Li Qiuyuan, Shen Haofei, Liu Ahui, Yu Liulin, Wang Liyan, Zhang Xuehong
The First School of Clinical Medicine, Lanzhou University, No. 1, Dong Gang Xi Road, Chengguan District, Lanzhou, Gansu 730000, China; Reproductive Medicine Center, The First Hospital of Lanzhou University, No. 1 Dong Gang Xi Road, Chengguan District, Lanzhou, Gansu 730000, China.
The First School of Clinical Medicine, Lanzhou University, No. 1, Dong Gang Xi Road, Chengguan District, Lanzhou, Gansu 730000, China; Reproductive Medicine Center, The First Hospital of Lanzhou University, No. 1 Dong Gang Xi Road, Chengguan District, Lanzhou, Gansu 730000, China; Key Laboratory for Reproductive Medicine and Embryo, Lanzhou, Gansu 730000, China.
Int J Biol Macromol. 2025 May;307(Pt 4):142181. doi: 10.1016/j.ijbiomac.2025.142181. Epub 2025 Mar 17.
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.
尽管近几十年来人类辅助生殖技术取得了重大进展，但与卵巢衰老相关的生育问题仍然是生殖医学中一个紧迫的挑战。由于颗粒细胞在支持卵母细胞方面起着关键作用，了解卵巢颗粒细胞衰老的机制对于解决与卵巢衰老相关的卵巢功能和卵母细胞质量下降至关重要。先前的研究表明，线粒体融合蛋白（MFN2）可能在卵巢衰老中起关键作用，并与辅助生殖技术的结果相关。然而，确切的潜在机制仍不清楚。在本研究中，我们发现MFN2的表达在卵巢颗粒细胞衰老过程中显著下调，并且MFN2的过表达延迟了衰老。此外，发现N6-甲基腺苷（m6A）修饰和去甲基化酶FTO在此过程中发挥重要的调节作用。从机制上讲，我们发现去甲基化酶FTO以YTH N6-甲基腺苷RNA结合蛋白F2依赖的方式增强了MFN2 mRNA的稳定性，从而抑制了颗粒细胞衰老。这些发现扩展了卵巢颗粒细胞衰老的表观遗传调控格局，并进一步证实了FTO和m6A修饰在延缓这一过程中的重要作用。这些发现为卵巢衰老的诊断和治疗提供了新的见解和分子靶点。
