Figure 4

The intrinsic apoptosis pathway. The intrinsic apoptotic pathway is triggered by intracellular stimuli. (a) Intracellular apoptotic stimuli upregulate the pro-apoptotic Bcl-2 family of proteins, such as Bax, Bid, Bak and Bad, leading to the mitochondrial release of cytochrome C, which binds to Apaf-1. The replacement of ADP by dATP/ATP in Apaf-1 triggers the formation of a heptameric apoptosome, which assembles with procaspase-9 to form the holo-apoptosome. The Apaf-1 apoptosome catalyses the cleavage and activation of procaspase-9, which triggers the caspase cascade, and the activation of caspase-3 and caspase-7 leads to eventual apoptosis. (b) Under ER stress, three upstream signalling proteins – IRE1, PERK and ATF6 – are activated, thus leading to a cascade of activity that induces apoptosis. (b1) The ER releases Ca²⁺ from the ER lumen into the cytoplasm, which triggers apoptosis by activating the calcium-sensing kinase CaMKII. Then, CaMKII activates procaspase, which in turn triggers caspase cascade activation. (b2) The prolonged activation of IRE1 can promote apoptosis. Phosphorylated IRE1 recruits TRAF2 (TNF receptor-associated factor 2) and triggers a cascade of phosphorylation events, such as the activation of ASK1 (apoptosis signalling kinase 1), which ultimately phosphorylates and activates JNK. Then, JNK phosphorylation activates pro-apoptotic Bim and blocks anti-apoptotic Bcl-2. (b3) The homomultimerization and autophosphorylation of PERK leads to eIF-2α (eukaryotic translation initiation factor 2α) phosphorylation, which increases the translation of ATF4 (activating transcription factor-4). Then, ATF4 upregulates the expression of CHOP (C/EBP-homologous protein), which promotes apoptosis through two of the major cell death pathways – the IP3R–Ca²⁺–CaMKII pathway and the Bcl-2 family member pathway (some inspiration came from these articles^{56, 57, 58, 59, 60, 61})