MON-145 Mitochondrial Biogenesis Inhibitor SR-18292: Disrupting Estrous Cycle Dynamics and Fertility in Female Mice

Abstract Disclosure: M.N. Mthethwa: None. G. Angelita: None. Y.P. Budi: None. E. Chang: None. Y. Jiang: None. Mitochondria, known as the powerhouses of the cell, are double-membrane organelles that also regulate calcium levels. Mitochondrial biogenesis, regulated by peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), is critical for maintaining energy demands and cellular functions in the female reproductive system. This study examines the impact of inhibiting mitochondrial biogenesis using SR-18292 on estrous cycle regulation, oocyte quality, and fertility outcomes in female ICR mice. Ten-week-old females were administered daily injections of SR-18292 (22.5 mg/kg) over five days, with estrous cycles monitored through vaginal smear analysis. Ovaries were collected for next-generation sequencing (NGS), and superovulation studies (22.5 mg/kg or 2.25 mg/kg) were conducted with subsequent in vitro fertilization (IVF). NGS data indicated increased expression of mitochondrial-related genes during the morning of proestrus. SR-18292 treatment caused a rapid regression from proestrus to metestrus and disrupted cycle progression, stalling at metestrus and diestrus, underscoring the role of mitochondrial biogenesis in estrous cycle dynamics. High-dose treatment elevated ovulated oocyte counts (≈15) but significantly increased degeneration (>50%) and impaired fertilization success. In contrast, control groups exhibited lower oocyte degeneration (≈22%) and significantly higher fertilization rates (≈70%), despite fewer ovulated oocytes (≈15). The low-dose treatment showed no statistically significant difference compared to the control group. These findings highlight the critical role of mitochondrial biogenesis in regulating estrous cycle stability and oocyte quality, with potential implications for enhancing assisted reproductive technology (ART) outcomes. Disruption of this process compromises fertility, emphasizing the need for further research into the molecular mechanisms linking mitochondrial function to reproductive health. Presentation: Monday, July 14, 2025