Abstract

Bisphenol A (BPA) is implicated in impairing ovarian function by disrupting the normal function of granulosa cells (GCs); however, the underlying molecular mechanisms remain unclear. Based on our previous results, this study used KGN cells as a model and combined functional assays with mechanistic analyses to investigate the role of the YY1/HIF-1α/NDUFA4L2 signaling axis in BPA-induced granulosa cell injury. The results showed that BPA treatment upregulated YY1, HIF-1α, and NDUFA4L2 expression, accompanied by decreased ATP levels, suppressed mitochondrial complex I activity, accumulation of mitochondrial reactive oxygen species, and increased apoptosis. Further analyses demonstrated that YY1 knockdown markedly attenuated BPA-induced mitochondrial dysfunction, oxidative stress, and apoptosis, while also suppressing HIF-1α and NDUFA4L2 expression. Mechanistically, YY1 promoted NDUFA4L2 expression mainly by enhancing HIF-1α protein stability. YY1 knockdown alleviated BPA-induced cellular injury, whereas restoration of HIF-1α substantially weakened this protective effect, and further silencing of NDUFA4L2 mitigated the injury phenotype again. Taken together, these findings indicate that BPA induces mitochondrial bioenergetic impairment, oxidative stress, and apoptosis in granulosa cells through activation of the YY1/HIF-1α/NDUFA4L2 signaling axis, and further suggest that YY1 serves as an important upstream regulatory node linking environmental exposure to mitochondrial injury.