Blockade of electron transport during ischemia preserves bcl-2 and inhibits opening of the mitochondrial permeability transition pore

FEBS Lett. 2011 Mar 23;585(6):921-6. doi: 10.1016/j.febslet.2011.02.029. Epub 2011 Feb 25.

Abstract

Myocardial ischemia damages the electron transport chain and augments cardiomyocyte death during reperfusion. To understand the relationship between ischemic mitochondrial damage and mitochondrial-driven cell death, the isolated perfused heart underwent global stop-flow ischemia with and without mitochondrial protection by reversible blockade of electron transport. Ischemic damage to electron transport depleted bcl-2 content and favored mitochondrial permeability transition (MPT). Reversible blockade of electron transport preserved bcl-2 content and attenuated calcium-stimulated mitochondrial swelling. Thus, the damaged electron transport chain leads to bcl-2 depletion and MPT opening. Chemical inhibition of bcl-2 with HA14-1 also dramatically increased mitochondrial swelling, augmented by exogenous H(2)O(2) stress, indicating that bcl-2 depleted mitochondria are poised to undergo MPT during the enhanced oxidative stress of reperfusion.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amobarbital / pharmacology
  • Animals
  • Benzopyrans / pharmacology
  • Cytochromes c / metabolism
  • Electron Transport / physiology
  • Hydrogen Peroxide / metabolism
  • Hydrogen Peroxide / pharmacology
  • Immunoblotting
  • In Vitro Techniques
  • Mitochondria, Heart / drug effects
  • Mitochondria, Heart / metabolism*
  • Mitochondrial Membrane Transport Proteins / metabolism*
  • Mitochondrial Permeability Transition Pore
  • Mitochondrial Swelling / drug effects
  • Myocardial Reperfusion Injury / metabolism
  • Myocardial Reperfusion Injury / physiopathology*
  • Nitriles / pharmacology
  • Oxidants / metabolism
  • Oxidants / pharmacology
  • Oxidative Phosphorylation / drug effects
  • Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • Rabbits
  • Reactive Oxygen Species / metabolism

Substances

  • Benzopyrans
  • Mitochondrial Membrane Transport Proteins
  • Mitochondrial Permeability Transition Pore
  • Nitriles
  • Oxidants
  • Proto-Oncogene Proteins c-bcl-2
  • Reactive Oxygen Species
  • ethyl 2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate
  • Cytochromes c
  • Hydrogen Peroxide
  • Amobarbital