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AIF pathway

Monday 8 November 2010

AIFM1 pathway

Multicellular organisms eliminate supernumerary, damaged or harmful cells by programmed cell death. This process of cell suicide, defined morphologically as apoptosis, is critical for developmental morphogenesis, tissue homeostasis and defence against pathogens.

The activation of apoptotic cascades triggers a series of events, one of which is the condensation and fragmentation of chromosomal DNA.

In mammals, at least three proteins have been implicated in this process: DFF40 (DNA Fragmentation Factor, 40-KD) /CAD (Caspase-Activated DNase); a mitochondrial endonuclease termed EndoG (Endonuclease-G); and the AIF (Apoptosis-Inducing Factor).

AIF is a conserved mitochondrial protein that is released into the cytoplasm and nucleus during mitochondrial membrane permeabilization, inducing chromatin condensation and DNA fragmentation.

AIF falls in the category of flavoproteins. It displays NAD(P)H oxidase as well as monodehydroascorbate reductase activities. The overall crystal structure of mature AIF displays a glutathione-reductase-like fold, with an FAD-binding domain, an NADH-binding domain, and a C-terminal domain that bears a small AIF-specific insertion region.

Under certain conditions, AIF exhibits a dualistic nature, with an antiapoptotic function in the mitochondria via its oxidoreductase region and a separate proapoptotic action in the nucleus via its DNA binding region.

AIF is normally confined to the mitochondrial intermembrane space, where it may act as an electron acceptor/donor with oxidoreductase activity.

After an apoptotic insult, the mitochondrial outer membrane is permeabilized, and AIF translocates to the cytosol and the nucleus, where it induces peripheral chromatin condensation, as well as DNA fragmentation.

Mitochondrial membrane permeabilization also leads to the release of other IMS (Intermembrane Space) proteins, such as CytoC (Cytochrome-C), SMAC (Second Mitochondria-Derived Activator of Caspase-12)/DIABLO and EndoG that take part in the apoptotic process.

BCLXL (Bcl2 Related Protein Long Isoform)AR-SA blocks both AIF and CytoC release from mitochondria. Loss of AIF and CytoC contribute to disruption of the respiratory chain, increased oxidative stress (with potential generation of reactive oxygen species such as O2− and H2O2), dissipation of the mitochondrial membrane potential, and decreased ATP synthesis.

Translocation of cytosolic AIF to the nucleus appears to be a general feature of apoptosis in mammalian cells.

DNA binding by AIF is required for its apoptogenic function, at least at the nuclear level. Structural evidence suggests that AIF binds DNA in a sequence-independent manner, perhaps as a dimmer, which in turn may facilitate the recruitment of other factors such as nucleases.

Three possibilities can be envisaged about the exact process of induction of chromatin condensation and DNA fragmentation by AIF.
- First, AIF could itself have some cryptic nuclease activity.
- Second, the interaction of AIF with DNA may increase the susceptibility of DNA to latent nucleases.
- Third, AIF might recruit downstream nucleases to induce partial chromatinolysis.

Once the nucleus condenses, the cell is doomed to die, because large-scale chromatin fragmentation usually accompanies nuclear condensation.

Additionally, cytosolic AIF acts on the mitochondria to collapse the mitochondrial membrane potential and initiates the release of CytoC, which activates Caspases. The late activation of Caspases after the executioner step of AIF release may facilitate the dissolution of the cell.

DNA damage elicits the activation of PARP1 (Poly[ADP-Ribose] Polymerase-1), a nuclear enzyme that facilitates DNA repair after injury, transferring ADP-ribose to nuclear proteins with consequent NADH depletion to very low levels.

Hence, there is decreased NADH oxidase activity by AIF since there is little or no NADH available to be oxidized.

Under those specific conditions, AIF might accept electrons from a source other than NADH, such as a potentially toxic free radical or H2O2, and thus act as a scavenger.

This redox cycling (alternate accepting and donating an electron), can serve as a protective mechanism.

Decrement in NAD+ is also perceived by the mitochondria, leading to translocation of AIF to the nucleus and initiation of nuclear condensation.

If these or similar conditions hold, then the oxidoreductase activity of AIF would be antiapoptotic while its DNA binding activity would be proapoptotic, resulting in dueling functions of different regions of AIF with potentially different outcomes dependent on cell type and insult.

The apoptogenic role of AIF seems to be essential for a death outcome only when certain signaling pathways to apoptosis are elicited.

The cell death machine indeed has many cogs that evidently mesh in various ways to generate internally disparate but parallel pathways.

Yet AIF now clearly has a recognized role as a cog in the life machine of cells, presumably due to protective redox processes effected through its nature as a flavoprotein.

This new view of the multifunctional roles of AIF leaves open a new dimension to explore the possibility of modulating AIF function, by generating small AIF-activating or AIF-inhibiting molecules, the aim being to use such compounds for the therapeutic manipulation of apoptosis.

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