Glucose deprivation-reperfusion induces labile iron overload and ferroptosis in renal tubules through V-ATPase-mTOR axis-mediated ferritinophagy and iron release by TPC2

Renal ischemia-reperfusion (IR) injury occurs commonly after kidney transplantation or partial nephrectomy. It is an important cause of impaired renal function with limited treatment. Ferroptosis, a distinct form of cell death characterized by iron-dependent lipid peroxidation, plays a crucial role in renal ischemia-reperfusion injury. However, the precise alteration of iron metabolism during IR, its regulation and its relationship with ferroptosis remain poorly understood. This current study revealed that glucose deprivation-reperfusion and energy metabolism disruption are the major factors triggering cellular labile iron overload during IR. The iron overload resulted from the downregulation of vascular ATPase-mTOR (mammalian Target of Rapamycin) axis induced by abnormal energy metabolism. The mTOR dysfunction induced iron release from lysosomes through two pore channel 2. Meanwhile, the downregulation of mTOR activated ferritinophagy, degrading ferritin and increasing free iron. Iron overload is a significant contributor to IR-induced ferroptosis, and targeting labile iron alleviated ferroptosis during IR. Our findings emphasize the effects of energy metabolism and vascular ATPase-mTOR axis on iron homeostasis and ferroptosis, and establish a link between cellular iron overload and ferroptosis during renal IR.