Jiangxi Provincial Key Laboratory of Basic Pharmacology, Department of Pharmacology, School of Pharmaceutical Science, Nanchang University, Nanchang, China.
Department of Biochemistry, College of Basic Medical Sciences, Nanchang University, Nanchang, China.
Cell Biol Int. 2021 Jul;45(7):1448-1458. doi: 10.1002/cbin.11583. Epub 2021 Mar 19.
Ischemia/reperfusion (I/R) is a well-known injury to the myocardium, but the mechanism involved remains elusive. In addition to the well-accepted apoptosis theory, autophagy was recently found to be involved in the process, exerting a dual role as protection in ischemia and detriment in reperfusion. Activation of autophagy is mediated by mitochondrial permeability transition pore (MPTP) opening during reperfusion. In our previous study, we showed that MPTP opening is regulated by VDAC1, a channel protein located in the outer membrane of mitochondria. Thus, upregulation of VDAC1 expression is a possible trigger to cardiomyocyte autophagy via an unclear pathway. Here, we established an anoxia/reoxygenation (A/R) model in vitro to simulate the I/R process in vivo. At the end of A/R treatment, VDAC1, Beclin 1, and LC3-II/I were upregulated, and autophagic vacuoles were increased in cardiomyocytes, which showed a connection of VDAC1 and autophagy development. These variations also led to ROS burst, mitochondrial dysfunction, and aggravated apoptosis. Knockdown of VDAC1 by RNAi could alleviate the above-mentioned cellular damages. Additionally, the expression of PINK1 and Parkin was enhanced after A/R injury. Furthermore, Parkin was recruited to mitochondria from the cytosol, which suggested that the PINK1/Parkin autophagic pathway was activated during A/R. Nevertheless, the PINK1/Parkin pathway was effectively inhibited when VDAC1 was knocked-down. Taken together, the A/R-induced cardiomyocyte injury was mediated by VDAC1 upregulation, which led to cell autophagy via the PINK1/Parkin pathway, and finally aggravated apoptosis.
缺血/再灌注（I/R）是一种众所周知的心肌损伤，但涉及的机制仍不清楚。除了公认的细胞凋亡理论外，最近发现自噬也参与其中，在缺血时发挥保护作用，在再灌注时则发挥损害作用。自噬的激活是由再灌注期间线粒体通透性转换孔（MPTP）的打开介导的。在我们之前的研究中，我们表明 MPTP 的打开受位于线粒体外膜的通道蛋白 VDAC1 调节。因此，VDAC1 表达的上调可能是通过尚不清楚的途径触发心肌细胞自噬的一个可能触发因素。在这里，我们建立了一个体外缺氧/复氧（A/R）模型，以模拟体内的 I/R 过程。在 A/R 处理结束时，VDAC1、Beclin 1 和 LC3-II/I 上调，心肌细胞中的自噬空泡增加，这表明 VDAC1 与自噬的发展有关。这些变化还导致 ROS 爆发、线粒体功能障碍和加重细胞凋亡。RNAi 敲低 VDAC1 可以减轻上述细胞损伤。此外，A/R 损伤后 PINK1 和 Parkin 的表达增强。此外，Parkin 从细胞质募集到线粒体，这表明 PINK1/Parkin 自噬途径在 A/R 期间被激活。然而，当敲低 VDAC1 时，PINK1/Parkin 途径被有效抑制。总之，A/R 诱导的心肌细胞损伤是由 VDAC1 上调介导的，通过 PINK1/Parkin 途径导致细胞自噬，最终加重细胞凋亡。
