Role of RGS12 in placental mitochondrial dysfunction and adverse pregnancy outcomes

Mitochondrial function and its regulation within the placenta are critical for maintaining a healthy pregnancy. This study investigated the role of G-protein signaling 12 (RGS12) in placental mitochondrial function and pregnancy outcomes. RGS12 was found to be localized within the mitochondria of placental trophoblast cells. RGS12 knockdown in human placental cells resulted in decreased mitochondrial abundance, impaired oxidative phosphorylation, and reduced antioxidant capacity. Mechanistically, RGS12 enhanced the function of ATP5B, a key mitochondrial enzyme, by promoting its tyrosine phosphorylation. In a mouse model, placental RGS12 deficiency led to reduced tolerance to preterm birth (PTB) challenge, decreased fetal weight, and trophoblast cell death. These adverse effects were associated with diminished ATP synthase activity and activation of the p38MAPK signaling pathway, while restoring RGS12 expression improved the phenotype of mitochondrial dysfunction in placental trophoblast cells. Furthermore, reduced RGS12 expression and impaired mitochondrial function were observed in placentas from cases experiencing PTB. Collectively, these findings provide hitherto undocumented evidence of a specific molecular mechanism by which placental mitochondrial dysfunction contributes to adverse pregnancy outcomes. Our study suggests that RGS12 may represent a novel therapeutic target for improving pregnancy outcomes through its role in regulating placental mitochondrial function.