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Mitochondrial Na+ Overload Is Caused by Oxidative Stress and Leads to Activation of the Caspase 3- Dependent Apoptotic Machinery

Mitochondrial Na+ Overload Is Caused by Oxidative Stress and Leads to Activation of the Caspase 3- Dependent Apoptotic Machinery

Kun-Ta Yang, Shwu-Fen Pan, Chung-Liang Chien, Su-Ming Hsu, Yung-Zu Tseng, Seu-Mei Wang, Mei-Lin Wu

FASEB J. 2004 Sep;18(12):1442-4.

PMID: 15231730

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 overload is an important upstream signal for the apoptotic machinery, and the prevention of [Na]m overload thus represents a particularly attractive target for strategies aimed at preventing oxidative stress-induced cell death.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
ISM6702	Hydrogen ionophore I - cocktail A			Price

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