Role of Mitochondria
Mitochondria play an important role in the regulation of cell death. For example, anti-apoptotic members of the Bcl-2 family of proteins, such as Bcl-2 and Bcl-XL, are located in the outer mitochondrial membrane and act to promote cell survival. Many of the pro-apoptotic members of the Bcl-2 family, such as Bad and Bax also mediate their effects though the mitochondria, either by interacting with Bcl-2 and Bcl-XL, or through direct interactions with the mitochondrial membrane. The roles that mitochondria play in apoptosis is summarised in the illustration below. Information on each of these roles is given below.
Mitochondria have the ability to promote apoptosis through release of cytochrome C, which together with Apaf-1 and ATP forms a complex with pro-caspase 9, leading to activation of caspase 9 and the caspase cascade.
It is unknown what factors promote the release of cytochrome C from the mitochondria. Since Bax, and other Bcl-2 proteins, show structural similarities with pore-forming proteins. It has therefore been suggested that Bax can form a transmembrane pore across the outer mitochondrial membrane, leading to loss of membrane potential and efflux of cytochrome C and AIF (apoptosis inducing factor). It is thought that Bcl-2 and Bcl-XL act to prevent this pore formation. Heterodimerisation of Bax or Bad with Bcl-2 or Bcl-XL is thought to inhibit their protective effects. It is also thought that proteins such as Bax and Bad can promote the formation of the large diameter PT pore, with subsequent loss of cytochrome C and initiation of apoptosis