The Role of Intrinsic Pathway in Apoptosis Activation and Progression in Peyronie’s Disease
Apoptosis works through two main, alternative pathways: death receptor-mediated (or extrinsic) and mitochondria-dependent (or intrinsic). The former pathway is initiated by ligation of specific death receptors by their ligands. The main death receptors—Fas and tumour necrosis factor- (TNF-) related apoptosis inducing ligand (TRAIL) receptors DR4 and DR5—induce cell death following ligation with Fas ligand (FasL) or TRAIL, respectively, followed by recruitment of procaspase 8. This process gives rise to caspase 8 activation. The latter induces apoptosis by directly activating caspase 3 or by cleaving bid (BH3 interacting domain death agonist), resulting in mitochondrial dysfunction and subsequent release of cytochrome C and activation of caspases 9 and 3. Caspase 3 promotes the typical apoptosis features, including DNA fragmentation and cell death in several tissues. The mitochondrial pathway is partly influenced by bcl family members bound to the mitochondrial membrane, including bax and bcl-2, which are, respectively, pro- or antiapoptotic regulatory proteins. The antiapoptotic proteins bcl-2 and bcl-XL inhibit cytochrome c release, whereas bcl-2—associated X protein(bax), bcl-2 homologous antagonist/killer (bak), and bid, all proapoptotic proteins, promote its release from mitochondria. Cytochrome C and deoxyadenosine triphosphate (dATP) bind to apoptotic protease activating factor (APAF-1) to form a multimeric complex that recruits and activates procaspase 9, an apoptosis-mediating executioner protease that in turn activates caspase 3, resulting in cell apoptosis.