Apoptosis inducing factor is involved in initiating a caspase-independent pathway of

apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes includ ...

(positive intrinsic regulator of apoptosis) by causing DNA fragmentation and chromatin condensation. Apoptosis inducing factor is a

flavoprotein Flavoproteins are proteins that contain a nucleic acid derivative of riboflavin. Flavoproteins are involved in a wide array of biological processes, including removal of radicals contributing to oxidative stress, photosynthesis, and DNA repair. ...

. It also acts as an

NADH Nicotinamide adenine dinucleotide (NAD) is a coenzyme central to metabolism. Found in all living cells, NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an aden ...

oxidase. Another AIF function is to regulate the permeability of the mitochondrial membrane upon apoptosis. Normally it is found behind the outer membrane of the mitochondrion and is therefore secluded from the nucleus. However, when the mitochondrion is damaged, it moves to the cytosol and to the nucleus. Inactivation of AIF leads to resistance of embryonic stem cells to death following the withdrawal of growth factors indicating that it is involved in apoptosis.

Function

Apoptosis Inducing Factor (AIF) is a protein that triggers chromatin condensation and

DNA fragmentation DNA fragmentation is the separation or breaking of DNA strands into pieces. It can be done intentionally by laboratory personnel or by cells, or can occur spontaneously. Spontaneous or accidental DNA fragmentation is fragmentation that gradually a ...

in a cell in order to induce programmed cell death. The mitochondrial AIF protein was found to be a

caspase Caspases (cysteine-aspartic proteases, cysteine aspartases or cysteine-dependent aspartate-directed proteases) are a family of protease enzymes playing essential roles in programmed cell death. They are named caspases due to their specific cystei ...

-independent death effector that can allow independent nuclei to undergo apoptotic changes. The process triggering apoptosis starts when the mitochondrion releases AIF, which exits through the mitochondrial membrane, enters the cytosol, and moves to the nucleus of the cell, where it signals the cell to condense its chromosomes and fragment its DNA molecules in order to prepare for cell death. Recently, researchers have discovered that the activity of AIF depends on the type of cell, the apoptotic insult, and its DNA-binding ability. AIF also plays a significant role in the

mitochondrial respiratory chain An electron transport chain (ETC) is a series of protein complexes and other molecules that transfer electrons from electron donors to electron acceptors via redox reactions (both reduction and oxidation occurring simultaneously) and couples thi ...

and metabolic redox reactions.

Synthesis

The AIF protein is located across 16 exons on the

X chromosome The X chromosome is one of the two sex-determining chromosomes ( allosomes) in many organisms, including mammals (the other is the Y chromosome), and is found in both males and females. It is a part of the XY sex-determination system and XO sex ...

in humans. AIF1 (the most abundant type of AIF) is translated in the cytosol and recruited to the

mitochondrial membrane A mitochondrion (; ) is an organelle found in the cells of most Eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is used ...

and intermembrane space by its N-terminal mitochondrial localization signal (MLS). Inside the mitochondrion, AIF folds into its functional configuration with the help of the cofactor flavin adenine dinucleotide (FAD). A protein called

Scythe A scythe ( ) is an agricultural hand tool for mowing grass or harvesting crops. It is historically used to cut down or reap edible grains, before the process of threshing. The scythe has been largely replaced by horse-drawn and then tractor m ...

(BAT3), which is used to regulate organogenesis, can increase the AIF lifetime in the cell. As a result, decreased amounts of Scythe lead to a quicker fragmentation of AIF. The X-linked inhibitor of apoptosis ( XIAP) has the power to influence the half-life of AIF along with Scythe. Together, the two do not affect the AIF attached to the inner mitochondrial membrane, however they influence the stability of AIF once it exits the mitochondrion.

Role in mitochondria

It was thought that if a recombinant version of AIF lacked the first N-terminal 120 amino acids of the protein, then AIF would function as an NADH and NADPH oxidase. However, it was instead discovered that recombinant AIF that do not have the last 100 N-terminal amino acids have limited NADP and NADPH oxidase activity. Therefore, researchers concluded that the AIF N-terminus may function in interactions with other proteins or control AIF redox reactions and substrate specificity. Mutations of AIF due to deletions have stimulated the creation of the mouse model of complex I deficiency. Complex I deficiency is the reason behind over thirty percent of human mitochondrial diseases. For example, complex I mitochondriopathies mostly affect infants by causing symptoms such as seizures, blindness, deafness, etc. These AIF-deficient mouse models are important for fixing complex I deficiencies. The identification of AIF-interacting proteins in the inner mitochondrial membrane and intermembrane space will help researchers identify the mechanism of the signalling pathway that monitors the function of AIF in the mitochondria.

Isozymes

Human genes encoding apoptosis inducing factor isozymes include: * AIFM1 * AIFM2 * AIFM3

Evolution

The apoptotic function of AIFs has been shown in organisms belonging to different eukaryotic organisms including mentioned above human factors: AIM1, AIM2, and AIM3 (Xie ''et al.'', 2005), yeast factors NDI1 and AIF1 as well as AIF of Tetrahymena. Phylogenetic analysis indicates that the divergence of the AIFM1, AIFM2, AIFM3, and NDI sequences occurred before the divergence of eukaryotes.

Role in cancer

Despite an involvement in cell death, AIF plays a contributory role to the growth and aggressiveness of a variety of cancer types including

colorectal The large intestine, also known as the large bowel, is the last part of the gastrointestinal tract and of the digestive system in tetrapods. Water is absorbed here and the remaining waste material is stored in the rectum as feces before being rem ...

, prostate, and

pancreatic The pancreas is an organ of the digestive system and endocrine system of vertebrates. In humans, it is located in the abdomen behind the stomach and functions as a gland. The pancreas is a mixed or heterocrine gland, i.e. it has both an endocr ...

cancers through its NADH oxidase activity. AIF enzymatic activity regulates metabolism but can also increase ROS levels promoting oxidative stress activated signaling molecules including the MAPKs. AIF-mediated redox signaling promotes the activation of

JNK1 Mitogen-activated protein kinase 8 (also known as JNK1) is a ubiquitous enzyme that in humans is encoded by the ''MAPK8'' gene. Function The protein encoded by this gene is a member of the MAP kinase and JNK family. MAP kinases act as an inte ...

, which in turn can trigger the cadherin switch.

References

External links

* {{DEFAULTSORT:Apoptosis-Inducing Factor Programmed cell death Cell signaling Apoptosis