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Keywords:

  • oxidative stress;
  • mitochondria;
  • calcium;
  • reactive oxygen species;
  • cyclosporine A;
  • permeability transition;
  • melatonin

Mitochondrial oxidative stress has been reported as the result of respiratory complex anomalies, genetic defects, or insufficient oxygen or glucose supply. Although Ca2+ has no direct effect on respiratory chain function or oxidation/reduction process, mitochondrial Ca2+ overload can lead to reactive oxygen species (ROS) increase. Even though Ca2+ is well known for its role as crucial second messenger in modulating many cellular physiological functions, Ca2+ overload is detrimental to mitochondrial function and may present as an important cause of mitochondrial ROS generation. Possible mechanisms include Ca2+ stimulated increase of metabolic rate, Ca2+ stimulated nitric oxide production, Ca2+ induced cytochrome c dissociation, Ca2+ induced cardiolipin peroxidation, Ca2+ induced mitochondrial permeability transition pore opening with release of cytochrome c and GSH-antioxidative enzymes, and Ca2+-calmodulin dependent protein kinases activation. Different mechanisms may exist under different mitochondrial preparations (isolated mitochondria vs. mitochondria in intact cells), tissue sources, animal species, or inhibitors used. Furthermore, mitochondrial ROS rise can modulate Ca2+ dynamics and augment Ca2+ surge. The reciprocal interactions between Ca2+ induced ROS increase and ROS modulated Ca2+ upsurge may cause a feedforward, self-amplified loop createing cellular damage far beyond direct Ca2+ induced damage.