Prostaglandin D2 reinforces mitochondrial quality control to enhance ovarian and embryonic competence.

Abstract

Prostaglandin D2 (PGD2) is a bioactive lipid mediator implicated in ovarian physiology; however, its role in mitochondrial regulation and aging-associated reproductive dysfunction remains insufficiently defined. Here, we investigated whether PGD2 restores ovarian competence through coordinated mitochondrial and endocrine remodeling using human granulosa (KGN) cells, primary ovarian cells from aged mice, and preimplantation embryos. PGD2 significantly enhanced cellular viability and attenuated senescence-associated β-galactosidase activity. Structural and functional analyses demonstrated restoration of mitochondrial network integrity, increased mitochondrial membrane potential (ΔΨm), elevated basal respiration, spare respiratory capacity, and ATP production, together with reduced proton leak, indicating improved oxidative phosphorylation efficiency. Mechanistically, PGD2 activated a mitochondrial stress-adaptive axis characterized by upregulation of SIRT1 and PINK1 and suppression of PARP1, suggesting enhanced mitochondrial quality control and preservation of metabolic flexibility. Concomitantly, PGD2 promoted steroidogenic activation, evidenced by increased StAR and CYP11A1 expression and significantly elevated estradiol and progesterone secretion. Adaptive remodeling of gonadotropin receptor signaling was observed, with increased LHR/LHCGR and reduced FSHR and AMH expression, reflecting a shift toward an LH-responsive maturation-aligned phenotype. Importantly, these ovarian cellular improvements translated to the embryonic stage. PGD2 enhanced mitochondrial membrane potential, accelerated cleavage kinetics, and improved progression to the morula and blastocyst stages. Blastocysts exhibited transcriptional patterns consistent with maternal metabolic reprogramming, including increased StAR, CYP11a1, Sirt1, and LHCGR expression. Collectively, these findings demonstrate that PGD2 restores ovarian resilience through hierarchical mitochondrial reinforcement, endocrine activation, and adaptive receptor remodeling, thereby enhancing embryonic developmental competence. PGD2 may represent a potential therapeutic modulator for improving reproductive outcomes under aging-associated ovarian dysfunction.