Figure 1.

A simplified schematic representation of the extrinsic and the intrinsic (mitochondrial) pathways of apoptosis and necroptosis. The mitochondrial (intrinsic) pathway of cell death is regulated both upstream (Bcl-2 proteins) and downstream (e.g., IAP proteins) of mitochondria. In response to stress, mitochondria undergo permeabilisation of the outer mitochondrial membrane (MOMP), which leads to a release of a number of pro-apoptotic factors such as cytochrome c, AIF or EndoG. The extrinsic pathway of apoptosis is activated via a complex signal transduction from the plasma membrane, whereby the death receptors (e.g., Fas, TNFR) bind their cognate ligands (e.g., FasL, TNF), oligomerize, activate their intracellular death domains and recruit a number of receptor-associated proteins such as RIP1 or TRADD. The multiprotein complex then recruits the initiatior pro-caspase-8 leading to its activation. Active caspase-8 propagates the apoptotic signal either by direct activation of executioner caspases, or by cleaving a BH3 protein Bid which then leads to MOMP. In addition, components of the protein machinery that regulates the extrinsic pathway of apoptosis are also involved in regulation of necrosis. The figure also demonstrates apoptosis regulatory microRNA and their target genes in apoptotic pathways