Apoptosis inducing factor

Mitochondrial permeability transition involves the opening of a larger channel in the inner mitochondrial membrane leading to free radical generation, release of calcium into the cytosol and caspase activation. These alterations in mitochondrial permeability lead eventually to disruption of the respiratory chain and dqDletion of ATP. This in turn leads to release of soluble intramito-chondrial membrane proteins such as cytochrome C and apoptosis-inducing factor, which results in apoptosis. 

The involvement of mitochondria in the pro-apoptotic effects of carotenoids has been clearly demonstrated by the fact that P-carotene induces the release of cytochrome c from mitochondria and alters the mitochondrial membrane potential (Aym) in different tumor cells (Palozza et al., 2003a). Moreover, the highly polar xanthophyll neoxanthin has been reported to induce apoptosis in colon cancer cells by a mechanism that involves its accumulation into the mitochondria and a consequent loss of mitochondrial transmembrane potential and releas of cytochrome c and apoptosis-inducing factor (Terasaki et al., 2007). 

Several different changes in mitochondria occur during apoptosis. These include a change in membrane potential (usually depolarization), increased production of reactive oxygen species, potassium channel activation, calcium ion uptake, increased membrane permeability and release of cytochrome c and apoptosis inducing factor (AIF) [25]. Increased permeability of the mitochondrial membranes is a pivotal event in apoptosis and appears to result from the formation of pores in the membrane the proteins that form such permeability transition pores (PTP) may include a voltage-dependent anion channel (VDAC), the adenine nucleotide translocator, cyclophilin D, the peripheral benzodiazepine receptor, hexokinase and... 

During apoptosis, the mitochondrial permeability is altered and apoptosis-specific protease activators are released from this organelle. The discontinuity of the outer mitochondrial membrane results in the release of cytochrome C to the cytosol followed by subsequent depolarization of the inner mitochondrial membrane (C5, PI). The release of cytochrome C further promotes activation of cas-pases, which are important molecules for initiating apoptosis (T6). Apoptosis inducing factor (AIF), another molecule released into the cytoplasm, has proteolytic activity and is by itself sufficient to induce apoptosis. 

Chen, L., Rao, K.V., He, Y.X. and Ramaswamy, K. (2002) Skin-stage schistosomula of Schistosoma mansoni produce an apoptosis-inducing factor that can cause apoptosis of T cells. Journal of Biological Chemistry 277, 34329-34335. 

Rashmi R, Santhosh Kumar TR, Karunagaran D. 2003. Human colon cancer cells differ in their sensitivity to curcumin-induced apoptosis and heat shock protects them by inhibiting the release of apoptosis-inducing factor and caspases. FEBS Lett 538 19-24. 

I I Granville DJ, Cassidy BA, Ruehlmann DO, etal. Mitochondrial release of apoptosis-inducing factor and cytochrome c during smooth muscle cell apoptosis. Am J Pathol 2001 159 305-3 I I. 

A-l AIF Akt ALG-2 cytosolic protein that binds to phosphorylated Bad, inactivating it anti-apoptotic member of Bcl-2 family apoptosis-inducing factor serine/threonine kinase apoptosis-linked gene-2... 

AIF Apoptosis-inducing factor Programmed cell death protein 8, mitochondrial... 

Mitochondria release not only cytochrome c but also many pro-apoptotic factors (Table 17.1). They are normally localized in the intermembrane space of mitochondria. However, except for cytochrome c and the apoptosis inducing factor (AIF), their functions in the mitochondria have not been determined or they may have no function under normal conditions. Because they are larger than 5kD, they remain inside the mitochondrion. Once the mitochondrial outer membrane is permeabi-... 

Dawson, T. M., Dawson, V. L. (2002). Mediation of poiy(ADP-ribose) poiymerase-1-dependent ceii death by apoptosis-inducing factor. Science 297, 259-263. 

Sustained elevations in intracellular Ca levels promote mitochondrial Ca uptake, which decreases the mitochondrial membrane potential and blocks the electron transport chain leading to ATP depletion. Large increases in mitochondrial Ca uptake also increase mitochondrial membrane permeability (Dubinsky and Levi, 1998) resulting in the release of proapoptotic factors such as cytochrome c and apoptosis inducing factor (AIL) (Luetjens et al, 2000). Cytochrome c binds to apoptotic protease-activation factor 1 (APAFl) and procaspase-9, forming a multiprotein complex known as the apoptosome that activates the caspase cascade. The apoptosome activates caspase-9, which in turn activates caspase-3. Caspase-3 activates caspase-activated DNase (CAD), resulting in DNA fragmentation, characteristic of apoptosis. 

Opening of the FTP leads to an osmotic disbalance between the mitochondrial matrix and cytosol, swelling of the matrix and, consequently, the loss of integrity of the outer mitochondrial membrane, thus releasing the intermembrane proteins into the cytosol. Among them, four proteins are of interest in this context cytochrome c, apoptosis-inducing factor (AIF), the second mitochondrial apoptosis-activating protein (Smac also abbreviated DIABLO), and procaspase 9. All these proteins are somehow involved in apoptosis. 

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