Oxidative stress caused by mitochondrial calcium overload.
Mitochondrial oxidative stress has been reported as the result of respiratory complex anomalies, genetic defects, or insufficient oxygen or glucose supply. Although Ca(2+) has no direct effect on respiratory chain function or oxidation/reduction process, mitochondrial Ca(2+) overload can lead to reactive oxygen species (ROS) increase. Even though Ca(2+) is well known for its role as crucial second messenger in modulating many cellular physiological functions, Ca(2+) overload is detrimental to mitochondrial function and may present as an important cause of mitochondrial ROS generation. Possible mechanisms include Ca(2+) stimulated increase of metabolic rate, Ca(2+) stimulated nitric oxide production, Ca(2+) induced cytochrome c dissociation, Ca(2+) induced cardiolipin peroxidation, Ca(2+) induced mitochondrial permeability transition pore opening with release of cytochrome c and GSH-antioxidative enzymes, and Ca(2+)-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 Ca(2+) dynamics and augment Ca(2+) surge. The reciprocal interactions between Ca(2+) induced ROS increase and ROS modulated Ca(2+) upsurge may cause a feedforward, self-amplified loop createing cellular damage far beyond direct Ca(2+) induced damage.
Peng
Tsung-I
TI
Department of Neurology, Chang Gung Memorial Hospital at Kee-Lung, Kee-Lung, Taiwan.
Jou
Mei-Jie
MJ
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002308:Cardiolipins / Q000737:chemistry; D016572:Cyclosporine / Q000494:pharmacology; D045304:Cytochromes c / Q000378:metabolism; D006801:Humans; D008550:Melatonin / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress; D017382:Reactive Oxygen Species; D015398:Signal Transduction
D002308:Cardiolipins; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D016572:Cyclosporine; D045304:Cytochromes c; D008550:Melatonin; D002118:Calcium