis in vitro and in vivo during mouse pregnancy. Importantly, we uncover a role for the phospholipase PLA2G6 (PNPLA9, iPLA2beta), known to metabolizes OOH-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 in the human and mouse placenta, and established a novel role for PLA2G6 in attenuating trophoblastic ferroptosis. Our data provide mechanistic insights to the ill-defined entity of placental lipotoxicity, and may inspire new therapeutic strategies that target PLA2G6 as a means to modulate ferroptosis in placental and non-placental tissue.
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| Overall design |
RNAseq of BeWo cells constantly expressing shControl or shGPX4 following ferrostatin-1 withdrawal
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| Contributor(s) |
Beharier O, Chu T, Sadovsky Y |
| Citation(s) |
33087576 |
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| Submission date |
Mar 27, 2020 |
| Last update date |
Feb 08, 2023 |
| Contact name |
Ofer beharier |
| E-mail(s) |
behariero@mwri.magee.edu
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| Phone |
4125968853
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| Organization name |
MWRI
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| Street address |
204 Craft Ave
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| City |
Pittsburgh |
| ZIP/Postal code |
15213 |
| Country |
USA |
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| Platforms (1) |
| GPL27644 |
Illumina Novaseq 6000 (Homo sapiens) |
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| Samples (4)
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| Relations |
| BioProject |
PRJNA615850 |
| SRA |
SRP254302 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE147625_fer3_geo.csv.gz |
341.7 Kb |
(ftp)(http) |
CSV |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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