Structural Biochemistry/Cell Signaling Pathways/Apoptosis-Inducing Factor

Apoptosis inducing factor (AIF) is a protein that plays a part in starting a caspase-independent pathway to apoptosis. Apoptosis inducing factor carries this out by causing chromatin condensation and DNA to fragment. Apoptosis inducing factor can also act as a NADH oxidase. Another function of apoptosis inducing factor is to regulate how permeable the mitochondrial membrane is upon apoptosis. Normally apoptosis inducing factor is found on the outer membrane of the mitochondria and is separated from the nucleus. However, in the case when the mitochondrion is damaged, the apoptosis inducing factor moves into the cytosol and to the nucleus.

Function
Apoptosis Inducing Factor is a protein that triggers DNA degradation and chromatin condensation in a cell which induces programmed cell death. Mitochondrial apoptosis inducing factor protein is a caspase-independent death effector that cause nuclei to undergo apoptotic changes. The apoptosis process begins when the mitochondria releases apoptosis inducing factor. The apoptosis inducing factor then leaves through the mitochondrial membrane and enters the cytosol. Eventually it ends up in the cell nucleus where it signals to the cell causing chromosome condensation and DNA fragmentation. This will eventually lead to cell death or apoptosis. The apoptosis inducing factor is different depending on the type of cell, the apoptotic insult, and its ability to bind to DNA. Apoptosis inducing factor also plays a large and important role in the mitochondrial respiratory chain and metabolic reduction-oxidation reactions.

Synthesis of Apoptosis Inducing Factor
In humans the apoptosis inducing factor is located across 16 exons on the X chromosome. A apoptosis inducing factor called AIF1 is translated in the cytosol and sent to the mitochondrial membrane and to the intermembrane space by the C-terminus of an MLS protein. Apoptosis inducing factor is transported with help from the N-terminal MLS protein to the inner and outer mitochondrial membrane enzymes which allows it to enter into the organelle. Once inside the mitochondria, apoptosis inducing factor folds into the functional configuration with assistance of the co-factor, flavin adenine dinucleotide. Then a protein called Scythe increases the apoptosis inducing factor's lifetime in the cell. So a decrease in amount of Scythe would lead to a quicker fragmentation and degradation of apoptosis inducing factors. The x-linked inhibitor of apoptosis can affect the half-life of apoptosis inducing factor similar to Scythe. The two don't affect the apoptosis inducing factor attached to the inner mitochondrial membrane but they influence the stability of the apoptosis inducing factor once it leaves the mitochondria.

Apoptosis Inducing Factor's Role in mitochondria
Recombinant apoptosis inducing factors that do not have the last 100 N-terminal amino acids have limited NADP and NADPH oxidase activity. It is determined that the apoptosis inducing factor N-terminus can function in many other interactions with other proteins or control apoptosis inducing factor reduction-oxidation reactions and substrate specificity.

Mutations of apoptosis inducing factor can occur due to deletions. This has caused the creation of the mouse model of complex I deficiency. Complex I deficiency is the cause of over 30% of human mitochondrial related diseases. These apoptosis inducing factor-deficient mouse models are useful in the study for finding cures for complex I deficiencies. The identification of apoptosis inducing factor-interacting proteins in the inner mitochondrial membrane and intermembrane will allow researchers to better identify and understand the mechanisms in the signaling pathway that monitors the function of apoptosis inducing factor in the mitochondria.