Copper regulates the synthesis of steroid hormones through CCS and ATOX1 dependent MEK1-ERK1/2 pathway in follicular granulosa cells of yak (Bos grunniens)

CCS and ATOX1 is a specific target of copper in hormone secretion of ovarian granulosa cells. • MEK1-ERK1/2 pathway is involved in copper-affected hormone secretion. • Copper affects hormones secretion through CCS and ATOX1 dependent MEK1-ERK1/2 pathway. Steroid hormone synthesis in granulosa cells (GCs) is crucial for normal follicular development and ovulation. Emerging evidence suggests that copper (Cu), a trace element, influences hormone secretion in yak granulosa cells (YGCs); however, the underlying mechanisms remain unclear. In this study, we demonstrated that Cu supplementation upregulates estradiol (E2) and progesterone (P4) secretion in YGCs through the activation of the MEK1-ERK1/2 signaling pathway. Our findings indicate that the Cu chaperones ATOX1 and CCS, but not the Cu-dependent enzyme LOX, are essential for Cu-induced MEK1-ERK1/2 activation and subsequent hormone secretion. Gene silencing of ATOX1 or CCS resulted in reduced MEK1-ERK1/2 phosphorylation and steroidogenesis, highlighting their regulatory roles in this pathway. Although LOX influenced hormone secretion, it did not affect MEK-ERK phosphorylation, suggesting a MEK-independent mechanism. These findings reveal that Cu regulates steroid hormone synthesis in YGCs via a CCS- and ATOX1-dependent MEK1–ERK1/2 pathway, providing new insights into the molecular basis of Cu-associated reproductive disorders in yaks. Download: Download high-res image (289KB) Download: Download full-size image