Ischemic preconditioning protects cardiomyocyte mitochondria through mechanisms independent of cytosol

J Mol Cell Cardiol. 2014 Mar:68:79-88. doi: 10.1016/j.yjmcc.2014.01.001. Epub 2014 Jan 13.


Mitochondria play a central role in the protection conferred by ischemic preconditioning (IP) by not fully elucidated mechanisms. We investigated whether IP protects mitochondria against ischemia-reperfusion (IR) injury through mechanisms independent of cytosolic signaling. In isolated rat hearts, sublethal IR increased superoxide production and reduced complex-I- and II-mediated respiration in subsarcolemmal (SS), but not interfibrillar (IF) mitochondria. This effect of IR on mitochondrial respiration was significantly attenuated by IP. Similar results were obtained in isolated cardiac mitochondria subjected to in vitro IR. The reduction in SS mitochondrial respiration in the heart and in vitro model was paralleled by an increase in oxidized cysteine residues, which was also prevented by IP. IP was also protective in mitochondria submitted to lethal IR. The protective effect of IP against respiratory failure was unaffected by inhibition of mitochondrial KATP channels or mitochondrial permeability transition. However, IP protection was lost in mitochondria from genetically-modified animals in which connexin-43, a protein present in SS but not IF mitochondria, was replaced by connexin-32. Our results demonstrate the existence of a protective mitochondrial mechanism or "mitochondrial preconditioning" independent of cytosol that confers protection against IR-induced respiratory failure and oxidative damage, and requires connexin-43.

Keywords: Cardioprotection; Heart; Ischemia; Mitochondria; Reperfusion.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Respiration
  • Connexin 43 / metabolism
  • Coronary Circulation
  • Cytosol / metabolism
  • In Vitro Techniques
  • Ion Channel Gating
  • Ischemic Preconditioning*
  • Male
  • Mice
  • Mice, Knockout
  • Mitochondria, Heart / physiology*
  • Mitochondrial Proteins / metabolism
  • Myocardial Reperfusion Injury / pathology
  • Myocardial Reperfusion Injury / prevention & control*
  • Oxidation-Reduction
  • Oxidative Phosphorylation
  • Oxidative Stress
  • Peroxynitrous Acid / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction
  • Superoxides / metabolism


  • Connexin 43
  • Mitochondrial Proteins
  • Superoxides
  • Peroxynitrous Acid