Mitochondrial JNK activation triggers autophagy and apoptosis and aggravates myocardial injury following ischemia/reperfusion.

Abstract

c-Jun N-terminal kinase (JNK) is a stress-activated mitogen-activated protein kinase that plays a central role in initiating apoptosis in disease conditions. Recent studies have shown that mitochondrial JNK signaling is partly responsible for ischemic myocardial dysfunction; however, the underlying mechanism remains unclear. Here we report for the first time that activation of mitochondrial JNK, rather than JNK localization on mitochondria, induces autophagy and apoptosis and aggravates myocardial ischemia/reperfusion injury. Myocardial ischemia/reperfusion induced a dominant increase of mitochondrial JNK phosphorylation, while JNK mitochondrial localization was reduced. Treatment with Tat-SabKIM1, a retro-inverso peptide which blocks JNK interaction with mitochondria, decreased mitochondrial JNK activation without affecting JNK mitochondrial localization following reperfusion. Tat-SabKIM1 treatment reduced Bcl2-regulated autophagy, cytochrome c-mediated apoptosis and myocardial infarct size. Notably, selective inhibition of mitochondrial JNK activation using Tat-SabKIM1 produced a similar infarct size-reducing effect as inhibiting universal JNK activation with JNK inhibitor SP600125. Moreover, insulin-treated animals exhibited significantly dampened mitochondrial JNK activation accompanied by reduced infarct size and diminished autophagy and apoptosis following reperfusion. Taken together, these findings demonstrate that mitochondrial JNK activation, rather than JNK mitochondrial localization, induces autophagy and apoptosis and exacerbates myocardial ischemia/reperfusion injury. Insulin selectively inhibits mitochondrial JNK activation, contributing to insulin cardioprotection against myocardial ischemic/reperfusion injury. This article is part of a Special Issue entitled: Autophagy and protein quality control in cardiometabolic diseases.

• Authors: Jie Xu, Xinghua Qin, Xiaoqing Cai, Lu Yang, Yuan Xing, Jun Li, Lihua Zhang, Ying Tang, Jiankang Liu, Xing Zhang, Feng Gao
• Journal: Biochimica et biophysica acta (Biochim Biophys Acta) Vol. 1852 Issue 2 Pg. 262-70 (Feb 2015) ISSN: 0006-3002 [Print] Netherlands
• PMID: 24859228 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier B.V. All rights reserved.

Chemical References

• Cardiotonic Agents
• Insulin
• Peptides
• Proto-Oncogene Proteins c-bcl-2
• JNK Mitogen-Activated Protein Kinases

Topics

• Animals
• Apoptosis (drug effects)
• Autophagy (drug effects)
• Cardiotonic Agents (pharmacology)
• Enzyme Activation (drug effects)
• Insulin (pharmacology)
• JNK Mitogen-Activated Protein Kinases (antagonists & inhibitors, metabolism)
• Male
• Mitochondria (drug effects, enzymology)
• Models, Biological
• Myocardial Reperfusion Injury (enzymology, pathology)
• Myocardium (pathology)
• Peptides (pharmacology)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Rats, Sprague-Dawley