MIT-001 ameliorates ferroptosis-induced mitochondrial dysfunction and enhances embryo quality in preimplantation embryos from aged female mice.

Abstract

Advanced maternal age is closely associated with reduced oocyte and embryo quality, impaired mitochondrial function, and decreased implantation potential. Ferroptosis, a regulated form of cell death driven by iron-dependent lipid peroxidation, has emerged as a key contributor to the age-related decline in reproductive capacity. In this study, we investigated the therapeutic potential of mitochondria-targeted 001 (MIT-001), a novel anti-ferroptosis agent, to improve the quality of preimplantation embryos derived from aged female mice. In vitro assays using human granulosa-like KGN cells demonstrated that MIT-001 effectively protected against Ras-selective lethal 3 (RSL3)-induced ferroptosis, restored cell viability, and recovered estradiol synthesis, indicating that steroidogenic function was restored. To evaluate the efficacy of MIT-001 in vitro, preimplantation embryos were collected from aged BDF1 mice and cultured in the presence of MIT-001. Embryos treated with MIT-001 showed significantly improved developmental progression and increased blastocyst formation rates compared with untreated controls. Furthermore, MIT-001 enhanced the mitochondrial membrane potential and oxygen consumption rate, as assessed by live confocal imaging and Seahorse assays, suggesting that mitochondrial function was restored. These findings highlight the role of ferroptosis in deterioration of embryo quality associated with maternal aging and demonstrate that MIT-001 mitigates ferroptosis-induced cellular damage. In conclusion, MIT-001 is a promising candidate for therapeutic intervention to improve clinical reproductive outcomes in aged females by targeting mitochondrial dysfunction and regulated cell death pathways.