Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, No 218 Jixi Road, Hefei, Anhui, 230022, China.
Key Laboratory of Population Health Across Life Cycle, Anhui Medical University, Ministry of Education of the People's Republic of China, No 81 Meishan Road, Hefei, Anhui, 230032, China.
Reprod Sci. 2024 Oct;31(10):3191-3201. doi: 10.1007/s43032-024-01647-z. Epub 2024 Jul 25.
Stress is an emotional state caused by an unexpected external environmental change or stimulus, and several experiments have demonstrated its negative impact on ovarian function, ultimately affecting reproductive ability. Melatonin (MT) has been shown to facilitate oocyte maturation and enhance ovarian function by regulating mitochondrial function. However, the specific effect and underlying molecular mechanisms of MT on stress-induced ovarian dysfunction remain largely unknown. In this study, we established a mouse model of chronic unpredictable mild stress (CUMS) to investigate its impact on ovarian function. Our findings revealed that CUMS led to premature ovarian insufficiency (POI) in mice, characterized by a reduction in follicle numbers and decreased levels of anti-Müllerian hormone (AMH) and bone morphogenetic protein 15 (BMP15). Furthermore, CUMS caused decreased expression of mitochondrial fission protein 1 (FIS1) and enhanced level of mitochondrial fusion protein optic atrophy 1(OPA1), mitofusin1(MFN1), as well as nucleus-encoded protein succinate dehydrogenase complex A (SDHA), reflecting mitochondrial dyshomeostasis. Additionally, CUMS resulted in excessive autophagy and apoptosis. However, MT reversed these effects and improved ovarian damage. Importantly, the protective effects of MT were mediated through the inhibition of the eIF2α-AFT4 pathway. Overall, this study provides valuable insights into the treatment of POI caused by CUMS.
压力是由意外的外部环境变化或刺激引起的一种情绪状态，多项实验已经证明其对卵巢功能的负面影响，最终影响生殖能力。褪黑素（MT）已被证明通过调节线粒体功能促进卵母细胞成熟和增强卵巢功能。然而，MT 对压力诱导的卵巢功能障碍的具体作用和潜在分子机制在很大程度上仍然未知。在本研究中，我们建立了慢性不可预测轻度应激（CUMS）的小鼠模型，以研究其对卵巢功能的影响。我们的研究结果表明，CUMS 导致小鼠发生卵巢早衰（POI），表现为卵泡数量减少和抗苗勒管激素（AMH）和骨形态发生蛋白 15（BMP15）水平降低。此外，CUMS 导致线粒体分裂蛋白 1（FIS1）表达减少，线粒体融合蛋白视神经萎缩 1（OPA1）、线粒体融合蛋白 1（MFN1）和核编码蛋白琥珀酸脱氢酶复合体 A（SDHA）表达增强，反映线粒体稳态失衡。此外，CUMS 导致过度自噬和细胞凋亡。然而，MT 逆转了这些影响并改善了卵巢损伤。重要的是，MT 的保护作用是通过抑制 eIF2α-AFT4 通路介导的。总体而言，这项研究为治疗 CUMS 引起的 POI 提供了有价值的见解。
