FIS1 explained

Mitochondrial fission 1 protein (FIS1) is a protein that in humans is encoded by the FIS1 gene on chromosome 7.^{[1] [2] [3]} This protein is a component of a mitochondrial complex, the ARCosome, that promotes mitochondrial fission.^{[3] [4]} Its role in mitochondrial fission thus implicates it in the regulation of mitochondrial morphology, the cell cycle, and apoptosis.^{[3] [4] [5] [6]} By extension, the protein is involved in associated diseases, including neurodegenerative diseases and cancers.^{[7] [8]}

Structure

The protein encoded by this gene is a 16 kDa integral protein situated in the outer mitochondrial membrane (OMM).^[5] It is composed of a transmembrane domain at the C-terminal and a cytosolic domain at the N-terminal.^{[5] [9] [10]} The transmembrane domain anchors FIS1 in the OMM, though it has been observed to target different cellular compartments, such as the peroxisome, depending on its hydrophobicity, charge, and length.^{[10] [11]} Meanwhile, the cytosolic domain contains a bundle of six helices, four of which contain two tandem tetratricopeptide repeat (TPR)-like motifs. These motifs form a concave surface by their combined superhelical structure and potentially bind another FIS1 protein to form a dimer, or other proteins.^{[5] [9]} Moreover, the N-terminal arm can dock at, and thus obstruct, the TPR motifs, allowing the protein to exist in a dynamic equilibrium between "open" and "closed" states.^[9]

Function

FIS1 is indirectly involved in mitochondrial fission via binding dynamin-related protein 1 (DRP1).^{[8] [11]} By extension, FIS1 helps regulate the size and distribution of mitochondria in response to local demand for ATP or calcium ions.^[9] In addition, mitochondrial fission may lead to release of cytochrome C, which eventually leads to cell death.^[5] In a separate apoptotic signalling pathway, FIS1 interacts with BCAP31 to form a complex, the ARCosome. The ARCosome promotes cell death by bridging the mitochondria and the endoplasmic reticulum (ER), allowing FIS1 to transmit a proapoptotic signal from the mitochondria to the ER and activate procaspase-8. The ARCosome then forms a platform with procaspase-8 to increase calcium load in the mitochondria, resulting in apoptosis.^{[4] [8]} Additionally, FIS1 is involved in other modes of shaping mitochondrial morphology. For example, it interacts with TBC1D15 to regulate mitochondrial morphology, particularly with regard to lysosome and endosome fusion.^[10] FIS1 also prevents mitochondria elongation, which would otherwise lead to cell cycle delay or arrest, and ultimately, senescence. Moreover, mitochondrial dysfunction results in elevated reactive oxygen species (ROS) levels, which cause DNA damage and induce transcriptional repression, as well as induce mitophagy.^{[5] [6]}

Clinical Significance

As a fission factor, FIS1 is associated with neurodegenerative diseases.^{[7] [8]} Stress, such as NO, can trigger aberrant mitochondrial fission and fusion, resulting in mitophagy.^{[5] [7]} For example, increased mitochondrial fragmentation and FIS1 levels were observed in Alzheimer's disease (AD) patients. Thus, FIS1 could serve as a biomarker for early detection of AD.^[7] FIS1 is also implicated in a variety of cancers, including acute myeloid leukemia, breast cancer, and prostate cancer.^[8]

Interactions

FIS1 has been shown to interact with:

• BCAP31,^[4]
• procaspase-8,^[4]
• TBC1D15,^[10]
• PEX11 family,^[11] and
• DNM1L.^[12]

Further reading

• Lai CH, Chou CY, Ch'ang LY, Liu CS, Lin W . Identification of novel human genes evolutionarily conserved in Caenorhabditis elegans by comparative proteomics . Genome Research . 10 . 5 . 703–13 . May 2000 . 10810093 . 310876 . 10.1101/gr.10.5.703 .
• James DI, Parone PA, Mattenberger Y, Martinou JC . hFis1, a novel component of the mammalian mitochondrial fission machinery . The Journal of Biological Chemistry . 278 . 38 . 36373–9 . Sep 2003 . 12783892 . 10.1074/jbc.M303758200 . free .
• Yoon Y, Krueger EW, Oswald BJ, McNiven MA . The mitochondrial protein hFis1 regulates mitochondrial fission in mammalian cells through an interaction with the dynamin-like protein DLP1 . Molecular and Cellular Biology . 23 . 15 . 5409–20 . Aug 2003 . 12861026 . 165727 . 10.1128/MCB.23.15.5409-5420.2003 .
• Kikuchi M, Hatano N, Yokota S, Shimozawa N, Imanaka T, Taniguchi H . Proteomic analysis of rat liver peroxisome: presence of peroxisome-specific isozyme of Lon protease . The Journal of Biological Chemistry . 279 . 1 . 421–8 . Jan 2004 . 14561759 . 10.1074/jbc.M305623200 . free .
• Suzuki M, Jeong SY, Karbowski M, Youle RJ, Tjandra N . The solution structure of human mitochondria fission protein Fis1 reveals a novel TPR-like helix bundle . Journal of Molecular Biology . 334 . 3 . 445–58 . Nov 2003 . 14623186 . 10.1016/j.jmb.2003.09.064 .
• Dohm JA, Lee SJ, Hardwick JM, Hill RB, Gittis AG . Cytosolic domain of the human mitochondrial fission protein fis1 adopts a TPR fold . Proteins . 54 . 1 . 153–6 . Jan 2004 . 14705031 . 3047745 . 10.1002/prot.10524 .
• Frieden M, James D, Castelbou C, Danckaert A, Martinou JC, Demaurex N . Ca(2+) homeostasis during mitochondrial fragmentation and perinuclear clustering induced by hFis1 . The Journal of Biological Chemistry . 279 . 21 . 22704–14 . May 2004 . 15024001 . 10.1074/jbc.M312366200 . free .
• Lee YJ, Jeong SY, Karbowski M, Smith CL, Youle RJ . Roles of the mammalian mitochondrial fission and fusion mediators Fis1, Drp1, and Opa1 in apoptosis . Molecular Biology of the Cell . 15 . 11 . 5001–11 . Nov 2004 . 15356267 . 524759 . 10.1091/mbc.E04-04-0294 .
• Koch A, Yoon Y, Bonekamp NA, McNiven MA, Schrader M . A role for Fis1 in both mitochondrial and peroxisomal fission in mammalian cells . Molecular Biology of the Cell . 16 . 11 . 5077–86 . Nov 2005 . 16107562 . 1266408 . 10.1091/mbc.E05-02-0159 .
• Yu T, Fox RJ, Burwell LS, Yoon Y . Regulation of mitochondrial fission and apoptosis by the mitochondrial outer membrane protein hFis1 . Journal of Cell Science . 118 . Pt 18 . 4141–51 . Sep 2005 . 16118244 . 10.1242/jcs.02537 . 21271384 .
• Yoon YS, Yoon DS, Lim IK, Yoon SH, Chung HY, Rojo M, Malka F, Jou MJ, Martinou JC, Yoon G . Formation of elongated giant mitochondria in DFO-induced cellular senescence: involvement of enhanced fusion process through modulation of Fis1 . Journal of Cellular Physiology . 209 . 2 . 468–80 . Nov 2006 . 16883569 . 10.1002/jcp.20753 . 22179820 .
• Alirol E, James D, Huber D, Marchetto A, Vergani L, Martinou JC, Scorrano L . The mitochondrial fission protein hFis1 requires the endoplasmic reticulum gateway to induce apoptosis . Molecular Biology of the Cell . 17 . 11 . 4593–605 . Nov 2006 . 16914522 . 1635393 . 10.1091/mbc.E06-05-0377 .
• Kobayashi S, Tanaka A, Fujiki Y . Fis1, DLP1, and Pex11p coordinately regulate peroxisome morphogenesis . Experimental Cell Research . 313 . 8 . 1675–86 . May 2007 . 17408615 . 10.1016/j.yexcr.2007.02.028 .
• Lee S, Jeong SY, Lim WC, Kim S, Park YY, Sun X, Youle RJ, Cho H . Mitochondrial fission and fusion mediators, hFis1 and OPA1, modulate cellular senescence . The Journal of Biological Chemistry . 282 . 31 . 22977–83 . Aug 2007 . 17545159 . 10.1074/jbc.M700679200 . free .

Notes and References

1. Stojanovski D, Koutsopoulos OS, Okamoto K, Ryan MT . Levels of human Fis1 at the mitochondrial outer membrane regulate mitochondrial morphology . Journal of Cell Science . 117 . Pt 7 . 1201–10 . Mar 2004 . 14996942 . 10.1242/jcs.01058 . free .
2. Kong D, Xu L, Yu Y, Zhu W, Andrews DW, Yoon Y, Kuo TH . Regulation of Ca2+-induced permeability transition by Bcl-2 is antagonized by Drpl and hFis1 . Molecular and Cellular Biochemistry . 272 . 1–2 . 187–99 . Apr 2005 . 16010987 . 10.1007/s11010-005-7323-3 . 21452703 .
3. Web site: Entrez Gene: FIS1 fission 1 (mitochondrial outer membrane) homolog (S. cerevisiae).
4. Iwasawa R, Mahul-Mellier AL, Datler C, Pazarentzos E, Grimm S . Fis1 and Bap31 bridge the mitochondria-ER interface to establish a platform for apoptosis induction . The EMBO Journal . 30 . 3 . 556–68 . Feb 2011 . 21183955 . 10.1038/emboj.2010.346 . 3034017.
5. Gomes LC, Scorrano L . High levels of Fis1, a pro-fission mitochondrial protein, trigger autophagy . Biochimica et Biophysica Acta (BBA) - Bioenergetics . 1777 . 7–8 . 860–6 . 2008 . 18515060 . 10.1016/j.bbabio.2008.05.442 . free .
6. Lee S, Park YY, Kim SH, Nguyen OT, Yoo YS, Chan GK, Sun X, Cho H . Human mitochondrial Fis1 links to cell cycle regulators at G2/M transition . Cellular and Molecular Life Sciences . 71 . 4 . 711–25 . Feb 2014 . 23907611 . 10.1007/s00018-013-1428-8 . 11694077 . 11113609 .
7. Wang S, Song J, Tan M, Albers KM, Jia J . Mitochondrial fission proteins in peripheral blood lymphocytes are potential biomarkers for Alzheimer's disease . European Journal of Neurology . 19 . 7 . 1015–22 . Jul 2012 . 22340708 . 10.1111/j.1468-1331.2012.03670.x . 21950507 .
8. Tian Y, Huang Z, Wang Z, Yin C, Zhou L, Zhang L, Huang K, Zhou H, Jiang X, Li J, Liao L, Yang M, Meng F . Identification of novel molecular markers for prognosis estimation of acute myeloid leukemia: over-expression of PDCD7, FIS1 and Ang2 may indicate poor prognosis in pretreatment patients with acute myeloid leukemia . PLOS ONE . 9 . 1 . e84150 . 2014 . 24416201 . 10.1371/journal.pone.0084150 . 3885535. 2014PLoSO...984150T . free .
9. Lees JP, Manlandro CM, Picton LK, Tan AZ, Casares S, Flanagan JM, Fleming KG, Hill RB . A designed point mutant in Fis1 disrupts dimerization and mitochondrial fission . Journal of Molecular Biology . 423 . 2 . 143–58 . Oct 2012 . 22789569 . 10.1016/j.jmb.2012.06.042 . 3456991.
10. Onoue K, Jofuku A, Ban-Ishihara R, Ishihara T, Maeda M, Koshiba T, Itoh T, Fukuda M, Otera H, Oka T, Takano H, Mizushima N, Mihara K, Ishihara N . Fis1 acts as a mitochondrial recruitment factor for TBC1D15 that is involved in regulation of mitochondrial morphology . Journal of Cell Science . 126 . Pt 1 . 176–85 . Jan 2013 . 23077178 . 10.1242/jcs.111211 . free .
11. Palmer CS, Elgass KD, Parton RG, Osellame LD, Stojanovski D, Ryan MT . Adaptor proteins MiD49 and MiD51 can act independently of Mff and Fis1 in Drp1 recruitment and are specific for mitochondrial fission . The Journal of Biological Chemistry . 288 . 38 . 27584–93 . Sep 2013 . 23921378 . 10.1074/jbc.M113.479873 . 3779755. free .
12. Yoon Y, Krueger EW, Oswald BJ, McNiven MA . The mitochondrial protein hFis1 regulates mitochondrial fission in mammalian cells through an interaction with the dynamin-like protein DLP1 . Molecular and Cellular Biology . 23 . 15 . 5409–20 . Aug 2003 . 12861026 . 165727 . 10.1128/MCB.23.15.5409-5420.2003 .