Mitochondrial Na+ overload is caused by oxidative stress and leads to activation of the caspase 3-dependent apoptotic machinery
Journal
FASEB Journal
Journal Volume
18
Journal Issue
12
Pages
1442-1444
Date Issued
2004
Author(s)
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.
SDGs
Other Subjects
caspase 3; hydrogen peroxide; sodium calcium exchange protein; sodium ion; animal cell; apoptosis; article; calcium cell level; cardiovascular disease; controlled study; heart muscle cell; membrane potential; mitochondrial membrane; mitochondrion; nonhuman; oxidative stress; priority journal; signal transduction; sodium cell level; Apoptosis; Calcium; Caspase 3; Caspases; Cytochromes c; Cytosol; Enzyme Activation; Hydrogen Peroxide; Mitochondria; Myocytes, Cardiac; Oxidative Stress; Signal Transduction; Sodium; Sodium-Calcium Exchanger; Animalia
Type
journal article