AMPK is critical for mitochondrial function during reperfusion after myocardial ischemia

Vlad G. Zaha, Dake Qi, Kevin N. Su, Monica Palmeri, Hui Young Lee, Xiaoyue Hu, Xiaohong Wu, Gerald I. Shulman, Peter S. Rabinovitch, Raymond R. Russell, Lawrence H. Young

Research output: Contribution to journalArticle

30 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)104-113
Number of pages10
JournalJournal of Molecular and Cellular Cardiology
Volume91
DOIs
StatePublished - Feb 1 2016

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AMP-Activated Protein Kinases
Reperfusion
Myocardial Ischemia
Phosphotransferases
Necrosis
Mitochondria
MAP Kinase Kinase 4
Coronary Occlusion
Reperfusion Injury
Cardiac Myocytes
Catalase
Hydrogen Peroxide
Cell Survival
Ischemia
Oxygen

Keywords

  • AMPK
  • Ischemia
  • Mitochondria
  • Reperfusion
  • Signal transduction

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

Cite this

AMPK is critical for mitochondrial function during reperfusion after myocardial ischemia. / Zaha, Vlad G.; Qi, Dake; Su, Kevin N.; Palmeri, Monica; Lee, Hui Young; Hu, Xiaoyue; Wu, Xiaohong; Shulman, Gerald I.; Rabinovitch, Peter S.; Russell, Raymond R.; Young, Lawrence H.

In: Journal of Molecular and Cellular Cardiology, Vol. 91, 01.02.2016, p. 104-113.

Research output: Contribution to journalArticle

Zaha, VG, Qi, D, Su, KN, Palmeri, M, Lee, HY, Hu, X, Wu, X, Shulman, GI, Rabinovitch, PS, Russell, RR & Young, LH 2016, 'AMPK is critical for mitochondrial function during reperfusion after myocardial ischemia', Journal of Molecular and Cellular Cardiology, vol. 91, pp. 104-113. https://doi.org/10.1016/j.yjmcc.2015.12.032
Zaha, Vlad G. ; Qi, Dake ; Su, Kevin N. ; Palmeri, Monica ; Lee, Hui Young ; Hu, Xiaoyue ; Wu, Xiaohong ; Shulman, Gerald I. ; Rabinovitch, Peter S. ; Russell, Raymond R. ; Young, Lawrence H. / AMPK is critical for mitochondrial function during reperfusion after myocardial ischemia. In: Journal of Molecular and Cellular Cardiology. 2016 ; Vol. 91. pp. 104-113.
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