Intrinsic apoptosis pathway

Cohen, G. M. Caspases The executioners of apoptosis. Biochem. J. 326(Pt 1), 1-16,1997. Fulda, S., and Debatin, K. M. Extrinsic versus intrinsic apoptosis pathways in anticancer chemotherapy. Oncogene 25, 4798-4811, 2006. 

N-terminus, a proline derivative in the third position, and an aromatic group at the fourth position. The studies mentioned above demonstrate Smac mimetics are effectors of both the extrinsic and the intrinsic apoptosis pathways. 

Chen W, Sulcove J, Frank I, Jaffer S, Ozdener H, Kolson DL (2002) Development of a human neuronal cell model for human immunodeficiency virus (HlV)-infected macrophage-induced neurotoxicity Apoptosis induced by HIV type 1 primary isolates and evidence for involvement of the Bcl-2/Bcl-xL-sensitive intrinsic apoptosis pathway. J Virol 76 9407-9419. 

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. 

Dvorakova K, Payne CM, Landowski TH, Tome ME, Halperin DS, Dorr RT. Imexon activates an intrinsic apoptosis pathway in RPMI8226 myeloma cells. Anticancer Drugs 2002 13(10) 1031-42. 

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). 

Increased activity of GSK-3/3 has been reported during neuronal degeneration (Beurel and Jope, 2006) and it has been associated with the promotion of the intrinsic mitochondrial pathway of apoptosis (Brazil and Hemmings, 2001). Pharmacological inhibition of GSK-3/3 reduces neuronal cell death caused by cerebral ischemia (Kelly et al., 2004), suggesting that prevention of GSK-3/3 activation may represent a potential approach to minimize neurodegeneration in the retina. 

Intrinsic (mitochondrial) pathway of caspase activation is initiated by the permeabilization of the mitochondrial outer membrane by proapoptotic members of the Bcl-2 family, resulting in a release of cytochrome c and other proteins from the intermembrane space of mitochondria into the cytosol. Cytochrome c translocation to the cytosol may follow a number of possible mechanisms. However, once in the cytosol, cytochrome c binds to apoptosis protease activating factor (Apaf-1) and in the presence of dATP or ATP facilitates Apaf-1 oligomerization and the recruitment of procaspase-9. The formation of this caspase-activating complex, termed the apoptosome, results in the activation of procaspase-9, and this in turn cleaves and activates the effector caspase-3 and -7. Activated effector caspases cleave key substrates in the cell and produce the cellular and biochemical events characteristic for apoptosis [33-35]. 

However, it appears that in cardiomyocytes, being typical type II cells, apoptosis predominantly proceeds via the intrinsic (mitochondrial) pathway [3, 40],... 

Little is known about the expression of other caspases in human MI. We have found positive immunohistochemical reaction for initiator caspase-8 and -9 in cardiomyocytes in the border zone of MI (Zidar, unpublished observation), consistent with the suggestion that both extrinsic and intrinsic pathways of caspase activation occur in the heart [36]. However, we have not observed a significant difference in caspase-8 and -9 expression in patients who received reperfusion treatment compared to those who did not. Thus, we were not able to confirm the hypothesis based on experimental studies that ischemia produces apoptosis through the intrinsic mitochondrial pathway,... 

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.

Apoptosis, induced either via the intrinsic (mitochondrial pathway) or extrinsic pathway can be measured for instance by nuclear condensation, staining of phosphatidyl serine (PS) on... 

Fig. 13.10 Caspase activation by extrinsic and intrinsic apoptotic pathways, (a) Extrinsic path. This path is mediated by members of the tumor necrosis factor (TNF) superfamily (see text), (b) Intrinsic pathway. This path may be mediated by various physiological or pathological changes, but only the modes of induction of this path in periodontitis are discussed (see text). Details of cytochrome c release and caspase activation are shown in Fig. 13.11 (This figure is modified from Fig. 1 in Schimmer AD (2004 Oct 15) Inhibitor of Apoptosis Proteins Translating Basic Knowledge into Clinical Practice. Cancer Research, 64 7183-7190)...

B-cell lymphoma 2 (Bcl-2) family members are regulators of the intrinsic apoptosis (programmed cell death) pathway, and anti-apoptotic family members have been strongly implicated in cancer [172]. Heterodimer-forming interactions between anti-apoptotic family members such as Bcl-xL or Bcl-2, and ot-helical domains of pro-apoptotic proteins control the ability of cells to carry out the apoptotic program. Several compounds have been reported to bind to and inhibit various anti-apoptotic Bcl-2 family members, but for most of these compounds reported affinities are poor, and structural information is unavailable [15]. 

Stoica, BA, Movsesyan, VA, Lea, IP and Faden, AI (2003) Ceramide-induced neuronal apoptosis is associated with dephosphorylation of Akt, BAD, FKHR, GSK-3beta, and induction of the mitochondrial-dependent intrinsic caspase pathway. Mol Cell Neurosci, 22, 365-382. 

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