Bcl-2 family members as sentinels of cellular integrity and role of mitochondrial intermembrane space proteins in apoptotic cell death

In addition to their function as major energy-providing organelles of the cell, mitochondria accomplish a crucial role in apoptosis. The pro-apoptotic BH3-only members of the Bcl-2 family continuously sense the cellular integrity and well-being at various subcellular levels. If these sentinels are induced, released or activated, they converge on the release of mitochondrial intermembrane space proteins such as cytochrome c, the oxidoreductase AIF, endonuclease G, Smac/DIABLO and the serine protease Omi/HtrA2. We discuss how Bcl-2 family members integrate diverse survival and death signals and act as central regulators of apoptosis. Furthermore, we describe the current knowledge on the role of mitochondrial proteins in apoptotic cell death, discuss the molecular mechanisms of their release and the apoptotic role of mitochondria from a phylogenetic and immunological point of view.