Apoptosis-Inducing Factor AIF

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. 

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-... 

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. 

Lorenzo HK, Susin SA, Penninger J, Kroemer G. 1999. Apoptosis inducing factor (AIF) a phylogenetically old, cas-pase-independent effector of cell death. Cell Death Differ. 6 516-24... 

C. Cande, 1. Cohen, E. Daugas, L. Ravagnan, N. Larochette, N. Zamzami andG. Kroemer, Apoptosis-inducing factor (AIF) a novel caspase-independent death effector released from mitochondria, Biochimie 84(2-3), 215-222 (2002). 

According to the conventional model, anti-apoptotic Bcl-2 proteins inhibit apoptosis by functional suppression of pro-apoptotic Bcl-2 family proteins the latter promote the release of proteins (e.g. cytochrome c, apoptosis-inducing factor (AIF), adenylate kinase-2, HSP60) from the mitochondrial membrane which induce cell death by apoptosis through interactions with Apaf-1 and downstream execution enzymes50,66,69,137. A rheostat mechanism has been proposed, in which the balance of expression between pro- and anti-apoptotic Bcl-2 family members ultimately dictates the life or death decisions of a given cell4. 

Proteins from the intermembrane space of the mitochondria are released from mitochondria of apoptotic cells Quantitation of cytoplasmic amounts of Cytochrome C Apoptosis inducing factor (AIF) Adenylate kinase Sulfite oxidase Procaspase 9 All need confirmation of release in conjunction with apoptotic death may also require confirmation of regulatory role for the factor on the apoptosis... 

In addition to cytochrome c, other factors such as apoptosis inducing factor (AIF), endonuclease G, and second mitochondria-derived activator of caspases (Smac/DIABLO) may also be released from the inter-mitochondrial membrane space to exert their pro-apoptotic effects (see later). Recently, the endoplasmic reticulum (ER) has been identified as another organelle that can initiate the intrinsic apoptotic cascade in response to cellular stress. The ER is essential for proper... 

Additional pro-apoptotic factors that are released from mitochondria are the Apoptosis Inducing Factor (AIF) and the inhibitors of lAPs-Smac/DlABLO and Omi/ HtrA2 (see earlier). 

The effect of 13-MTD on expression of several regulatory genes involved in apoptosis induction was studied (unpublished observation). 13-MTD and myristic acid decreased the expression of the p53 gene to the same extent, with no significant difference between treatments. CLA increased the messenger RNA (mRNA) level of caspase-3 and increased its activity. 13-MTD had no effect on expression of caspase-8, apoptosis-inducing factor (AIF), Bax, Bad, and BcI-Xl. 

Apoptosis-inducing factor (AIF) is a mitochondrial protein that upon translocation to nucleus produces large-scale DNA fragmentation. Although some studies indicate that mitochondrial dysfunction triggers the translocation of AIF to the nucleus, the molecular mechanism and stimulus for the cytosolic release and nuclear translocation AIF remains unknown (Chaitanya and Babu, 2008 Li et al., 2007). The time course of nuclear translocation of AIF after experimental stroke varies with the severity of injury and is increased by oxidative stress associated with reperfusion and nitric oxide (NO) production. AIF translocation to the nucleus... 

Figure 2. Primary structure of apoptosis-inducing factor (AIF). AIF has an oxidoreductase domain, mitochondrial localization signal (MLS) and nuclear localization signal (NLS).

Figure 4. Possible mechanisms of mitochondrial release of apoptosis-inducing factor (AIF).

Mate MJ, Ortiz-Lombardia M, Boitel B et al. The crystal structure of the mouse apoptosis-inducing factor AIF. Nat Struct Biol 2002 9(6) 442-6. 

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