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Center for Cell Death, Injury and Regeneration


Mitochondrial Permeability Transition: Increased Ca2+, formation of reactive oxygen and nitrogen species, and oxidation of pyridine nucleotides and glutathione promote a phenomenon called the mitochondrial permeability transition (MPT) that, in turn, leads to mitochondrial depolarization and uncoupling of oxidative phosphorylation. Our studies in living cells show that the MPT initially induces the sequestration and lysosomal degradation of mitochondria by the process of autophagy, a selective process also called mitophagy. However, excess MPT induction induces both necrotic cell death and apoptosis during reperfusion injury, oxidative stress, excitotoxicity, calcium ionophore-induced toxicity, drug toxicity, exposure to tumor necrosis factor-alpha (TNFa) and Fas ligation to liver, heart, tumor, and brain cells. Inhibitors of the MPT, such as cyclosporin A, decrease or abolish cell killing in these models. Progression to apoptosis or necrosis after the MPT depends on the presence or absence, respectively, of ATP. Often, features of both apoptotic and necrotic cell death develop after death signals and toxic stresses. We introduce the term ‘‘necrapoptosis’’ to emphasize the shared pathways leading to both forms of cell death. These findings offer new strategies to rescue cells and tissues from irreversible toxic and ischemic injury. Figure 1 shows the pathways during onset of MPT due to ischemia reperfusion injury leading to necortic or apapototic cell death.

Figure 1.  MPT: a shared pathway leading to apoptosis and necrosis. Ischemia/reperfusion increases mitochondrial Ca2+ and  ROS formation, which in turn promote opening of PT pores and onset of the MPT. CsA and acidotic pH prevent reperfusion-induced MPT. After onset of the MPT, changes of ATP regulate the mode of cell death. When ATP loss is profound due to interruption of mitochondrial oxidative phosphorylation, the plasma membrane permeability barrier fails, leading to necrosis. Glycine prevents this membrane failure. ATP depletion simultaneously inhibits apoptotic signaling. When ATP loss is rescued by glycolysis of fructose or other glycolytic substrate, necrosis is prevented. Instead, mitochondrial swelling after the MPT causes release of proapoptotic molecules, such as cytochrome c, leading to caspase 3 activation and apoptosis. If ATP levels fall subsequent to caspase 3 activation, then secondary necrosis develops.


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