Endoplasmic reticulum stress-autophagy axis is involved in copper-induced ovarian ferroptosis

Copper (Cu) contamination has emerged a global public health problem due to the extensive use of Cu in industrial production and daily life. Reproductive damage resulting from Cu exposure has been particularly evident. Wilson's disease (WD) is a recessive genetic disease characterized by impaired Cu metabolism. Female WD patients have often been associated with reproductive impairment. Ferroptosis, a form of iron-dependent regulated cell death, has been identified as being caused by massive lipid peroxide-mediated membrane damage. However, it remains unclear whether ferroptosis is associated with Cu-induced ovarian damage. In this study, the role of ferroptosis in ovarian damage induced by Cu accumulation and its underlying mechanisms were examined through both in vivo and in vitro experiments. The findings indicated that excessive Cu deposition in the ovaries could lead to follicular atresia and ovulation dysfunction, and trigger ferroptosis in ovarian and granulosa cells (GCs). The mechanism may be related to endoplasmic reticulum (ER) stress mediated by the protein kinase RNA-like ER kinase (PERK) pathway, and hyperactivation of autophagy. In addition, Cu-induced autophagy in GCs was found to increase intracellular iron levels via the ferritinophagy pathway, thereby inducing ferroptosis. We also found that mitochondrial reactive oxygen species (MitoROS) may be an onstream facilitator of Cu-induced ferroptosis via activation of the ER stress-autophagy pathway. Our findings suggested that ferroptosis is associated with Cu-induced ovarian damage and is regulated by the MitoROS-ER stress-autophagy axes. These results might provide insights for developing treatment for WD and other diseases related to Cu exposure.