Abstract
Extensive studies performed in the last 10 years have unveiled a considerable amount of the molecular basis of cell death including apoptosis and some forms of necrosis, which are implicated in various diseases. A change in mitochondrial membrane permeability is one of the most critical events in cell death in mammals because it leads to mitochondrial dysfunction (necrosis) as well as the release of apoptogenic factors, including cytochrome c, into the cytoplasm, which in turn activates apoptosis-driving proteases called caspases. The Bcl-2 family of proteins, consisting of anti-cell death and pro-cell death members, regulate cell death mainly by controlling mitochondrial membrane permeability, although precise mechanism is still to be elucidated. Various models for apoptotic mitochondrial membrane permeabilization have been proposed, including the formation of a protein-conducting pore which consists of either oligomeric pro-apoptotic members of Bcl-2 family such as Bax/Bak or VDAC with Bax (Bak), the formation of transient lipidic pore and physical rupture resulting from either mitochondrial swelling or membrane instability. I will summarize currently proposed models and introduce our recent findings, and discuss how the mitochondrial membrane permeability is controlled during cell death. [Jpn J Physiol 54 Suppl:S27 (2004)]
