Molecular mechanisms of mitochondrial apoptogenic factor release through pores and megachannels

ABSTRACT

Mitochondrial membrane permeabilization is a biochemically well-defined phenomenon that occurs in response to numerous physiological and pathological processes that regulate cell survival. In many situations, mitochondrial membrane permeabilization is triggered by an excess of reactive oxygen species (ROS), Ca2+ overload, and the interference of BH3-only proteins of the BCL-2 family, as well as by activated caspases that can act on components of the inner or outer membrane to cause the opening, assembly and/or activation of membrane mitochondrial permeability transition pores. These pores permit the release of apoptogenic factors such as cytochrome c, apoptosis-inducing factor, Smac/Diablo, HtrA2/Omi and endonuclease G from the intermembrane space to the cytosol where they mediate many of the biochemical and morphological features of apoptosis and necrosis. In this review, we discuss the pharmacological, genetic and biochemical evidence that proteins, protein complexes and membrane structures can form pores through which apoptogenic factors can be released from mitochondria.