Mitochondrial Membrane Permeabilization in Physiological and Pathological Cell Death

Abstract

Mitochondrial membrane permeabilization (MMP) is a hallmark of early apoptosis, including apoptosis occurring in neurons. Evidence is accumulating that mitochondria play a prime role in the processes of ischemia/reperfusion damage, excitotoxicity and neurodegeneration. MMP is regulated by pro-and anti-apoptotic members of a Bax/Bcl-2 family of proteins, via a process that may involve sessile mitochondrial proteins organized in the two membrane-spanning permeability transition pore complex (PTPC). Apoptotic MMP differentially affects the outer and inner mitochondrial membranes. The inner mitochondrial membrane becomes permeable to solutes up to 1500 Da, yet retains matrix proteins in their normal localization. In contrast, the outer mitochondrial membrane becomes completely permeabilized to proteins, leading to the release of soluble proteins from the mitochondrial intermembrane space to an ectopic (extramitochondrial) localization. Several intermembrane proteins can activate catabolic hydrolases involved in the apoptotic process. One such protein is cytochrome c, which participates in the caspase activation cascade. Another functionally important intermembrane protein is apoptosis inducing factor (AIF), which provokes nuclear DNA fragmentation and chromatin condensation via a caspase-independent process. In addition to its local nuclear effects, AIF may also participate in the overall regulation of apoptosis, since neutralization of AIF by microinjection of a specific antibody can abort MMP and subsequent apoptosis, at least in some models. The relevance of AIF for caspase-independent neuronal cell death remains to be established.