Mitochondrial-mediated apoptotic signaling

Figure 3.22 Mitochondrial-mediated apoptotic signaling. Cyt c release from the mitochondrion leads to formation of the apoptosome and activation of procaspase-9. Active caspase-9 cleaves and activates caspase-3, which ieads to apoptosis.

Fig. 1. Proposed mechanism of action of rituximab associated with the apoptosis pathway. Binding of rituximab with the CD20 antigen up-regulates the production of interleukin-10 (IL-10). The IL-10 autocrine loop down-regulates the expression of the bcl-2 protein, which inhibits the intrinsic pathway (or mitochondrial mediated pathway) of apoptosis. The mitochondrial pathway is induced by intracellular stress signals. The translocation of the bcl-2 protein into the mitochondria leads to the activation of caspase 9 via release of cytochrome c and apoptotic protease-activating factor 1. The other pathway, the extrinsic pathway (or death receptor mediated pathway) activates caspase 8. Subsequently, caspase 8 or 9 activates caspase 3, leading to programmed cell death (apoptosis).

The execution of apoptotic cell death is mediated by the intrinsic and extrinsic apoptotic pathways (Fig. 2). Both of these pathways eventually converge, leading to activation of caspases, cysteine-dependent aspartyl-specific proteases that represent the effector arm of apoptotic signaling [12]. The intrinsic or mitochondrial pathway is initiated by developmental cues or cellular stress signals [13]. These signals activate Bcl-2-homology 3 (BH3) proteins leading to neutralization of the anti-apoptotic proteins Bcl-2, Bcl-xL or Mcl-1, activation of pro-apoptotic proteins, Bax and Bak, and subsequent disruption of mitochondrial membrane potential. Consequent release of cytochrome c from the mitochondria into the cytoplasm leads to Apaf-1-mediated caspase-9 activation, which in turn activates effector... 

Apoptosis (programmed cell death) is a genetically controlled cell suicide process that has an essential role for the maintenance of homeostasis and prevention of cancer and some other diseases substantially in all living cells [141], Apoptosis is an optional elimination method for irreversibly damaged cells. The two major pathways that initiate apoptosis are extrinsic (death receptor mediated) and intrinsic (mitochondrial mediated). In addition, mitogenic and stress-responsive pathways are involved in the regulation of apoptotic signaling [142],... 

Based on this model, moderate NADVATP depletion or the (ADP-ribose)n polymer itself triggers the apoptotic pathway. In addition, p53-induced mediators, as well as HI.2 released from the nucleus into the cytoplasm, act synergistically to induce apoptosis via mitochondrial dysfunction. At high intensity DNA damage, PARP overactivarion and PARP-independent mediators may also tri er mitochondrial alterations but downstream apoptotic signaling is incapacitated by the lack of ATP/NAD. ... 

Activated MAPKs have been found to modulate mitochondria-mediated apoptotic pathways, JNK in particular [71]. In fact, it appears that MAPK signaling may represent a potential cross-link between die different apoptotic pathways. JNK activation is not required for death-receptor-mediated apoptosis but is required for caspase-9 activation by the mitochondrial pathway, induced by a variety of proapoptotic stimuli [72,73]. JNK activation and c-Jun phosphorylation were found to be necessary to promote cytochrome c release from mitochondria, with the sequential assembly of the apoptosome and caspase-3 activation. The molecular mechanism of this effect was unclear, but it appeared to involve regulation of the expression and phosphorylation state of the Bcl-2 protein family and their recruitment to the mitochondrial outer membrane (Fig. 4). In a number of apoptotic models, JNK activation was associated with a downregulation of the antiapoptotic Bcl-2 and Bc1-Xl and upregulation of the proapoptotic Bax and Bad [74—77]. Two cell culture studies provided very strong evidence that JNK activation resulted in the phosphorylation of Bcl-2 and Bc1-Xl ex vivo, with the induction of apoptosis [76,77]. In other words, Bcl-2 and Bc1-Xl appear to be substrates of JNK, and phosphorylation results in their inactivation, thereby abolishing their ability to prevent cytochrome c release. 

Caspase activation occurs as a late and common step in all cells undergoing apoptosis. Nevertheless, there are many initial pathways that can result in caspase activation. Probably, each distinct pathway is triggered by different apoptotic stimuli. In mammalian cells, the apoptotic response is usually mediated by the intrinsic and extrinsic pathways, depending on the origin of the death signal. The intrinsic pathway can further be divided into mitochondrial and ER stress pathways. 

Figure 1. Schematic of the apoplotic signaling pathways. The intrinsic apoptotic pathway consists of the mitochondrial pathway. The extrinsic pathway mediates apoptosis through activation of the death receptors, TNF-o/Fas receptors. Apoptosis is executed by activation of proteases, known as caspascs. ATP is essential for apoptosis. Bel-2 family proteins are apoptosis regulating proteins Bcl-2 inhibits while Bid, Bax, Bad facilitate apoptosis. An interaction between these two apoptotic pathways exists. See text for a more detailed explanation.

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