Plat safeguards maternally aged oocytes against programmed cell death through activating the Erk1/2 pathway

The decline in oocyte quality and developmental potential with female reproductive aging is well recognized, yet the underlying mechanisms remain insufficiently investigated. In this study, an integrative analysis of transcriptomes and morphologies of individual oocytes from young and aged mice identifies morphologically defective aged oocytes with distinct transcriptomic features. Further analysis demonstrates that both apoptotic and ferroptotic pathways are activated in the defective aged oocytes, and simultaneously blocking both pathways reverses the defective morphology to the largest extent. The Plat gene, which encodes tissue-type plasminogen activator (tPA), is down-regulated with oocyte aging, and Plat knockdown increases oocyte susceptibility to both apoptosis and ferroptosis. Mechanistically, tPA functions as an upstream signaling molecule for Erk1/2 activation by interacting with particular phosphorylation kinases such as Alk. Consequently, Plat loss downregulates Erk1/2 pathway activity in oocytes, leading to degeneration through PCD. Supplementing exogenous tPA in vitro oocyte maturation cultures reduces the defect rate of aged oocytes, thereby improving oocyte quality and developmental potential. Collectively, Plat plays a pivotal role in protecting aged mouse oocytes from PCD, and tPA supplementation may serve as a potential clinical strategy to enhance oocyte quality in females of advanced maternal age.