Zhang Hualu, Yang Ningzhi, He Haiyan, Chai Junwu, Cheng Xinxin, Zhao Huanhuan, Zhou Dongming, Teng Tianming, Kong Xiangrong, Yang Qing, Xu Zhelong
Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, 300070, China.
Department of Cardiac Surgery, Tianjin First Central Hospital, Tianjin, 300192, China.
Basic Res Cardiol. 2021 Sep 28;116(1):54. doi: 10.1007/s00395-021-00894-4.
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 Zn may control mitophagy by regulating mitochondrial membrane potential (MMP), we hypothesized that the zinc transporter ZIP7 that controls Zn 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 Zn and, accumulation of PINK1 and Parkin in mitochondria, suggesting that the decrease in mitochondrial Zn 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.
虽然通过线粒体自噬消除受损线粒体被认为具有心脏保护作用，但再灌注时线粒体自噬的调节及其潜在机制仍不清楚。由于线粒体锌可能通过调节线粒体膜电位（MMP）来控制线粒体自噬，我们推测控制线粒体内锌水平的锌转运体ZIP7会通过调节线粒体自噬导致再灌注损伤。对小鼠心脏进行体内缺血/再灌注。通过检测线粒体LC3II、线粒体Keima和线粒体质量控制蛋白（mitoQC）来评估线粒体自噬。用二氢乙锭（DHE）和线粒体B测量活性氧（ROS）。用TTC染色测量梗死面积。采用CRISPR/Cas9系统构建心脏特异性ZIP7条件性敲除小鼠（ZIP7 cKO）。从心脏移植手术的供体和受体获取人类心脏样本。ZIP7的敲除或条件性敲除在生理条件下增加了线粒体自噬。小鼠心脏再灌注早期线粒体自噬未被激活。ZIP7在再灌注时上调，ZIP7 cKO增强了再灌注时的线粒体自噬。ZIP7的条件性敲除通过增加线粒体锌导致线粒体去极化，以及PINK1和帕金蛋白在线粒体内的积累，这表明ZIP7上调导致的线粒体锌减少从而引起线粒体超极化，可能会阻碍PINK1和帕金蛋白在线粒体内的积累。值得注意的是，心力衰竭（HF）患者心脏线粒体中ZIP7明显上调，而线粒体PINK1的积累和线粒体自噬受到抑制。此外，ZIP7 cKO通过依赖PINK1的方式减少线粒体ROS生成和心肌梗死，而ZIP7的过表达加剧了心肌梗死。我们的研究结果表明，ZIP7上调导致线粒体自噬受抑制是心肌再灌注损伤的一个关键特征。及时抑制心脏ZIP7上调或使ZIP7失活对于治疗再灌注损伤至关重要。
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