Mitophagy Protects Against Cisplatin-Induced Injury in Granulosa Cells

Cisplatin, a widely used chemotherapeutic agent, is known to induce premature ovarian insufficiency (POI) and infertility in women of reproductive age. Among the contributing factors, cisplatin-induced apoptosis of ovarian granulosa cells is considered a primary driver of ovarian dysfunction; however, the underlying mechanisms remain incompletely understood. In this study, we investigated the cytotoxicity of cisplatin on the granulosa cell line KGN in vitro and explored the associated mechanisms. Our results demonstrate that cisplatin induces KGN cell apoptosis in a dose-dependent manner and impairs mitochondrial function, as evidenced by excessive ROS production, membrane potential collapse, and reduced ATP synthesis. Mitophagy, a key cellular self-protection mechanism that selectively removes damaged mitochondria, was activated following cisplatin treatment, mitigating its detrimental effects on KGN cells. Activation of mitophagy with urolithin A (UA) ameliorated cisplatin-induced mitochondrial dysfunction and apoptosis, whereas inhibition of mitophagy with cyclosporine A (CsA) exacerbated these effects. Furthermore, pretreatment with the clinical drug melatonin significantly enhanced mitophagy, effectively attenuating cisplatin-induced apoptosis in KGN cells. This study proposes a novel therapeutic strategy for patients undergoing tumor chemotherapy, aiming to preserve treatment efficacy while reducing the adverse effects of chemotherapeutic agents on ovarian function, thereby improving patients' quality of life.