SCAN-seq2 reveals mitochondrial metabolic alterations and proteostasis-related transcriptional signatures during human oocyte aging

Ovarian aging, characterized by declines in both oocyte quantity and quality, represents a major challenge to female reproductive health. However, the age-associated transcriptional alterations underlying human oocyte aging remain incompletely understood. Differential expression analysis between young and aged oocytes identified 63 age-associated differentially expressed genes, including increased expression of ribosome-associated genes, oxidative-phosphorylation-related genes such as COX5B and UQCRC2 , the ubiquitin-associated gene UBA52 , and mtDNA-encoded OXPHOS transcripts including MT-ND4 and MT-ND4L , together with reduced expression of the antioxidant-response gene GSTA1 and the mitochondrial respiratory-chain gene NDUFA9 . Functional enrichment analyses revealed biological processes related mainly to translation, protein targeting, ribosomal functions, and oxidative phosphorylation. Further subcluster analysis identified an aged-enriched oocyte population with broader mitochondrial-related transcriptional alterations and enrichment of DNA-damage-response pathways. Subsequent PPI analysis of the intersecting genes identified two exploratory functional modules related to mitochondrial respiratory-chain processes and ribosome/ubiquitin-associated proteostasis. These findings highlight age-associated transcriptional signatures in human oocytes involving mitochondrial metabolism and proteostasis-associated processes, and reveal molecular heterogeneity among aged oocyte populations. Together, these results provide insights into the molecular changes associated with human oocyte aging and establish a transcriptomic framework for future studies of reproductive aging.