VDAC1 promotes cardiomyocyte autophagy in anoxia/reoxygenation injury via the PINK1/Parkin pathway

Abstract

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.

RETRACTED: Molecular Perspectives of Mitophagy in Myocardial Stress: Pathophysiology and Therapeutic Targets

“…When an acute myocardial injury, such as myocardial infarction, occurs, cardiomyocytes are in a state of stress and their mitochondria are extremely vulnerable to damage ( Ji et al, 2016 ; Alakoski et al, 2019 ; Lassen et al, 2021 ), so autophagy is crucial to eliminate damaged mitochondria and avoid further oxidative stress and apoptosis ( Kubli et al, 2015 ). PINK1/Parkin-induced mitophagy was found to be significantly upregulated during myocardial stress in response to ischemia and hypoxia ( Steffen et al, 2020 ; Yang et al, 2021b ). The loss of PINK1 was reported to inhibit mitophagy and induce reactive oxygen species accumulation and inflammation, leading to cardiomyocyte death and myocardial dysfunction ( Dhanabalan et al, 2020 ).…”

Circ-CIMIRC inhibition alleviates CIH-induced myocardial damage via FbxL4-mediated ubiquitination of PINK1

“… 23 VDAC1 regulate PINK1/Parkin pathway to promote autophagy, thereby aggravating anoxia/reoxygenation-induced apoptosis of cardiomyocytes. 24 Qiliqiangxin, a traditional Chinese medicine compound, inhibits apoptosis of cardiomyocytes and improves heart function in myocardial infarction rats by regulating PINK1/Parkin pathway-mediated mitophagy. 25 In the present work, we observed downregulation of PINK1 and Parkin, and increased levels of PINK1 ubiquitination in CIH rats.…”

Protective effects of Shen Yuan Dan on myocardial ischemia-reperfusion injury via the regulation of mitochondrial quality control

“…A growing number of studies have revealed that the regulation of PINK1/Parkin pathway is critical for the alleviation of MIRI. For example, Yang and co-workers have found that the suppression of PINK1/Parkin pathway by VDAC1 downregulation could attenuate MIRI ( 65 ). Additionally, the regulation of PINK1/Parkin pathway by the inhibition of myosin IIA-actin interaction-induced actomyosin contractility could impede MIRI ( 66 ).…”