ZIP14 upregulation leads to ferroptosis and lysosomal dysfunction through intracellular iron overload and induces myocardial ischemia/reperfusion injury in mouse hearts.

Abstract

While the ZIP family Zntransporters such as ZIP2 and ZIP7 play critical roles in myocardial ischemia/reperfusion (I/R) injury by regulating Znhomeostasis, little is known about the roles of the other ZIP family Zntransporters in I/R injury. Here we report that ZIP14, a ZIP family Zntransporter, contributes to the pathogenesis of myocardial I/R injury by controlling Fehomeostasis. Mouse hearts were subjected to I/R in vivo. Lipid peroxides were measured with C11-BODIPY and MDA. Infarct size was measured with the TTC staining. The cardiac-specific ZIP14 knockdown (AAV-shZIP14) and overexpression (AAV-ZIP14) mice were generated by adopting the AAV system. AAV-shZIP14 decreased but AAV-ZIP14 increased Felevels in cardiomyocytes. ZIP14 is upregulated at reperfusion, and AAV-shZIP14 reduced but AAV-ZIP14 enhanced ferroptosis caused by I/R. ZIP14 upregulation led to lysosomal lipid peroxidation in a Fe-dependent manner, which ultimately contributes to myocardium injury by causing lysosomal membrane permeabilization (LMP) and impairment of autophagic flux. Our findings identify upregulation of ZIP14 leading to ferroptosis, LMP, and suppression of autophagic flux as a critical feature of myocardial I/R injury. Targeting cardiac ZIP14 upregulation may serve as a therapeutic strategy for the treatment of myocardial I/R injury.