Vitamin E alleviates energy stress-induced injury in yak granulosa cells by blocking the AMPK/mTOR-mitophagy-ferroptosis axis

BACKGROUND: Energy stress-induced dysfunction of granulosa cells (GCs) is a major etiological factor in diminished female reproductive performance. Although vitamin E affords cytoprotection to GCs, its specific mechanisms of action under energy stress conditions in the yak model remain unclear. RESULTS: This study aimed to elucidate the pathways and cell fate decisions through which vitamin E alleviates energy stress-induced damage in yak GCs. Our results indicate that energy stress triggers a signaling cascade initiated by the AMPK-mTOR pathway, which functions as an upstream regulator for downstream events. Activation of this pathway promotes PINK1/Parkin-mediated mitophagy, leading to ferroptosis, characterized by the downregulation of SLC7A11 and GPX4 and the upregulation of ACSL4. This cascade ultimately drives the cells toward apoptosis, as evidenced by an increased Bax/Bcl-2 ratio and elevated levels of Cleaved-caspase-3, along with impaired intercellular communication due to downregulation of Cx43 and Cx37. Vitamin E intervention mitigated apoptosis and rescued the expression of gap junction proteins by intercepting this AMPK-mTOR-mitophagy-ferroptosis axis. CONCLUSION: Our study suggests a mechanism by which vitamin E modulates GC fate via this pathway. These findings provide insight into ovarian follicular pathophysiology in yaks and may inform strategies targeted at reproductive disorders associated with energy metabolic dysregulation.