FTO-mediated m6A modification elevates the MFN2 mRNA stability to suppress ovarian granulosa cell senescence

Although significant progress has been made in human-assisted reproductive technology in recent decades, fertility issues related to ovarian senescence remain a pressing challenge in reproductive medicine. As granulosa cells play a critical role in supporting oocytes, understanding the mechanisms of ovarian granulosa cell senescence is crucial to addressing the decline in ovarian function and oocyte quality associated with ovarian senescence. Previous studies have indicated that the mitochondrial fusion protein (MFN2) may play a key role in ovarian senescence and is linked to the outcomes of assisted reproductive technology. However, the precise underlying mechanism remains unclear. In this study, we found that the expression of MFN2 was significantly downregulated during ovarian granulosa cell senescence and that the overexpression of MFN2 delayed senescence. Moreover, N6-methyladenosine (m6A) modification and demethylase FTO were found to play important regulatory roles in this process. Mechanistically, we discovered that the demethylase FTO enhanced the stability of MFN2 mRNA in a YTH N6-methyladenosine RNA binding protein F2-dependent manner, thereby inhibiting granulosa cell senescence. These findings expand the epigenetic regulatory landscape of ovarian granulosa cell senescence and further confirm the significant role of FTO and m6A modifications in delaying this process. These findings provide new insights and molecular targets for diagnosing and treating ovarian senescence.