Teng Sun1, Wei Ding2, Tao Xu1, Xiang Ao1, Tao Yu1, Mengyang Li3, Ying Liu1, Xuejuan Zhang2, Lin Hou3, Jianxun Wang1,3. 1. Institute for Translational Medicine, Qingdao University, Qingdao, China. 2. Department of Comprehensive Internal Medicine, Affiliated Hospital, Qingdao University, Qingdao, China. 3. School of Basic Medical Sciences, Qingdao University, Qingdao, China.
Abstract
Aims: Cardiomyocyte death critically contributes to the pathogenesis of cardiac disorders, such as myocardial infarction, heart failure, and cardiac ischemia/reperfusion (I/R) injury. As one of the main forms of cardiac cell death, necrosis plays a critical role in heart diseases. Multiple signaling pathways of necrosis have been demonstrated, in which death receptors, receptor-interacting serine/threonine-protein 1 and 3 kinases, and cyclophilin-D (CypD) have been deeply implicated. However, the fundamental mechanism underlying myocardial necroptosis, especially the mitochondrial permeability transition pore (mPTP)-CypD-dependent death pathway, is poorly understood. Parkin functions as an E3 ubiquitin protein ligase that mainly mediates mitophagy cascades. As yet, it is not clear whether Parkin participates in regulating necrosis and myocardial I/R injury. Results: Here, our results showed that Parkin mediated mitophagy and inhibited necrosis under oxidative stress. In further exploring the underlying mechanisms, we found that Parkin suppressed mPTP opening by catalyzing the ubiquitination of CypD in necrotic cascades, which were not involved in Parkin-regulated mitophagy. Parkin inhibited necrosis, reduced myocardial I/R injury, and improved cardiac function. Innovation: Our present work reveals a highlighted connection between the mitochondrial matrix-localized Parkin and the mPTP-CypD-dependent necrotic signaling pathway in cardiac injury. Conclusion: Our results revealed a novel myocardial necrotic regulating model composed of Parkin, CypD, and mPTP, which may provide potential therapeutic targets and strategies to modulate the levels of these molecules.
Aims: Cardiomyocyte death critically contributes to the pathogenesis of cardiac disorders, such as myocardial infarction, heart failure, and cardiac ischemia/reperfusion (I/R) injury. As one of the main forms of cardiac cell death, necrosis plays a critical role in heart diseases. Multiple signaling pathways of necrosis have been demonstrated, in which death receptors, receptor-interacting serine/threonine-protein 1 and 3 kinases, and cyclophilin-D (CypD) have been deeply implicated. However, the fundamental mechanism underlying myocardial necroptosis, especially the mitochondrial permeability transition pore (mPTP)-CypD-dependent death pathway, is poorly understood. Parkin functions as an E3 ubiquitin protein ligase that mainly mediates mitophagy cascades. As yet, it is not clear whether Parkin participates in regulating necrosis and myocardial I/R injury. Results: Here, our results showed that Parkin mediated mitophagy and inhibited necrosis under oxidative stress. In further exploring the underlying mechanisms, we found that Parkin suppressed mPTP opening by catalyzing the ubiquitination of CypD in necrotic cascades, which were not involved in Parkin-regulated mitophagy. Parkin inhibited necrosis, reduced myocardial I/R injury, and improved cardiac function. Innovation: Our present work reveals a highlighted connection between the mitochondrial matrix-localized Parkin and the mPTP-CypD-dependent necrotic signaling pathway in cardiac injury. Conclusion: Our results revealed a novel myocardial necrotic regulating model composed of Parkin, CypD, and mPTP, which may provide potential therapeutic targets and strategies to modulate the levels of these molecules.
Authors: Anthony R Anzell; Garrett M Fogo; Zoya Gurm; Sarita Raghunayakula; Joseph M Wider; Kathleen J Maheras; Katlynn J Emaus; Timothy D Bryson; Madison Wang; Robert W Neumar; Karin Przyklenk; Thomas H Sanderson Journal: Cell Death Dis Date: 2021-05-12 Impact factor: 8.469
Authors: Juliana de F Germano; Chengqun Huang; Jon Sin; Yang Song; Kyle C Tucker; David J R Taylor; Hannaneh Saadaeijahromi; Aleksandr Stotland; Honit Piplani; Roberta A Gottlieb; Robert M Mentzer; Allen M Andres Journal: Sci Rep Date: 2020-05-19 Impact factor: 4.379