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

作者：Wenxiu Chen, Hongyan Zhang, Bao Guo, Yumei Tao, Junhui Zhang, Jiayi Wang, Guangyi Chen, Mengting Cheng, Qiang Hong, Yunxia Cao, Fenfen Xie · 发表于：Cellular and Molecular Life Sciences · 年份：2025 · DOI：10.1007/s00018-025-05609-9 · 被引用次数：15 · 研究领域：Circadian rhythm and melatonin、Mitochondrial Function and Pathology、Genetics, Aging, and Longevity in Model Organisms

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 significan...