Mitochondrial Na+ overload is caused by oxidative stress and leads to activation of the caspase 3- dependent apoptotic machinery

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
Kun-Ta YangMei-Lin Wu

Abstract

Oxidative stress is one of the major causes of cell death. Using time-lapse confocal recording of live cardiomyocytes, we showed that H2O2 (OH*) caused a marked increase in Na+ and Ca2+ levels in both the cytosol ([Na]cyt, [Ca]cyt) and mitochondria ([Na]m, [Ca]m). The H2O2-induced intracellular Na+ ([Na]i) overload contributed to the H2O2-induced [Ca]cyt/[Ca]m overload via activation of the reverse mode of the Na-Ca exchanger. When myocytes were treated for 40 min with 100 microM H2O2 in normal medium, then returned to H2O2-free medium, the percentage of apoptotic cells increased from 4% at 0 h to 55 and 85% at 4.5 and 16 h, respectively. H2O2-induced apoptosis was completely prevented by using Na-free, but not Ca-free, medium. When a Na+ ionophore cocktail in Ca-free medium was used instead of H2O2 to increase the [Na]i by more than 30 mM without any change in the [Ca]i, cytochrome c release and caspase 3-dependent apoptosis occurred, showing that [Na]i overload per se induced apoptosis. We also showed that the increase in the mitochondrial, but not the cytosolic, Na+ levels resulted in the opening of the permeation transition pore, followed by cytochrome c release. Our findings therefore suggest that H2O2-induced [Na]m overlo...Continue Reading

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Citations

Nov 8, 2006·Journal of Nutritional Science and Vitaminology·Gustavo Bajotto, Yoshiharu Shimomura
Nov 13, 2012·Toxicology and Applied Pharmacology·Marco PelinAurelia Tubaro
Sep 27, 2008·Journal of Molecular and Cellular Cardiology·Lianguo WangAlexander S Clanachan
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Feb 22, 2017·The EMBO Journal·Tsipi Ben-Kasus NissimIsrael Sekler
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