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

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 necroptosis-relevant 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 necroptosis-relevant 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.