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]
↑Stojanovski D, Koutsopoulos OS, Okamoto K, Ryan MT (Mar 2004). "Levels of human Fis1 at the mitochondrial outer membrane regulate mitochondrial morphology". Journal of Cell Science. 117 (Pt 7): 1201–10. doi:10.1242/jcs.01058. PMID14996942.
↑Kong D, Xu L, Yu Y, Zhu W, Andrews DW, Yoon Y, Kuo TH (Apr 2005). "Regulation of Ca2+-induced permeability transition by Bcl-2 is antagonized by Drpl and hFis1". Molecular and Cellular Biochemistry. 272 (1–2): 187–99. doi:10.1007/s11010-005-7323-3. PMID16010987.
↑ 6.06.1Lee S, Park YY, Kim SH, Nguyen OT, Yoo YS, Chan GK, Sun X, Cho H (Feb 2014). "Human mitochondrial Fis1 links to cell cycle regulators at G2/M transition". Cellular and Molecular Life Sciences. 71 (4): 711–25. doi:10.1007/s00018-013-1428-8. PMID23907611.
↑ 7.07.17.27.3Wang S, Song J, Tan M, Albers KM, Jia J (Jul 2012). "Mitochondrial fission proteins in peripheral blood lymphocytes are potential biomarkers for Alzheimer's disease". European Journal of Neurology. 19 (7): 1015–22. doi:10.1111/j.1468-1331.2012.03670.x. PMID22340708.
↑ 10.010.110.210.3Onoue 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 (Jan 2013). "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. doi:10.1242/jcs.111211. PMID23077178.
James DI, Parone PA, Mattenberger Y, Martinou JC (Sep 2003). "hFis1, a novel component of the mammalian mitochondrial fission machinery". The Journal of Biological Chemistry. 278 (38): 36373–9. doi:10.1074/jbc.M303758200. PMID12783892.
Kikuchi M, Hatano N, Yokota S, Shimozawa N, Imanaka T, Taniguchi H (Jan 2004). "Proteomic analysis of rat liver peroxisome: presence of peroxisome-specific isozyme of Lon protease". The Journal of Biological Chemistry. 279 (1): 421–8. doi:10.1074/jbc.M305623200. PMID14561759.
Suzuki M, Jeong SY, Karbowski M, Youle RJ, Tjandra N (Nov 2003). "The solution structure of human mitochondria fission protein Fis1 reveals a novel TPR-like helix bundle". Journal of Molecular Biology. 334 (3): 445–58. doi:10.1016/j.jmb.2003.09.064. PMID14623186.
Frieden M, James D, Castelbou C, Danckaert A, Martinou JC, Demaurex N (May 2004). "Ca(2+) homeostasis during mitochondrial fragmentation and perinuclear clustering induced by hFis1". The Journal of Biological Chemistry. 279 (21): 22704–14. doi:10.1074/jbc.M312366200. PMID15024001.
Yu T, Fox RJ, Burwell LS, Yoon Y (Sep 2005). "Regulation of mitochondrial fission and apoptosis by the mitochondrial outer membrane protein hFis1". Journal of Cell Science. 118 (Pt 18): 4141–51. doi:10.1242/jcs.02537. PMID16118244.
Yoon YS, Yoon DS, Lim IK, Yoon SH, Chung HY, Rojo M, Malka F, Jou MJ, Martinou JC, Yoon G (Nov 2006). "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. doi:10.1002/jcp.20753. PMID16883569.
Kobayashi S, Tanaka A, Fujiki Y (May 2007). "Fis1, DLP1, and Pex11p coordinately regulate peroxisome morphogenesis". Experimental Cell Research. 313 (8): 1675–86. doi:10.1016/j.yexcr.2007.02.028. PMID17408615.
Lee S, Jeong SY, Lim WC, Kim S, Park YY, Sun X, Youle RJ, Cho H (Aug 2007). "Mitochondrial fission and fusion mediators, hFis1 and OPA1, modulate cellular senescence". The Journal of Biological Chemistry. 282 (31): 22977–83. doi:10.1074/jbc.M700679200. PMID17545159.
