Apoptotic pathways in mitochondria

Abstract

Apoptosis or programmed cell death is a fundamental process for embryogenesis, tissue homeostasis and prevention of oncogenesis. Dysregulated apoptosis contributes to the pathogenesis of many human diseases, such as cancer, diabetes and neurodegenerative disorders. The extrinsic or death receptor-mediated and mitochondrial apoptotic pathways are two main apoptosis pathways in mammalian cells. The most critical step of apoptosis is the release of prodeath proteins including cytochrome c from mitochondria through permeabilization of outer mitochondrial membrane. Smac/DIABLO, AIF, HtrA2 and ARTS are among the other prodeath molecules released from mitochondria. Bcl-2 protein family members act as major regulators of apoptosis by controlling mitochondrial permeabilization. Their function is dictated by protein-protein interactions as a result selective binding patterns of BH3-only proteins with antiapoptotic Bcl-2 proteins. Multidomain proapoptotic Bcl-2 proteins Bax and Bak are crucial for mitochondrial permeabilization and they facilitate the release of cytochrome c from mitochondria by forming pores in the outer mitochondrial membrane. Currently, there are two diff erent models explaining Bax and Bak activation upstream of cytochrome c release. In addition, mitochondrial remodeling by Opa1 and Parl also contributes to apoptosis by controlling mitochondrial cristae junctions. In this chapter we briefly address these concepts to help in understanding the mechanisms of apoptosis regulation by mitochondria. A better understanding of these pathways would allow us to develop novel therapeutic tools for human diseases and to improve preventive measures targeting human health.