Quercetin ameliorates oxidative stress in BMP15-deficient oocytes by regulating the ERK1/2-GSK3β-CypD pathway

Bone morphogenetic protein 15 (BMP15) is an oocyte-secreted growth factor, which interacts with ovarian follicular somatic cells and in turn promotes oocyte maturation. Disrupting BMP15 by CRISPR-ctRNP has been found to severely impair in vitro maturation (IVM) of porcine oocytes, accompanied with mitochondrial dysfunction and increased accumulation of reactive oxygen species (ROS). To investigate whether the plant-derived antioxidant quercetin (QUE) is able to rescue the IVM of BMP15-deficient oocytes, porcine oocytes microinjected with CRISPR-ctRNP targeting BMP15 were treated with 10 μM QUE, and we found that QUE can effectively rescue the impaired IVM of BMP15-deficient oocytes by restoring the impaired mitochondrial functions and reducing ROS through activating extracellular signal-regulated kinase 1/2 (ERK1/2) pathway. Activated ERK1/2 in turn inactivated glycogen synthase kinase-3β (GSK3β), which subsequently reduced Cyclophilin D (CypD) levels, and probably modulated the status of the permeability transition pore (PTP) of mitochondria, contributing to the reduced oxidative stress and apoptosis in porcine oocytes, and thus the improved oocyte quality and IVM. Our study further revealed the molecular mechanisms of QUE on alleviating oxidative stress of BMP15-deficient oocytes, suggesting that QUE may be a promising candidate for improving quality of oocytes with BMP15 mutations.