From CellBiology

Individual Project

Apoptosis Inducing Factor (AIF)

What is AIF?

The AIF gene has been conserved throughout the eukaryotes. It is a phylogenetically old flavoprotien. It is called a flavoprotein because it is able to be stably bound to FAD (flavin adenine dinucleotide). AIF is a positive intrinsic regulator of apoptosis and a redox enzyme needed for normal respiratory function within the mitochondria (Feraud et al, 2006). It is a mitochondrial oxidoreductase. AIF resides within the inter-membranous layer of the mitochondria. There are said to be three isoforms , AIF, AIF-exB (different exon), and AIFsh (of short).

Topology and Gene location

Crystal structure

ZAIF crystal structure.JPG

  • AIF consists of a three domains, a mitochondrial localization sequence (MLS), a spacer sequence, and a oxidoreductase amino acid domain (Cande et al, 2002).

Gene location

Xq25-q26. The gene which encodes for AIF is the apoptosis-inducing factor, mitochondrion-associated, 1 (AIFM1). it is located on the X chromosome and is on the long arm at position 25-26.


ZAIF Diagram.jpg

Current studies

AIF and Diabetes in Animal models

A recent study by Schulthess et al (2009) demonstrated the importance of AIF in maintaining beta cell mass in mice. It is this decline of beta cell mass which is a major contributor to diabetes within humans. Harlequin (Hq) mutant mice have been used in previous studies to demonstrate the role of AIF in scavenging for free radicals to prevent apoptosis (Modjtahedi et al, 2006). Hq mice mutant are inserted with a provirus into the gene which results in 80% less AIF production. As a consequence these mice show evidence of a significant reduction in oxidative phosphorylation (OxP) and subsequently a reduction of ATP. This effect of reduced OxP and mitochondrial function has been shown to influence insulin resistance (Schulthess et al, 2009). In this current study by Schulthess et al (2009) the depletion of AIF in mice showed a significant decrease of beta cell mass and a continual decline with age. It was shown that the proliferation of the beta cells did not reduce, but it was the cell cycle that was disrupted. It was hypothesised that the G2 phase of the cell’s development was interrupted by the presence of oxidative stress. it could then be hypothesised that it is the AIF which scavenge for oxidants. A G2 check point is triggered by the oxidative stress and this server disruption induces apoptosis. The effect of a depletion of AIF could be a significant factor in beta cell mass loss.

AIF in Colon Cancer

It is known that some cellular changes that inhibit apoptosis can induce the development of abnormal growths, such as cancer. It has been seen that blockage of the AIF signalling pathway could be implicated in chemo-resistance in some cancer types such as non small cell lung carcinoma. Unlike these cancers colon cancer has shown to have a different interaction with AIF. AIF has been seen to reduce chemical induced apoptosis and it sustains the abnormal formation of the malignant cell. Although this concept has some unsolved issues it has been shown by Urbano et al (2009) that AIF deficient cells were excessively susceptible to apoptosis. AIF could in the future be a potential target for cancer drug therapy. This enables a potential drug alternative to those patients whom have developed drug resistance to regular chemoradiotherapeutic intervention.



  • oxidoreductase: An enzymes which is known to dehydrogenases or oxidase, catalyzing the removal of hydrogen atoms and electrons from the substance.
  • free radical: a highly unstable and reactive atom (or group of atoms), due to at least one unpaired electron.
  • redox: stands for reducation-oxidation reaction,that results in a change of oxidation state (and number). Oxidation is the gain of and electron and reduction is the lose of an electron
  • bioenergetics: the stuy of the flow of energy through a living thing.
  • PARP-1: Poly (ADP-ribose) polymerase family, member 1.
  • calprins: Ca2+-dependent protease.
  • cathepsin: proteolytic enzymes that reside in endolysosomal vesicles.
  • ATP: adenosine triphosphate, transports chemical energy within cells for metabolism.
  • NAD+: Nicotinamide adenine dinucleotide,is involved in redox reactions, transporting electrons.
  • immunostaining:method to detect a specific protein in a sample using antibody-based techniques.
  • chromatin:the loosley coiled form of DNA and associated protiens within the cell.
  • Oxidative phosphorylation: the synthesis of ATP by phosphorylation of ADP, where energy is attained from the transport of electrons.this process takes place in mitochondria during aerobic respiration.


Candé C, Vahsen N, Kouranti I, Schmitt E, Daugas E, Spahr C, Luban J, Kroemer RT, Giordanetto F, Garrido C, Penninger JM, Kroemer G (2004) AIF and cyclophilin A cooperate in apoptosis-associated chromatinolysis. Oncogene. 26;23(8):1514-21.

Candé C, Cohen I, Daugas E, Ravagnan L, Larochette N, Zamzami N, Kroemer G (2002). Apoptosis-inducing factor (AIF): a novel caspase-independent death effector released from mitochondria. Biochimie. 84(2-3):215-22.

Millan A, Huerta S (2009) Apoptosis-inducing factor and colon cancer. J Surg Res. 151(1):163-70. Epub 2007 Dec 3

Modjtahedi N, Giordanetto F, Madeo F, Kroemer G (2006) Apoptosis-inducing factor: vital and lethal. Trends Cell Biol. 16(5):264-72. Epub 2006 Apr 18.

Joza N, Susin SA, Daugas E, Stanford WL, Cho SK, Li CY, Sasaki T, Elia AJ, Cheng HY, Ravagnan L, Ferri KF, Zamzami N, Wakeham A, Hakem R, Yoshida H, Kong YY, Mak TW, Zúñiga-Pflücker JC, Kroemer G, Penninger JM.(2000)Essential role of the mitochondrial apoptosis-inducing factor in programmed cell death.Nature.410(6828):549-54

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

Porter AG, Urbano AGL. (2006) Does apoptosis-inducing factor (AIF) have both life and death functions in cells?. BioEssays 28:834-843.


--Beatrix Palmer 15:52, 11 May 2009 (EST) mark, could you please remove an uploaded pic, z crystal structure AIF. thanks.

--Mark Hill 09:22, 16 April 2009 (EST) All on track, kee up the good work!

--Mark Hill 18:13, 19 March 2009 (EST) Thank you for your feedback. Yes nucleosomes are important, not only for DNA packing, but also in our initial understanding of how apoptosis works.

  • Formed by DNA wrapped around histones.

--Mark Hill 15:25, 25 March 2009 (EST) The complete ribosome does not exist unless attached to a messenger RNA, it occurs as the 2 major subunits in the cytoplasm. Initial binding of a subunit occurs at the 5' amino- encoding end of the mRNA and the other subunit now assembles to form the complete ribosome. t-RNA now docks and brings the first amino acid and protein synthesis at AA1 has begun.The next AA is added and synthesis occurs as the ribosome translocates (moves) along the mRNA to the 3' carboxy- terminal at the end of the forming protein.

--Mark Hill 22:44, 31 March 2009 (EST) Yes both these processes, but I had told you these in the lecture, so it was not as if you have tried to find additional cellular processes that require lots of energy. --Beatrix Palmer 15:56, 5 April 2009 (EST) I did look on the internet after class as well, i just thought you wanted a couple of examples. sorry.

  • Muscle cells (cardiac, skeletal and smooth muscle cels), for contraction.
  • Sperm, within the tail for motility.

--Mark Hill 09:39, 3 April 2009 (EST) Correct for CAM terms, lots of science today uses acronyms (because the terms or gene names are very long), but what this means is that several acronyms can mean different things to different people.