褪黑激素通过调节昼夜节律基因时钟改善多囊卵巢综合征的卵巢线粒体功能障碍

Melatonin refines ovarian mitochondrial dysfunction in PCOS by regulating the circadian rhythm gene Clock

褪黑激素通过调节昼夜节律基因时钟改善多囊卵巢综合征的卵巢线粒体功能障碍

Authors: Wenxiu Chen, Hongyan Zhang, Bao Guo, Yumei Tao, Junhui Zhang, Jiayi Wang, Guangyi Chen, Mengting Cheng, Qiang Hong, Yunxia Cao, Fenfen Xie

Source: Cellular And Molecular Life Sciences

DOI: 10.1007/s00018-025-05609-9

Abstract

Mitochondrial dysfunction is present in the ovaries of patients with polycystic ovary syndrome (PCOS). Melatonin (MT) has shown promise in treating PCOS by improving mitochondrial dysfunction, though the underlying mechanisms remain unclear. In this study, we first assessed the levels of proteins associated with mitochondrial autophagy and dynamics in ovary granulosa cells (GCs) of PCOS patients and in the ovaries of DHEA-induced PCOS mice. We found abnormal expression of these proteins, indicating the presence of mitochondrial dysfunction in PCOS ovaries. Notably, the expression of the circadian gene Clock and melatonin synthetic enzymes were also decreased in the ovaries of PCOS patients. Studies have suggested a potential role of circadian rhythm genes in the pathogenesis and progression of PCOS. We subsequently observed that pretreatment with MT could ameliorate the abnormal levels of mitochondrial-related proteins, reverse the low expression of CLOCK, and reduce pyroptosis in PCOS ovaries. Given the potential interaction between MT and Clock, we focused on whether exogenous MT improves mitochondrial dysfunction in PCOS ovaries by regulating the expression of the circadian gene Clock. Through in vitro culture of the human ovarian granulosa cell line KGN, we further found that when CLOCK levels were inhibited, the beneficial effects of MT on abnormal mitochondrial autophagy, disturbed mitochondrial dynamics, and mitochondrial dysfunction in PCOS ovaries were not significant, and there was no notable improvement in ovary GCs pyroptosis. Our study suggests that MT may improve ovary mitochondrial dysfunction by regulating circadian gene Clock while also reducing GCs pyroptosis in PCOS.

Keywords: Clock; Melatonin; Mitochondrial dysfunction; Polycystic ovary syndrome; Pyroptosis.

摘要：

多囊卵巢综合征（PCOS）患者的卵巢存在线粒体功能障碍。褪黑素（MT）有望通过改善线粒体功能障碍来治疗多囊卵巢综合征，但其潜在机制仍不清楚。在本研究中，我们首先评估了多囊卵巢综合征患者卵巢颗粒细胞（GCs）和 DHEA 诱导的多囊卵巢综合征小鼠卵巢中与线粒体自噬和动态相关的蛋白质水平。我们发现这些蛋白表达异常，表明多囊卵巢综合症卵巢中存在线粒体功能障碍。值得注意的是，在多囊卵巢综合症患者的卵巢中，昼夜节律基因 Clock 和褪黑激素合成酶的表达也有所下降。研究表明，昼夜节律基因在多囊卵巢综合症的发病和发展过程中可能起着重要作用。我们随后观察到，用 MT 预处理可改善多囊卵巢综合征卵巢中线粒体相关蛋白的异常水平，逆转 CLOCK 的低表达，并减少嗜热症。鉴于 MT 和 Clock 之间的潜在相互作用，我们重点研究了外源性 MT 是否能通过调节昼夜节律基因 Clock 的表达来改善 PCOS 卵巢的线粒体功能障碍。通过对人类卵巢颗粒细胞系 KGN 的体外培养，我们进一步发现，当 CLOCK 水平受到抑制时，MT 对 PCOS 卵巢线粒体自噬异常、线粒体动力学紊乱和线粒体功能障碍的有益影响并不显著，卵巢 GCs 的热凋亡也没有明显改善。我们的研究表明，MT可通过调节昼夜节律基因时钟改善卵巢线粒体功能障碍，同时也可减少多囊卵巢综合征的GCs热解。

关键词：时钟；褪黑素；线粒体功能障碍；多囊卵巢综合征；裂解症