Journal
CELL DEATH AND DIFFERENTIATION
Volume 13, Issue 10, Pages 1815-1826Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.cdd.4401813
Keywords
mitochondrial Na+ overload; TRPM2; PARP; apoptosis; necrosis
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Overproduction of reactive oxygen species is one of the major causes of cell death in ischemic-reperfusion (I/R) injury. In I/R animal models, electron microscopy (EM) has shown mixed apoptotic and necrotic characteristics in the same cardiomyocyte. The present study shows that H2O2 activates both apoptotic and necrotic machineries in the same myocyte and that the ultrastructure seen using EM is very similar to that in I/R animal studies. The apoptotic component is caused by the activation of clotrimazole-sensitive, NAD(+)/ DP ribose/poly (ADP-ribose) polymerase (PARP)-dependent transient receptor potential M2 (TRPM2) channels, which induces mitochondrial [Na+](m) (and [Ca2+] m) overload, resulting in mitochondrial membrane disruption, cytochrome c release, and caspase 3-dependent chromatin condensation/ fragmentation. The necrotic component is caspase 3-independent and is caused by PARP-induced [ATP](i)/NAD(+) depletion, resulting in membrane permeabilization. Inhibition of either TRPM2 or PARP activity only partially inhibits cell death, while inhibition of both completely prevents the ultrastructural changes and myocyte death.
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