Mitochondria as triggers and executors of cell death

Abstract

Necrosis and apoptosis can occur simultaneously in heart infarction, stroke, and ischemia or in chemical poisoning. By regulating the intracellular ATP level, mitochondria might influence the mode of cell death execution.In cerebellar neurons the endogenous mediator nitric oxide and the exogenous mitochondrial toxin MPP+ triggered indirect excitotoxicity. Apoptosis under this condition was characterised by: i) initial intracellular ATP depletion, ii) [Ca2+]i increase, iii)?DYm dissipation and iv) cyt c release. The putative food excitotoxin aspartame (APM) triggered NMDA-R-dependent excitotoxicity in CGC. Caspases were not activated in APM-induced apoptosis. Apoptosis inducing factor (AIF) was translocated from mitochondria to the nucleus in APM and in glutamate treated cells. Release of AIF preceded cytochrome c release.Jurkat cells exposed to staurosporine (STS) undergo apoptosis in a caspase-dependent manner. ATP depletion converted STS-induced cell death from apoptosis to necrosis. TBT decreased intracellular ATP and triggered apoptosis or necrosis in Jurkat cells depending on the concentration used. ATP levels in the cells modulate the switch between apoptosis and necrosis. Two different steps are involved in this phenomenon: i) release of mitochondrial proteins and ii) caspase activation. Restoration of ATP led to DYm loss, mitochondrial swelling, cyt c and adenylate kinase release and caspase activation. Under ATP depleted conditions, release of mitochondrial protein and loss of DYm were delayed and caspases were not activated.Mitochondria can play a role at all stages of cell death. Mitochondrial are involved in the initiation of cell death in excitotoxicity. Mitochondrial damage (calcium, nitric oxide, toxins) can induce enhancing loops within the death program. Release of mitochondrial proapoptotic proteins and ATP levels can decide if caspase-dependent apoptosis, caspase-independent apoptosis or necrosis is the mode of cell death.