Mitochondrial-targeted strategies for advancing ovarian cryopreservation: enhancing follicular survival and reproductive health

Global fertility rates are in decline, underscoring the importance of effective fertility preservation strategies. Ovarian tissue cryopreservation and transplantation (OTCT) shows great promise but faces challenges like oxidative stress, ischemia-reperfusion injury, and poor follicle survival due to burn out. Protecting and preserving a greater number of primordial follicles remains pivotal to the success of this technology. While current strategies predominantly rely on antioxidants, their efficacy is constrained by non-specificity and the inability to achieve sustained release at the transplantation site. In this study, we explored the potential of elamipretide (SS31), a novel mitochondrial-targeted antioxidant peptide, to address these limitations. By combining SS31 with a recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) gel, we achieved localized and sustained release of SS31 at the transplantation site in rabbits. This combination demonstrated synergistic effects by reducing oxidative stress, improving mitochondrial function, and enhancing follicular survival. Notably, reproductive endocrine function was restored 8 weeks post-transplantation. Proteomics and metabolomics analyses revealed that these improvements were primarily attributed to the activation of energy metabolism pathway. Our findings suggest improved transplantation outcomes in preclinical settings, highlighting the potential of this strategy to serve as an efficient and precise approach for women requiring urgent fertility preservation in the future.