Apoptotic pathways Intrinsic mitochondrial pathway

The third mechanism is Ca2+-dependent and also involves the intrinsic mitochondrial pathway. Some apoptotic stimuli induce Ca2+ release from the ER, and this process may be regulated by the Bcl-2 family members that reside in this organelle (Szegezdi et al., 2003). Bax and Bak seem to induce Ca2+ release, while antiapoptotic members, such as Bcl-2, seem to reduce this process. Ca2+ ions released from the ER eventually accumulate in mitochondria, which induces permeabilization of the outer mitochondrial membrane through PTP formation. Release of apoptogenic factors... 

Two main apoptotic pathways have been identified in mammalian cells the extrinsic pathway that is activated by the binding of ligands to cell-surface death receptors, and the intrinsic pathway that involves the mitochondrial release of cytochrome cP The activation of extrinsic and intrinsic apoptotic pathways promotes the cleavage into the active form of the pro-caspase-8 and pro-caspase-9, respectively, that mainly determine the activation of effector caspase-3. ° The intrinsic pathway is the main apoptotic pathway activated by chemotherapeutic drugs, while the cytotoxic drug-induced activation of the extrinsic pathway is a more controversial issue. ... 

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).

How do supranormal Ca2+ signals induce apoptosis of HD MSN The best known link between Ca2+ overload and apoptosis involves mitochondrial Ca2+ overload and activation of intrinsic apoptotic pathway (Choi, 1995 Hajnoczky et al., 2003 Orrenius et al., 2003 Rizzuto et al., 2003). Consistent with this idea, we found that glutamate-induced apoptosis of YAC128 MSN in our experiments can be prevented by Ruthenium 360 (Ru360), an inhibitor of mitochondrial Ca2+ uniporter/channel (MCU) (Figure 6). 

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.

The mitochondria have emerged as a central component of the intrinsic apoptotic signaling pathways and are now known to control apoptosis via the release of apopto-genic proteins (Fig.15.8). The apoptotic signals that are channeled through the mitochondrial pathway of apoptosis include various stresses like DNA damage, oxidative stress, UV radiation, protein kinase inhibition, and growth factor deprivation. 

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... 

The critical step in the initiation of intrinsic apoptosis pathways is the release of cytochrome c from mitochondria. There exist several models for the release of the pro-apoptotic mitochondrial proteins (1) regulation of an existing pore (such as permeability transition pore, FTP) by Bcl-2 family members (2) the formation of a channel by Bcl-2 proteins or (3) oligomerization of apoptotic Bcl-2 family proteins to form a pore through which cytochrome c can be released. 

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],... 

Fig. 13.1 Schematic of Apoptosis Components Affected by Ethanoi Five generai eiements of apoptotic pathways in neurons have been shown to be impacted by ethanoi. They tire iiiustrated by the block arrows. There are two basic pathways that have been reported to be activated by ethanoi, extrinsic receptor activation and intrinsic mitochondrialiy mediated pathways. In general, developmental exposure to ethanol shifts expression of Bcl-2 family proteins in a pro apoptotic direction which may be mechanistically connected to the observed enhanced mitochondrial release of cytochrome c (cyto c) and apoptosis inducing factor (AIF). These factors, in turn, likely play roles in the subsequent activation of the effector caspase-3 (cytochrome c) and DNA fragmentation (AIF) (See also Color Insert)...

Figure 2. Apoptotic pathways-serine and cysteine proteases. Intrinsic and extrinsic Fas and granzyme B apoptotic pathways that are potentially targeted by Serp-2 and Crm A are illustrated. Staurosporine activates mitochondrial apoptotic pathways, Fas ligand and Granzyme B activate extrinsic apoptotic pathways Camptothecin inhibits topoisomerase and blocks DNA repair.

Similar interactions have been observed with the CDK inhibitor flavopiridol. Initial studies demonstrated that flavopiridol interacted synergistically with TNF to induce apoptosis in lung cancer cells. Subsequently, it was shown that co-administration of TRAIL with flavopiridol resulted in a marked increase in mitochondrial damage and apoptosis in other tumor cell types (Senderowicz 1999 Rosato et al. 2004). Given evidence that flavopiridol acts at least in part to induce apoptosis in tumor cells via induction of mitochondrial injury, it seems plausible to propose that the potent tu-moricidal effects of a regimen combining TRAIL with flavopiridol, as in the case of HDACIs, stems from simultaneous activation of the intrinsic and extrinsic apoptotic pathways. 

Mitochondria play pivotal roles in both the life and the death of the cell. First, mitochondrial integrity and the efficiency of oxidative phosphorylation are essential for cellular bioenergetics and viability [9]. Second, mitochondria appear to play a central role in apoptosis [10,11]. Specifically, mitochondria-dependent apoptotic pathways are responsive to intrinsic proapoptotic stimuli such as oxidative stress. The latter is of particular interest in that the oxyradical generation by the mitochondrial respiratory... 

There is a growing recognition that mitochondria play a central role in apoptosis [10,11], Mitochondria-dependent apoptotic pathways are responsive to intrinsic proapoptotic stimuli that cause perturbations in the intracellular environment, particularly oxidative stress. In addition, other apoptotic signaling pathways appear to converge onto the mitochondria. This raises the question of whether flavonoids may modulate events upstream or downstream of the mitochondria-dependent apoptotic cascade, in addition to their potential effect on mitochondrial respiration, oxidative phosphorylation, and oxyradical generation (as discussed earlier). 

---