Mitochondrial calcium release induced by prooxidants.
Hydrogen peroxide, a physiological metabolite, and a variety of other potentially toxic prooxidants, cause oxidation of the pyridine nucleotides NAD(P)H to NAD(P)+ in mitochondria. In Ca(2+)-loaded mitochondria NAD+ thus formed is hydrolyzed to ADP-ribose and nicotinamide. Subsequent to NAD+ hydrolysis, Ca2+ is released from the organelles via a specific pathway which is sensitive to several inhibitors, among them cyclosporine A and some of its derivatives. The release is probably regulated by peptidyl-prolyl cis-trans isomerase. Prolonged stimulation of the release pathway by certain prooxidants followed by re-uptake and release of Ca2+ (Ca2+ 'cycling') leads to collapse of the mitochondrial membrane potential, and is detrimental to the organelles. Excessive Ca2+ 'cycling' is likely to be a basis for the cell toxicity of some prooxidants. On the other hand, the toxicity of inhibitors of the prooxidant-induced Ca2+ release pathway may be due to long-term Ca2+ overloading of mitochondria.
Richter
C
C
Laboratorium für BIochemie I, ETH Zürich Schweiz.
Schlegel
J
J
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D016877:Oxidants / Q000494:pharmacology*; D010084:Oxidation-Reduction
D016877:Oxidants; D002118:Calcium