Role of Mitochondrial Inner Membrane Permeabilization in Necrotic Cell Death, Apoptosis, and Autophagy

Abstract

Inhibition of mitochondrial oxidative phosphorylation progresses to uncoupling when opening of cyclosporin A-sensitive permeability transition pores increases permeability of the mitochondrial inner membrane to small solutes. Involvement of the mitochondrial permeability transition (MPT) in necrotic and apoptotic cell death is implicated by demonstrations of protection by cyclosporin A against oxidative stress, ischemia/reperfusion, tumor necrosis factor-alpha exposure, Fas ligation, calcium overload, and a variety of toxic chemicals. Confocal microscopy directly visualizes the MPT in single mitochondria within living cells from the translocation of impermeant fluorophores, such as calcein, across the inner membrane. Simultaneously, mitochondria release potential-indicating fluorophores. Subsequently, mitochondria swell, causing outer membrane rupture and release of cytochrome c and other proapoptotic proteins from the intermembrane space. In situ a sequence of decreased NAD(P)H, increased free calcium, and increased reactive oxygen species formation within mitochondria promotes the MPT and subsequent cell death. Necrotic and apoptotic cell death after the MPT depends, in part, on ATP levels. If ATP levels fall profoundly, glycine-sensitive plasma membrane permeabilization and rupture ensue. If ATP levels are partially maintained, apoptosis follows the MPT. The MPT also signals mitochondrial autophagy, a process that may be important in removing damaged mitochondria. Cellular features of necrosis, apoptosis, and autophagy frequently occur together after death signals and toxic stresses. A new term, necrapoptosis, describes such death processes that begin with a common stress or death signal, progress by shared pathways, but culminate in either cell lysis (necrosis) or programmed cellular resorption (apoptosis), depending on modifying factors such as ATP.

Excitotoxic Calcium Overload in a Subpopulation of Mitochondria Triggers Delayed Death in Hippocampal Neurons

“…This elevation of average basal [Ca] mito arises because [Ca] mito in a fraction of mitochondria did not return to control levels in ϳ35% of cells. Most mitochondria in this subset of cells had normal ultrastructure, but the ϳ17% that still retained a high Ca load appeared to be irreversibly damaged and in the process of disintegration and autophagic removal (Lemasters et al, 2002). It is plausible that the persistence of injured mitochondria at this late time after overstimulation marks the cells that were most vulnerable.…”

The p75 Neurotrophin Receptor Can Induce Autophagy and Death of Cerebellar Purkinje Neurons

“…These studies demonstrate that autophagy may be a mechanism for mutant protein degradation and the prevention of plaque formation. Similarly, in cases in which mitochondria are extensively damaged, autophagy may be protective by sequestering and degrading defective mitochondria before they can release death-inducing proteins (Lemasters et al, 2002;Tolkovsky et al, 2002). One can speculate that the degree and specificity of autophagy may determine cell fate.…”

The interactions of flavonoids within neuronal signalling pathways

“…4). Additionally, oxidative stress may affect mitochondria by influencing the mitochondrial transition pore (mPT) and/or release of cytochrome c [88,102]. There is strong evidence linking the activation of JNK to neuronal death in response to a wide array of pro-apoptotic stimuli both in developmental and degenerative death signalling [46,118].…”