Upregulation of mitochondrial E3 ubiquitin ligase 1 in rat heart contributes to ischemia/reperfusion injury

• Published in: Canadian journal of physiology and pharmacology Vol. 98; no. 5; pp. 259 - 266
• Main Authors: Wang, Shi-Jing, Chen, Heng, Tang, Li-Jing, Tu, Hua, Liu, Bin, Li, Nian-Sheng, Luo, Xiu-Ju, Peng, Jun
• Format: Journal Article
• Language: English
• Published: Canada NRC Research Press 01.05.2020; Canadian Science Publishing NRC Research Press
• Subjects: Adenosine Triphosphate - metabolism; Animals; Apoptosis; Cell death; Cell Line; Creatine; Creatine kinase; E3 ubiquitine ligase mitochondriale 1; Gene Knockdown Techniques; Genes; Hypoxia; hypoxia/reoxygenation; hypoxie/réoxygénation; Ischemia; ischemia/reperfusion; ischémie/reperfusion; Kinases; Ligases; lésions myocardiques; Male; Membrane potential; Membrane Potential, Mitochondrial; Mitochondria; Mitochondria - metabolism; mitochondrial E3 ubiquitin ligase 1; Mitochondrial Proteins - deficiency; Mitochondrial Proteins - genetics; Mitochondrial Proteins - metabolism; mitochondrie; myocardial injury; Myocardial Reperfusion Injury - genetics; Myocardial Reperfusion Injury - metabolism; Myocardial Reperfusion Injury - pathology; p53; p53 Protein; Rats; Rats, Sprague-Dawley; Reactive oxygen species; Reactive Oxygen Species - metabolism; Reperfusion; SUMO protein; SUMOylation; Tumor proteins; Tumor Suppressor Protein p53 - metabolism; Ubiquitin; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - deficiency; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Up-Regulation; China; ischemia/reperfusion; mitochondrie; myocardial injury; mitochondria; mitochondrial E3 ubiquitin ligase 1; SUMOylation; lésions myocardiques; E3 ubiquitine ligase mitochondriale 1; hypoxie/réoxygénation; hypoxia/reoxygenation; ischémie/reperfusion; p53
• ISSN: 0008-4212; 1205-7541
• DOI: 10.1139/cjpp-2019-0285

Mitochondrial dysfunctions are responsible for myocardial injury upon ischemia/reperfusion (I/R), and mitochondrial E3 ubiquitin ligase 1 (Mul1) plays an important role in maintaining mitochondrial functions. This study aims to explore the function of Mul1 in myocardial I/R injury and the underlying mechanisms. The Sprague–Dawley rat hearts were subjected to 1 h of ischemia plus 3 h of reperfusion, which showed the I/R injury (increase in infarct size and creatine kinase release) and the elevated total and mitochondrial protein levels of Mul1 and p53 accompanied by the enhanced interactions between Mul1 and p53 as well as p53 and small a ubiquitin-like modifier (SUMO1). Consistently, hypoxia/reoxygenation (H/R) treated cardiac (H9c2) cells displayed cellular injury (apoptosis and necrosis), upregulation of total and mitochondrial protein levels of Mul1 and p53, and enhanced interactions between p53 and SUMO1 concomitant with mitochondrial dysfunctions (an increase in mitochondrial membrane potential and reactive oxygen species production with a decrease in ATP production); these phenomena were attenuated by knockdown of Mul1 expression. Based on these observations, we conclude that a novel role of Mul1 has been identified in the myocardial mitochondria, where Mul1 stabilizes and activates p53 through its function of SUMOylation following I/R, leading to p53-mediated mitochondrial dysfunction and cell death.