Melatonin alleviates mitochondrial damage by regulating SIRT3-mediated mitochondrial dynamics in granulosa cells under PCOS-like conditions

The present study investigated the role of melatonin (MT) in regulating mitochondrial function via sirtuin 3 (SIRT3) in granulosa cells (GCs) from patients with polycystic ovary syndrome (PCOS), with a focus on mitochondrial protection. Notably, GCs isolated from patients with PCOS exhibited mitochondrial dysfunction. Using an in vitro PCOS model established by treating KGN cells with dihydrotestosterone (DHT), decreased SIRT3 expression, dysregulated mitochondrial dynamics and hyperactivation of mitophagy were observed. Both SIRT3 overexpression and MT treatment restored the mitochondrial membrane potential, rebalanced mitochondrial dynamics and suppressed excessive autophagy in DHT-treated cells. Additionally, MT levels were shown to be reduced in the follicular fluid of patients with PCOS. Notably, the protective effects of MT on proteins associated with both mitochondrial dynamics and autophagy were abolished upon SIRT3 inhibition. In conclusion, mitochondrial dysfunction and aberrant mitophagy in GCs may serve a role in the pathogenesis of PCOS. MT appears to ameliorate these defects by modulating mitochondrial dynamics and function in a SIRT3-dependent manner. Moreover, the current study identified SIRT3 as a key molecular target of MT in PCOS.