title: AMPK is critical for mitochondrial function during reperfusion after myocardial ischemia.
abstract: AMP-activated kinase (AMPK) is a stress responsive kinase that regulates cellular metabolism and protects against cardiomyocyte injury during ischemia-reperfusion (IR). Mitochondria play an important role in cell survival, but the specific actions of activated AMPK in maintaining mitochondrial integrity and function during reperfusion are unknown. Thus, we assessed the consequences of AMPK inactivation on heart mitochondrial function during reperfusion. Mouse hearts expressing wild type (WT) or kinase-dead (KD) AMPK were studied. Mitochondria isolated from KD hearts during reperfusion had intact membrane integrity, but demonstrated reduced oxidative capacity, increased hydrogen peroxide production and decreased resistance to mitochondrial permeability transition pore opening compared to WT. KD hearts showed increased activation of the mitogen activated protein kinase kinase 4 (MKK4) and downstream c-Jun terminal kinase (JNK) and greater necrosis during reperfusion after coronary occlusion. Transgenic expression of mitochondrial catalase (MCAT) prevented the excessive cardiac JNK activation and attenuated the increased myocardial necrosis observed during reperfusion in KD mice. Inhibition of JNK increased the resistance of KD hearts to mPTP opening, contractile dysfunction and necrosis during IR. Thus, intrinsic activation of AMPK is critical to prevent excess mitochondrial reactive oxygen production and consequent JNK signaling during reperfusion, thereby protecting against mPTP opening, irreversible mitochondrial damage and myocardial injury.
authors.affiliation: Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Vlad G
authors.initials: VG
authors.lastname: Zaha
authors.affiliation: Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Dake
authors.initials: D
authors.lastname: Qi
authors.affiliation: Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Kevin N
authors.initials: KN
authors.lastname: Su
authors.affiliation: Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Monica
authors.initials: M
authors.lastname: Palmeri
authors.affiliation: Section of Endocrinology and Metabolism, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Hui-Young
authors.initials: HY
authors.lastname: Lee
authors.affiliation: Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Xiaoyue
authors.initials: X
authors.lastname: Hu
authors.affiliation: Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Wu
authors.affiliation: Section of Endocrinology and Metabolism, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA; Department of Molecular and Cellular Physiology, Yale University School of Medicine, New Haven, CT, USA; Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Gerald I
authors.initials: GI
authors.lastname: Shulman
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Rabinovitch
authors.affiliation: Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Raymond R
authors.initials: RR
authors.lastname: Russell
authors.affiliation: Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA; Department of Molecular and Cellular Physiology, Yale University School of Medicine, New Haven, CT, USA. Electronic address: lawrence.young@yale.edu.
authors.forename: Lawrence H
authors.initials: LH
authors.lastname: Young
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002374:Catalase / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006861:Hydrogen Peroxide / Q000037:antagonists & inhibitors / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D009203:Myocardial Infarction / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015425:Myocardial Reperfusion; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009336:Necrosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction; D019076:Transgenes
chemical_list: D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D047428:Protein Kinase Inhibitors; D006861:Hydrogen Peroxide; D002374:Catalase; D048670:MAP Kinase Kinase 4
keywords: AMPK; Ischemia; Mitochondria; Reperfusion; Signal transduction