Mitochondrial pathway of apoptosis

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. 

CafforioP, Dammacco F,Gernone A, SilvestrisF. Statins activate the mitochondrial pathway of apoptosis in human lymphoblasts and myeloma cells. Carcinogenesis 2005 26 883-891. 

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. 

Depending on the cell type, two different downstream pathways are triggered. In type I cells, processed caspase-8 produced in large amounts directly activates a caspase cascade. Among the caspases activated are caspase-3, which cleaves other caspases or vital substrates of the cell and thus paves the way for the execution phase of apoptosis. In type II cells, proper activation of effector caspases requires amplification via the mitochondrial pathway of apoptosis. Here, smaller amounts of active caspase-3 are produced which cleave the pro-apoptotic Bcl-2 family member Bid. The truncated form of Bid activates mitochondria by an unknown mechanism, which now release pro-apoptotic proteins like cytochrome c and Smac/Diablo (see Section 15.5). Cytochrome c release triggers the formation of the apoptosome, resulting in the activation of caspase-9 and subsequently caspase-3, which in turn can activate caspase-8 outside the Fas-DISC. 

Apple juice phenolic compound extracts have the property to induce apoptosis in HT-29 cells [147]. Quercetin and phloretin dose-dependently induced both caspase-3 activity and DNA cleavage under serum-free conditions. Phloretin at 100 pM induced both the death receptor as well as the mitochondrial pathway of apoptosis induction, detected by activation of the initiator caspases-8 and -9 and the effector caspases-3 and -7 as well as by PARP cleavage. Activation of caspase-9 was accompanied by release of cytochrome c and the mitochondrial protein Smac/DIABLO from the mitochondria to the cytoplasm, and upregulation of proapoptotic Bax levels [43,44,148]. In general, berry extracts have the ability to stimulate apoptosis of the HT-29, COX-2-expressing colon cancer cells. Black raspberry and strawberry extracts showed the most significant proapoptotic effects against this cell line [43] (Tables 1 and 6). 

Bender CE, Fitzgerald P, Tait SW, Llamni F, McStay GP, Tupper DO, Pellettier J, Sanchez-Alvarado A, Salversden GS, Green DR. Mitochondrial pathway of apoptosis is ancestral in metazoans. Proc Natl Acad Sci USD. 2012 109 4904-9. 

Leonarduzzi, G., G. Poli, B. Sottero, and F. Biasi. 2007. Activation of the mitochondrial pathway of apoptosis by oxysterols. FwntBio 12 791-9. 

Together these data demonstrate roles for ceramide in both the mitochondrial and non-mitochondrial pathways of apoptosis. These appear to involve distinct compartments for ceramide generation and perhaps different enzymatic and regulatory pathways. Additional studies will certainly assist in verifying the importance of ceramide generation in apoptosis. 

Yoshida H, Kong YY, Yoshida R, Elia AJ, Hakem A, Hakem R, Penninger JM, Mak TW. Apafl is required for mitochondrial pathways of apoptosis and brain development. Cell 1998 94(6) 739-750. 

Changes in intracellular calcium levels are known to activate the mitochondrial pathway of apoptosis. A key regulator of Ca -dependent proteins is calmodulin. SM has been shown to cause a time-dependent induction of calmodulin in keratinocytes (Simbulan-Rosenthal et al., 2006). Moreover, depletion of calmodulin using antisense probes attenuated SM-induced activation of caspases involved in the mitochondrial pathway of apoptosis. Both antisense and pharmacological inhibition of calmodulin prevented SM-induced nuclear fragmentation in the keratinocytes. Bad, a proapoptotic Bcl-2 family member present in an inactive phosphorylated form in viable cells, was also activated by SM. Furthermore, cyclosporine A, a selective inhibitor of calcineurin, a Bad phosphatase, inhibited SM-induced keratinocyte apoptosis. These results suggest that calcium-dependent activation of Bad may be a mechanism by which SM induces apoptosis in keratinocytes. 

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