Phosphoglycerate mutase 5 promotes necroptosis in trophoblast cells through activation of dynamin‐related protein 1 in early‐onset preeclampsia

Abstract

Objectives: Placentae from patients with preeclampsia have increased susceptibility to necroptosis and phosphoglycerate mutase 5 (PGAM5) plays a role in many necrosis pathways. We determined whether PGAM5 promotes necroptosis of trophoblast cells and the underlying mechanisms in this study. Methods:The injury model was established by treating JEG3 cells with hypoxia for 24 h. The functional measurements were assessed by the cell counting kit-8, propidium iodide (PI)/Annexin V staining, JC-1 staining and firefly luciferase ATP assay. The expression of proteins in human placentae and JEG3 cells was measured Western blot.PGAM5 was knocked down to study its role in hypoxia-induced necroptosis. Results:The placentae from patients with preeclampsia showed up-regulation of PGAM5 and decreased levels of p-Drp1-S637, accompanied by increased necroptosisrelevant proteins expression. The expression of PGAM5 in JEG3 cells was up-regulated under hypoxia, which promoted dephosphorylation of Drp1 at Serine 637 residue, mitochondrial dysfunction (elevated ROS level and reduced mitochondrial membrane potential and ATP content) and cellular necroptosis (increased PI + /Annexin V + cells and decreased cell viability), accompanied by increased expression of necroptosisrelevant proteins; knockdown of PGAM5 attenuated these phenomena. Conclusions: Our results indicate that PGAM5 can promote necroptosis in trophoblast cells through, at least in part, activation of Drp1. It may be used as a new therapeutic target to prevent trophoblast dysfunction in preeclampsia.

Thrombospondin‐1 Regulates Trophoblast Necroptosis via NEDD4‐Mediated Ubiquitination of TAK1 in Preeclampsia

“…[44] Zhang et al found an upregulation of PGAM5 and increased necroptosis-relevant protein expression in placentae from preeclampsia pregnancies. [45] But Cheng et al found no evidence of necroptosis-associated events in placental tissues from patients with early-onset or late-onset PE. [46] We provide new evidence for the presence of necroptosis and found an increase in the expression of DAMPs molecules in both the human and mice preeclamptic placenta.…”

“…found an upregulation of PGAM5 and increased necroptosis‐relevant protein expression in placentae from preeclampsia pregnancies. [ 45 ] But Cheng et al. found no evidence of necroptosis‐associated events in placental tissues from patients with early‐onset or late‐onset PE.…”

Methods and criteria for validating the multimodal functions of perinatal derivatives when used in oncological and antimicrobial applications

“…AMPs have potent cardioprotective effects in H9c2 cells by inhibiting the Ca2+ overload and the mitochondrial membrane potential dysfunction during hypoxia ( Faridvand et al, 2019 ). Furthermore, there are few studies that evaluated mitochondrial membrane potential in placental trophoblast cells from patients with preeclampsia ( Zhang et al, 2022 ). The anticancer effect of PnDs have not yet been evaluated with the mitochondrial dye JC-1.…”

Necroptosis in recurrent implantation failure: A bioinformatics analysis of key genes and therapeutic targets

“…[ 7 – 9 ] Additionally, levels of cell-derived microparticles (cMPs), released during cell activation or apoptosis, are found to increase significantly in RIF patients. [ 10 ] Moreover, trophoblast necroptosis plays a complex role in pregnancy disorders such as preeclampsia [ 11 , 12 ] and recurrent abortion. [ 13 ] Thus, a potential link exists between RIF and necroptosis, highlighting necroptosis as a promising target for understanding and treating RIF.…”