Obesity concurrent with gestational diabetes mellitus dysregulates mitochondria-endoplasmic reticulum contacts in human placenta

Obesity concurrent with gestational diabetes mellitus (GDM) markedly increases the risk of adverse pregnancy outcomes, wherein placental dysfunction acts as a key mediating factor, however, the underlying mechanisms involved remain elusive. This study was designed to focus on the role of mitochondria-endoplasmic reticulum contacts (MERCs) in obesity with GDM-induced placental dysfunction. Term placental tissues from pregnant women with obesity and GDM or healthy control were analyzed. Reduced cell count of placental trophoblasts, disorganized cell arrangement, and higher apoptosis rate were observed in placental tissue from women with obesity and GDM. In addition, oxidative stress levels and protein expression levels of endoplasmic reticulum (ER) stress markers IRE1 and CHOP were both markedly upregulated compared to the healthy controls. Of note, proximity ligation assay (PLA) revealed increased formation of MERCs core complexes MFN1-MFN2 and IP3R1-VDAC1 in obesity and GDM group. These findings suggest that obesity comorbid with GDM may induce MERCs restructuring via oxidative stress and ER stress, thereby triggering trophoblast apoptosis and subsequent placental dysfunction. Our study sheds light on the underlying mechanisms driving placental pathology in women with obesity and GDM.