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

ABSTRACT The decline in oocytes quality and developmental potential with female reproductive aging is well recognized, yet the underlying mechanisms remain insufficiently investigated. In this study, through an integrative analysis of transcriptomes and morphologies of individual oocytes from young and aged mice, morphologically defective aged oocytes are identified 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 downregulated with oocyte aging, and Plat knockdown increases oocytes 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 programmed cell death. Supplementing exogenous tPA in in vitro oocyte maturation cultures reduces defect rate of aged oocytes, thereby improving oocyte quality and developmental potential. Collectively, Plat plays a pivotal role in protecting aged mouse oocytes from programmed cell death, and tPA supplementation may serve as a potential clinical strategy to enhance oocyte quality in females of advanced maternal age.