FIS1

Protein-coding gene in the species Homo sapiens

FIS1

Available structures

PDB

Ortholog search: PDBe RCSB

List of PDB id codes
1NZN, 1PC2

Identifiers

Aliases

FIS1, TTC11, CGI-135, fission, mitochondrial 1

External IDs

OMIM: 609003; MGI: 1913687; HomoloGene: 41099; GeneCards: FIS1; OMA:FIS1 - orthologs

Gene location (Human)

Chr.	Chromosome 7 (human)^[1]

Band	7q22.1	Start	101,239,458 bp^[1]
Band	7q22.1	End	101,252,316 bp^[1]

Gene location (Mouse)

Chr.	Chromosome 5 (mouse)^[2]

Band	5\|5 G2	Start	136,982,129 bp^[2]
Band	5\|5 G2	End	136,995,088 bp^[2]

RNA expression pattern

Bgee

Human

Mouse (ortholog)

Top expressed in

C1 segment

apex of heart

prefrontal cortex

muscle of thigh

anterior pituitary

gastrocnemius muscle

anterior cingulate cortex

right frontal lobe

right auricle

left ventricle

Top expressed in

interventricular septum

blood

granulocyte

right kidney

dentate gyrus of hippocampal formation granule cell

superior frontal gyrus

visual cortex

primary visual cortex

right lung lobe

More reference expression data

BioGPS

n/a

Gene ontology
Molecular function	protein binding signaling receptor binding protein-containing complex binding
Cellular component	integral component of membrane membrane peroxisomal membrane peroxisome mitochondrial outer membrane mitochondrion integral component of peroxisomal membrane endoplasmic reticulum integral component of mitochondrial outer membrane protein-containing complex
Biological process	mitochondrial fusion mitochondrial fission regulation of mitochondrion organization positive regulation of cytosolic calcium ion concentration protein targeting to mitochondrion peroxisome fission positive regulation of cysteine-type endopeptidase activity involved in apoptotic process autophagy of mitochondrion negative regulation of endoplasmic reticulum calcium ion concentration positive regulation of mitochondrial calcium ion concentration mitochondrion morphogenesis calcium-mediated signaling using intracellular calcium source positive regulation of intrinsic apoptotic signaling pathway release of cytochrome c from mitochondria positive regulation of protein targeting to membrane apoptotic process response to muscle activity cellular response to glucose stimulus cellular response to toxic substance response to hypobaric hypoxia positive regulation of neuron apoptotic process mitochondrial fragmentation involved in apoptotic process protein homooligomerization cellular response to lipid positive regulation of mitochondrial fission cellular response to peptide response to flavonoid response to nutrient levels response to fluoride
Sources:Amigo / QuickGO

Orthologs

Species

Human

Mouse

Entrez


51024


66437

Ensembl


ENSG00000214253


ENSMUSG00000019054

UniProt


Q9Y3D6


Q9CQ92

RefSeq (mRNA)


NM_016068


NM_001163243 NM_025562 NM_001347504

RefSeq (protein)


NP_057152


NP_001156715 NP_001334433 NP_079838

Location (UCSC)

Chr 7: 101.24 – 101.25 Mb

Chr 5: 136.98 – 137 Mb

PubMed search

^[3]

^[4]

Wikidata

View/Edit Human

View/Edit Mouse

Mitochondrial fission 1 protein (FIS1) is a protein that in humans is encoded by the FIS1 gene on chromosome 7.^[5]^[6]^[7] This protein is a component of a mitochondrial complex, the ARCosome, that promotes mitochondrial fission.^[7]^[8] Its role in mitochondrial fission thus implicates it in the regulation of mitochondrial morphology, the cell cycle, and apoptosis.^[7]^[8]^[9]^[10] By extension, the protein is involved in associated diseases, including neurodegenerative diseases and cancers.^[11]^[12]

Structure

The protein encoded by this gene is a 16 kDa integral protein situated in the outer mitochondrial membrane (OMM).^[9] It is composed of a transmembrane domain at the C-terminal and a cytosolic domain at the N-terminal.^[9]^[13]^[14] 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.^[14]^[15] 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.^[9]^[13] 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.^[13]

Function

FIS1 is indirectly involved in mitochondrial fission via binding dynamin-related protein 1 (DRP1).^[12]^[15] By extension, FIS1 helps regulate the size and distribution of mitochondria in response to local demand for ATP or calcium ions.^[13] In addition, mitochondrial fission may lead to release of cytochrome C, which eventually leads to cell death.^[9] 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.^[8]^[12] 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.^[14] 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.^[9]^[10]

Clinical Significance

As a fission factor, FIS1 is associated with neurodegenerative diseases.^[11]^[12] Stress, such as NO, can trigger aberrant mitochondrial fission and fusion, resulting in mitophagy.^[9]^[11] 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.^[11] FIS1 is also implicated in a variety of cancers, including acute myeloid leukemia, breast cancer, and prostate cancer.^[12]

Interactions

FIS1 has been shown to interact with:

BCAP31,^[8]
procaspase-8,^[8]
TBC1D15,^[14]
PEX11 family,^[15] and
DNM1L.^[16]

References

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000214253 – Ensembl, May 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000019054 – Ensembl, May 2017
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ 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. PMID 14996942.
^ 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. PMID 16010987. S2CID 21452703.
^ ^a ^b ^c "Entrez Gene: FIS1 fission 1 (mitochondrial outer membrane) homolog (S. cerevisiae)".
^ ^a ^b ^c ^d ^e Iwasawa R, Mahul-Mellier AL, Datler C, Pazarentzos E, Grimm S (Feb 2011). "Fis1 and Bap31 bridge the mitochondria-ER interface to establish a platform for apoptosis induction". The EMBO Journal. 30 (3): 556–68. doi:10.1038/emboj.2010.346. PMC 3034017. PMID 21183955.
^ ^a ^b ^c ^d ^e ^f ^g Gomes LC, Scorrano L (2008). "High levels of Fis1, a pro-fission mitochondrial protein, trigger autophagy". Biochimica et Biophysica Acta (BBA) - Bioenergetics. 1777 (7–8): 860–6. doi:10.1016/j.bbabio.2008.05.442. PMID 18515060.
^ ^a ^b Lee 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. PMC 11113609. PMID 23907611. S2CID 11694077.
^ ^a ^b ^c ^d Wang 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. PMID 22340708. S2CID 21950507.
^ ^a ^b ^c ^d ^e 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 (2014). "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. Bibcode:2014PLoSO...984150T. doi:10.1371/journal.pone.0084150. PMC 3885535. PMID 24416201.
^ ^a ^b ^c ^d Lees JP, Manlandro CM, Picton LK, Tan AZ, Casares S, Flanagan JM, Fleming KG, Hill RB (Oct 2012). "A designed point mutant in Fis1 disrupts dimerization and mitochondrial fission". Journal of Molecular Biology. 423 (2): 143–58. doi:10.1016/j.jmb.2012.06.042. PMC 3456991. PMID 22789569.
^ ^a ^b ^c ^d 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 (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. PMID 23077178.
^ ^a ^b ^c Palmer CS, Elgass KD, Parton RG, Osellame LD, Stojanovski D, Ryan MT (Sep 2013). "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. doi:10.1074/jbc.M113.479873. PMC 3779755. PMID 23921378.
^ Yoon Y, Krueger EW, Oswald BJ, McNiven MA (Aug 2003). "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. doi:10.1128/MCB.23.15.5409-5420.2003. PMC 165727. PMID 12861026.