Apoptosis mitochondrial-dependent pathway

The essential role of cytochrome c release from injured mitochondria in the activation of caspase 9 has been alluded to above. This pathway is especially important in proapoptotic stimuli that are not initiated by surface receptors for apoptosis, such as UV irradiation, and may involve mitochondrial dependent pathways [83]. Continued respiration in the presence of an open mitochondrial pore may result in the generation of reactive oxygen species. Release of cytochrome c may be mediated by the opening of the mitochondrial FT pore, a non-selective channel whose composition is only partially defined [84]. Inhibitors of FT pore opening, such as cyclosporine, which binds to the adenine nucleotide translocator (ANT), a component of the FT pore, and bongkrekic acid, as well as Bcl-2, prevent cytochrome c release and inhibit apoptosis [85] whereas activators of the FT pore, such as atractyloside and Bax induce it [86]. Oxidants can rupture the outer membrane of mitochondria and release caspase-activating proteins [87]. Some studies have shown cytochrome c release before collapse of the mitochondrial membrane potential [83] suggesting alternate control of the FT pore. Many, but not all, of the members of the Bd-2 family of proteins reside in the inner mitochondrial membrane, form ionic channels in hpid membranes and increase rates of proton extrusion in mitochondria [88] and thus may control the FT pore. The antiapoptotic and mitochondrial affects of Bd-2 are independent of caspase activity as they occur in the presence of caspase inhibitors and also in yeast that lack caspases [86]. 

Bcl-2 was first discovered as a proto-oncogene in follicular B-cell lymphoma. It has since been identified as a mammalian homologue to the apoptosis repressor Ced-9. The mitochondrial-dependent pathway in the human Bel-family includes both pro-apoptotic (Bax, Bak, and Bok) and anti-apoptotic proteins (Bcl-2, Bc1-Xl, Bcl-w, etc.) [10]. Although the precise mechanisms of the mammalian Bcl-2 family of proteins are still a matter of debate, it has been established that their main function is to regulate the release of cytochrome c and other proteins from the mitochondria [24],... 

Boyd CS, Cadenas E (2002) Nitric oxide and cell signaling pathways in mitochondrial-dependent apoptosis. Biol Chem 383 411-423... 

Herrera, B., Carracedo, A., Diez-Zaera, M., Gomez del Pulgar, T., Guzman, M., and Velasco, G. The CB2 cannabinoid receptor signals apoptosis via ceramide-dependent activation of the mitochondrial intrinsic pathway. Exp Cell Res, 312, 2006, 2121-2131. 

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. 

Mechanisms underlying SM-induced apoptosis have been carefully explored using primary cultures of human keratinocytes. Treatment of keratinocytes with 100-300 pM SM resulted in activation of caspase 8, which initiates the Fas-dependent death receptor pathway, and caspase 9, which initiates the mitochondrial apoptotic pathway (Rosenthal et al., 2003). Fas and Fas ligand were upregulated in a concentration-dependent manner by SM leading to activation of caspase 3, the central executioner protease. Transfection of immortalized keratinocytes with a dominant-negative Fas-activated death domain resulted in a blunted caspase response to SM. Micro vesication and tissue injury produced in vivo by SM exposure of transfected cells after grafting onto athymic nude mice was also reduced by this treatment. 

Bcl-2 is a key apoptosis regulatory protein of the mitochondrial death pathway. It is dependent on posttranslational modifications, such as ubiquitination and proteasomal degradation (Dimmeler et al. 1999). NO S-nitrosylates Bcl-2 and inhibits... 

Bcl-2 is a key apoptosis regnlatory protein of the mitochondrial death pathway whose function is dependent on its expression levels. NO prevented Bcl-2 cleavage and suppressed cytochrome c release in TNF-a and actinomycin D-treated adenocarcinoma (MCF-7) cells exposed to SNAP (Kim et al. 1998). This level is regulated by a ubiqutination-proteasome degradation system. There was inhibition of NO production by the NO scavenger. The NO donors DPTA/NONO and sodium nitro-prusside effectively upregulated Bcl-2 S-nitrosylation, decreased its ubiquitination, and inhibited apoptotic cell death induced by chromium. The effect of NO on Bcl-2 stability was shown to be independent of its dephosphorylation (Azad et al. 2006). 

Suliman, A., Lam, A., Datta, R., and Srivastava, R.K. (2001). Intracellular mechanisms of trail Apoptosis through mitochondrial-dependent and -independent pathways. Oncogene 20, 2122-2133. 

---