The zinc transporter ZIP7 (Slc39a7) controls myocardial reperfusion injury by regulating mitophagy

Abstract

Whereas elimination of damaged mitochondria by mitophagy is proposed to be cardioprotective, the regulation of mitophagy at reperfusion and the underlying mechanism remain elusive. Since mitochondrial Zn²⁺ may control mitophagy by regulating mitochondrial membrane potential (MMP), we hypothesized that the zinc transporter ZIP7 that controls Zn²⁺ levels within mitochondria would contribute to reperfusion injury by regulating mitophagy. Mouse hearts were subjected to ischemia/reperfusion in vivo. Mitophagy was evaluated by detecting mitoLC3II, mito-Keima, and mitoQC. ROS were measured with DHE and mitoB. Infarct size was measured with TTC staining. The cardiac-specific ZIP7 conditional knockout mice (ZIP7 cKO) were generated by adopting the CRISPR/Cas9 system. Human heart samples were obtained from donors and recipients of heart transplant surgeries. KO or cKO of ZIP7 increased mitophagy under physiological conditions. Mitophagy was not activated at the early stage of reperfusion in mouse hearts. ZIP7 is upregulated at reperfusion and ZIP7 cKO enhanced mitophagy upon reperfusion. cKO of ZIP7 led to mitochondrial depolarization by increasing mitochondrial Zn²⁺ and, accumulation of PINK1 and Parkin in mitochondria, suggesting that the decrease in mitochondrial Zn²⁺ in response to ZIP7 upregulation resulting in mitochondrial hyperpolarization may impede PINK1 and Parkin accumulation in mitochondria. Notably, ZIP7 is markedly upregulated in cardiac mitochondria from patients with heart failure (HF), whereas mitochondrial PINK1 accumulation and mitophagy were suppressed. Furthermore, ZIP7 cKO reduced mitochondrial ROS generation and myocardial infarction via a PINK1-dependet manner, whereas overexpression of ZIP7 exacerbated myocardial infarction. Our findings identify upregulation of ZIP7 leading to suppression of mitophagy as a critical feature of myocardial reperfusion injury. A timely suppression of cardiac ZIP7 upregulation or inactivation of ZIP7 is essential for the treatment of reperfusion injury.

Keywords: Mitochondrial Zn2+; Mitophagy; ROS; Reperfusion injury; ZIP7.