The role of mitochondrial fusion protein 2 in regulating ER stress in premature placental aging

Advanced maternal age (AMA) is associated with an increased risk of adverse perinatal outcomes, which may be attributed to premature placental aging. Previous studies have demonstrated that mitochondrial fusion protein 2 (Mfn2) plays a critical role in aging-related neurodegenerative disorders, metabolic diseases, and vascular pathologies. However, its expression in AMA pregnancies and its impact on placental function remain poorly understood. This study aimed to investigate the expression patterns of Mfn2 in placental tissues from AMA pregnancies and elucidate its regulatory role in endoplasmic reticulum (ER) stress through the protein kinase R-like ER kinase (PERK) signaling pathway. The downregulation of Mfn2 expression in AMA exacerbates placental senescence by dysregulating ER stress via PERK. Mfn2 binds to PERK, inhibits phosphorylation, and alleviates oxidative stress and senescence, highlighting its therapeutic potential. Placental tissues from 20 women with AMA and 20 young women were analyzed using real-time quantitative reverse transcription PCR‌. An H ₂ O ₂ -induced HTR-8/SVneo trophoblast cell line senescence model was established. Functional assays (cell counting kit-8, wound healing, Transwell, and β-galactosidase staining) and oxidative stress markers (reactive oxygen species/malondialdehyde/superoxide dismutase) were evaluated. Western blotting was used to assess the expression of PERK pathway proteins (phosphorylated protein kinase R-like endoplasmic reticulum kinase, activating transcription factor 4, and CCAAT/enhancer binding protein homologous protein) and senescence markers (P16 and P53). Immunoprecipitation verified the Mfn2-PERK interaction. Mfn2 expression was significantly downregulated in AMA placentas and negatively correlated with PERK expression. Mfn2 overexpression reversed the H ₂ O ₂ -induced suppression of trophoblast viability, migration, invasion, and senescence while reducing the levels of reactive oxygen species and malondialdehyde and restoring the activity of superoxide dismutase. Mfn2 inhibited PERK pathway activation (phosphorylated protein kinase R-like endoplasmic reticulum kinase, activating transcription factor 4, and CCAAT/enhancer binding protein homologous protein) and the expression of senescence markers (P16/P53). Mfn2 interacted directly with PERK.