Naringin and hesperidin protect ovarian granulosa cells from cisplatin-induced mitochondrial dysfunction by enhancing bioenergetics and mitophagy

BACKGROUND: Cisplatin (CDDP) is a widely deployed chemotherapeutic medication used to treat various solid tumors, but its clinical utility is limited by dose-dependent ovarian toxicity. Naringin (NG) and hesperidin (HD) are two naturally occurring flavonoids found in citrus fruits and have protective effects on mitochondrial function. RESULTS: The current study examined the protective effects of NG and HD on CDDP-induced mitochondrial dysfunction and cytotoxicity in granulosa cells. The cells are treated with CDDP alone or with NG or HD. CDDP reduced cell viability, ATP synthesis, oxygen consumption rate (OCR), mitochondrial membrane potential (MMP), and mitochondrial complex functions in a dose-dependent pattern. It also altered mitochondrial dynamics and enhanced glycolytic activity, as exhibited by lactate levels. MMF increased, and fatty acid composition changed, resulting in a higher unsaturated/saturated ratio. PINK1 and PARKIN levels were reduced upon CDDP treatment, suggesting mitophagy disruption. Co-treatment of NG and HD enhanced complex activity, MMP, OCR, ATP generation, and cell viability. MMF was protected by NG and HD, which also stabilized fatty acids and enhanced ion permeability and mitochondrial swelling. Compared to NG, HD preserved numerous attributes more effectively and restored them almost completely. CONCLUSIONS: NG and HD effectively preserve mitochondrial bioenergetics, structure, and dynamics in granulosa cells, mitigating CDDP-induced dysfunction. These findings highlight their potential as natural adjuvants to reduce ovarian toxicity and support fertility preservation in female cancer patients.