褪黑素通过eIF 2 α-AFT 4信号通路对慢性应激所致小鼠线粒体稳态失调和卵巢损伤的保护作用

Melatonin Protects Against Mitochondrial Dyshomeostasis and Ovarian Damage Caused by Chronic Unpredictable Mild Stress Through the eIF2α-AFT4 Signaling Pathway in Mice        

褪黑素通过eIF 2 α-AFT 4信号通路对慢性应激所致小鼠线粒体稳态失调和卵巢损伤的保护作用

Authors: Ding SM, Shi LG, Xing F, Cui SS, Cheng HR, Liu Y, Ji DM, Liang D, Cao YX, Liu YJ.

Source：Reprod Sci. 2024 Jul 25. doi: 10.1007/s43032-024-01647-z.

Abstract

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.

Keywords: Chronic unpredictable mild stress; Melatonin; Mitochondrial dyshomeostasis; Ovary function; eIF2α-AFT4 pathway.

摘要

压力是一种由意外的外部环境变化或刺激引起的情绪状态，几项实验已经证明了它对卵巢功能的负面影响，最终影响生殖能力。褪黑激素（MT）通过调节线粒体功能促进卵母细胞成熟，增强卵巢功能。然而，MT对应激诱导的卵巢功能障碍的具体作用和潜在的分子机制仍不清楚。本研究通过建立慢性轻度不可预知应激（unpredictable mild stress，CWS）小鼠模型，探讨CWS对卵巢功能的影响。我们的研究结果表明，BRAS导致小鼠卵巢功能不全（POI），其特征是卵泡数量减少，抗苗勒管激素（AMH）和骨形态发生蛋白15（BMP 15）水平降低。此外，BRAS引起线粒体分裂蛋白1（FIS 1）表达减少，线粒体融合蛋白视神经萎缩1（OPA 1），线粒体融合蛋白1（MFN 1），以及核编码蛋白琥珀酸脱氢酶复合物A（SDHA）的水平增加，反映线粒体稳态异常。此外，Cysts导致过度的自噬和细胞凋亡。然而，MT逆转了这些作用并改善了卵巢损伤。重要的是，MT的保护作用是通过抑制eIF 2 α-AFT 4途径介导的。总的来说，这项研究提供了有价值的见解，治疗POI引起的POIS。

关键词：慢性不可预见性轻度应激;褪黑素;线粒体稳态失调;卵巢功能; eIF 2 α-AFT 4通路