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

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.