SS-31 improves the quality of maternally aged oocytes by ameliorating mitochondrial function and metabolism

Reproductive aging is closely associated with poor oocyte quality in vitro maturation, but effective approaches to ameliorate it have still not been fully determined. Here, we found that SS-31 supplementation efficaciously improved oocyte maturation and early embryonic development from aged mice. Specifically, SS-31 remarkably restored the normal spindle/chromosome structure, fertilization ability, mitochondrial distribution, ΔΨm and mitophagy in aged oocytes. In contrast, SS-31 reduced oocyte aneuploidy, ROS accumulation and DNA damage. Mechanistically, single-cell transcriptome analysis reveals that SS-31 increased the maternal mRNA degradation, and the levels of genes associated with mitochondrial function and mitophagy in aged oocytes, such as Pink1, Rps27a, Tomm7 and Map1lc3b. In addition, SS-31 suppressed chromatin organization, histone modification and chromatin remodeling pathways. Moreover, we applied the single-cell untargeted metabolomics to identify that SS-31 increased the levels of spermidine and GSH, which were critical metabolites to protect oocytes against aging. Our data reveal that the beneficial effect of SS-31 on oocyte quality from advanced age is mainly mediated by restoration of mitochondrial function, mitophagy and anti-aging metabolites. It provides a potential strategy for improving oocyte quality to extend the reproductive lifespan of female animals. The underlying mechanism of SS-31 improving the quality of maternally aged oocytes in mouse. SS-31 supplementation effectively improves meiotic maturation of aged oocytes by maintaining normal spindle/chromosome structure, whereas reducing oocyte aneuploidy, ROS accumulation and DNA damage. In particular, SS-31 enhances mitophagy activity and mitochondrial function, and increases anti-aging metabolites, such as spermidine and GSH in aged oocytes.