- 1 Individual Project
- 2 Apoptosis Inducing Factor (AIF)
- 3 What is AIF?
- 4 Topology and Gene location
- 5 Signalling
- 6 Abnormalities
- 7 Research today
- 8 A current finding
Apoptosis Inducing Factor (AIF)
What is AIF?
The AIF gene has been conserved throughout the eukaryotes, making this protein 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. It is a mitochondrial oxidoreductase. Resides in two locations, within the intermembrane space or within the innermembrane space of the mitochodria
Topology and Gene location
- AIF consists of a three domains, a mitochondrial localization sequence (MLS), a spacer sequence, and a oxidoreductase amino acid domain (Cande et al, 2002).
Xq25-q26. The gene is made up of 17 exons. Image:
How it works
There are two proposed functions in which AIF has been associated with, free radical scavengers and DNA fragmentation in apoptosis. The first has been well documented in AIF knockout mice, which has seen resulting in neuronal degeneration (Klein et al, 2002). It should be mentioned that mouse AIF has strong 92% amino acid similarity homology to human AIF (Cande et al, 2002). This study by Klein et al (2002) demonstrated that without AIF expression there is oxidative stress from too many free radicals. The second is a caspase independent pathway via which apoptosis is induced. AIF in this pathway contributed to the fragmentation of DNA and chromatin condensation (Millan et al, 2007).
AIF is transcribed from X chromosome gene within in the nucleus. It is translated to the cytosol of the cell where if forms a precursor protein (Modjtahedi et al, 2006). It was mentioned that it resides within the mitochondrion, and it does. AIF is translocated to the inner membranous region of the organelle where it truncated to become matures. Here the AIF is responsible for metabolite redox and vital bioenergetics within the mitochondria (Modjtahedi et al, 2006). It remains within the mitochondria until sufficient stimulus has altered the mitochondrial outer membrane allowing translation of the AIF back into the cytosol. The exact mechanism by which the outer membrane of the mitochondria becomes more permeable to AIF is not fully understood. All that is known is it is released in response to a death stimulus, either by an intrinsic pathway or extrinsic pathway (Cande et al, 2002). Once in the cytosol AIF cleaves into a smaller protein, catalysted by the enzymatic reaction with calprins and cathepsin.
Once the AIF is within the nucleus there it has been shown to bind to cyclophilians A (Cyp A). The AIF and the Cyp A bind to DNA where there is the formation of a trimolecular complex. This interation allows for the degeneration of the DNA (Modjtahedi et al, 2006). This mechanism however has been shown to not be so at embryonic levels. Cyp A knockout mice in a study by Colagan et al (2000), showed there to be no major defects at the embryonic level. It was postulated that this was because at this developmental stage different proteins interact with AIF (Cande et al, 2004).
The use of animal models in research. Mouse model for AIF knock out.
A current finding
AIF in Colon Cancer
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.
Knockout AIF mice: The embroyoid cavity fails to form killing mice before birth. Demonstrating the need for apoptosis in tissue morphology.
--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.