MFN2

Mitofusin-2 is a protein that in humans is encoded by the MFN2 gene.[5][6] Mitofusins are GTPases embedded in the outer membrane of the mitochondria. In mammals MFN1 and MFN2 are essential for mitochondrial fusion.[7] In addition to the mitofusins, OPA1 regulates inner mitochondrial membrane fusion, and DRP1 is responsible for mitochondrial fission.[8]

MFN2
Identifiers
Aliases	MFN2, CMT2A, CMT2A2, CPRP1, HSG, MARF, HMSN6A, mitofusin 2, CMT2A2A, CMT2A2B
External IDs	OMIM: 608507 MGI: 2442230 HomoloGene: 8915 GeneCards: MFN2
Gene location (Human) Chr. Chromosome 1 (human)[1] Band 1p36.22 Start 11,980,181 bp[1] End 12,013,514 bp[1]
Gene location (Mouse) Chr. Chromosome 4 (mouse)[2] Band 4|4 E2 Start 147,873,599 bp[2] End 147,904,704 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • nucleotide binding • GTP binding • GO:0001948 protein binding • hydrolase activity • ubiquitin protein ligase binding • GTPase activity Cellular component • cytosol • membrane • microtubule cytoskeleton • mitochondrial outer membrane • mitochondrion • integral component of membrane • intrinsic component of mitochondrial outer membrane Biological process • mitochondrial fusion • negative regulation of smooth muscle cell proliferation • protein localization to pre-autophagosomal structure • mitochondrion localization • protein targeting to mitochondrion • blood coagulation • blastocyst formation • negative regulation of Ras protein signal transduction • autophagy • response to unfolded protein • cell cycle arrest • macroautophagy • mitochondrial membrane organization • camera-type eye morphogenesis • apoptotic process • parkin-mediated stimulation of mitophagy in response to mitochondrial depolarization • positive regulation of vascular smooth muscle cell proliferation • positive regulation of vascular associated smooth muscle cell apoptotic process • positive regulation of cold-induced thermogenesis Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	9927	170731
Ensembl	ENSG00000116688	ENSMUSG00000029020
UniProt	O95140	Q80U63
RefSeq (mRNA)	NM_001127660 NM_014874	NM_001285920 NM_001285921 NM_001285922 NM_001285923 NM_133201 NM_001355590 NM_001355591
RefSeq (protein)	NP_001121132 NP_055689	NP_001272849 NP_001272850 NP_001272851 NP_001272852 NP_573464 NP_001342519 NP_001342520
Location (UCSC)	Chr 1: 11.98 – 12.01 Mb	Chr 4: 147.87 – 147.9 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Function

Mitofusin-2 is a mitochondrial membrane protein that participates in mitochondrial fusion and contributes to the maintenance and operation of the mitochondrial network.[9] Mitochondria function as a dynamic network constantly undergoing fusion and fission. The balance between fusion and fission is important in maintaining the integrity of the mitochondria and facilitates the mixing of the membranes and the exchange of DNA between mitochondria. MFN1 and MFN2 mediate outer membrane fusion while OPA1 is involved in inner membrane fusion.[10]

Mitochondrial fusion is essential for embryonic development. Knockout mice for either MFN1 or MFN2 have fusion deficits and die midgestation. MFN2 knockout mice die at embryonic day 11.5 due to a defect in the giant cell layer of the placenta.[7]

Fusion is also important for mitochondrial transport and localization in neuronal processes.[11] Conditional MFN2 knockout mice show degeneration in the Purkinje cells of the cerebellum, as well as improperly localized mitochondria in the dendrites.[12] MFN2 also associates with the MIRO-Milton complex which links the mitochondria to the kinesin motor.[11]

Clinical significance

Mutations of the gene are implicated in Charcot-Marie-Tooth disease. Charcot-Marie-Tooth disease type 2A (CMT2A) is caused by mutations in the MFN2 gene. While the symptoms of CMT2A are variable they are characterized by a sometimes early onset, severe phenotype, and optic atrophy. Mutations in OPA1 also cause optic atrophy, which suggests a common role of mitochondrial fusion in neuronal dysfunction.[12] The exact mechanism of how mutations in MFN2 selectively cause the degeneration of long peripheral axons is not known. There is evidence suggesting that it could be due to defects in the axonal transport of mitochondria.[12]

The MFN2 protein may play a role in the pathophysiology of obesity.[13] Mitochondria arrest fusion by downregulating Mfn2 in obesity and diabetes, which leads to a fragmented mitochondrial network.[14] This fragmentation is obvious in the pancreatic beta-cells in the Islets of Langerhans and can inhibit mitochondrial quality control mechanisms such as mitophagy and autophagy - leading to a defect in insulin secretion and eventual beta-cell failure.[15] The expression of MFN2 in skeletal muscle is proportional to insulin sensitivity in this tissue,[16] and its expression is reduced in high-fat diet fed mice[17] and Zucker fatty rats.[16]

This protein is involved in the regulation of vascular smooth muscle cell proliferation.[9]

References

1. GRCh38: Ensembl release 89: ENSG00000116688 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000029020 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Karbowski M, Lee YJ, Gaume B, Jeong SY, Frank S, Nechushtan A, Santel A, Fuller M, Smith CL, Youle RJ (Dec 2002). "Spatial and temporal association of Bax with mitochondrial fission sites, Drp1, and Mfn2 during apoptosis". J Cell Biol. 159 (6): 931–8. doi:10.1083/jcb.200209124. PMC 2173996. PMID 12499352.
6. Santel A, Fuller MT (Feb 2001). "Control of mitochondrial morphology by a human mitofusin". J Cell Sci. 114 (Pt 5): 867–74. PMID 11181170.
7. Chan DC (June 2006). "Mitochondria: dynamic organelles in disease, aging, and development". Cell. 125 (7): 1241–52. doi:10.1016/j.cell.2006.06.010. PMID 16814712.
8. Liesa, Marc; Shirihai, Orian S. (2013). "Mitochondrial Dynamics in the Regulation of Nutrient Utilization and Energy Expenditure". Cell Metabolism. 17 (4): 491–506. doi:10.1016/j.cmet.2013.03.002. PMC 5967396. PMID 23562075.
9. "Entrez Gene: MFN2 mitofusin 2".
10. Chan DC (November 2006). "Dissecting mitochondrial fusion". Dev. Cell. 11 (5): 592–4. doi:10.1016/j.devcel.2006.10.009. PMID 17084350.
11. Sheng ZH, Cai Q (February 2012). "Mitochondrial transport in neurons: impact on synaptic homeostasis and neurodegeneration". Nat. Rev. Neurosci. 13 (2): 77–93. doi:10.1038/nrn3156. PMC 4962561. PMID 22218207.
12. Cartoni R, Martinou JC (August 2009). "Role of mitofusin 2 mutations in the physiopathology of Charcot-Marie-Tooth disease type 2A". Exp. Neurol. 218 (2): 268–73. doi:10.1016/j.expneurol.2009.05.003. PMID 19427854.
13. Zorzano A, Sebastián D, Segalés J, Palacín M (September 2009). "The molecular machinery of mitochondrial fusion and fission: An opportunity for drug discovery?". Curr Opin Drug Discov Dev. 12 (5): 597–606. PMID 19736619.
14. Liesa, Marc; Shirihai, Orian S. (2013). "Mitochondrial Dynamics in the Regulation of Nutrient Utilization and Energy Expenditure". Cell Metabolism. 17 (4): 491–506. doi:10.1016/j.cmet.2013.03.002. PMC 5967396. PMID 23562075.
15. Trudeau, Kyle M.; Colby, Aaron H.; Zeng, Jialiu; Las, Guy; Feng, Jiazuo H.; Grinstaff, Mark W.; Shirihai, Orian S. (2016-07-04). "Lysosome acidification by photoactivated nanoparticles restores autophagy under lipotoxicity". J Cell Biol. 214 (1): 25–34. doi:10.1083/jcb.201511042. ISSN 0021-9525. PMC 4932370. PMID 27377248.
16. Bach, Daniel; Pich, Sara; Soriano, Francesc X.; Vega, Nathalie; Baumgartner, Bernhard; Oriola, Josep; Daugaard, Jens R.; Lloberas, Jorge; Camps, Marta (2003-05-09). "Mitofusin-2 Determines Mitochondrial Network Architecture and Mitochondrial Metabolism A NOVEL REGULATORY MECHANISM ALTERED IN OBESITY". Journal of Biological Chemistry. 278 (19): 17190–17197. doi:10.1074/jbc.M212754200. ISSN 0021-9258. PMID 12598526.
17. Sorianello, Eleonora; Soriano, Francesc X.; Fernández-Pascual, Sergio; Sancho, Ana; Naon, Deborah; Vila-Caballer, Marian; González-Navarro, Herminia; Portugal, José; Andrés, Vicente (2012-04-01). "The promoter activity of human Mfn2 depends on Sp1 in vascular smooth muscle cells". Cardiovascular Research. 94 (1): 38–47. doi:10.1093/cvr/cvs006. ISSN 0008-6363. PMID 22253285.

Further reading

• Zorzano A, Bach D, Pich S, Palacín M (2004). "[Role of novel mitochondrial proteins in energy balance]". Revista de medicina de la Universidad de Navarra. 48 (2): 30–5. PMID 15382611.
• Pawlikowska P, Orzechowski A (2007). "[Role of transmembrane GTPases in mitochondrial morphology and activity]". Postepy Biochem. 53 (1): 53–9. PMID 17718388.

External links

• GeneReviews/NCBI/NIH/UW entry on Charcot-Marie-Tooth Neuropathy Type 2
• Overview of all the structural information available in the PDB for UniProt: O95140 (Mitofusin-2) at the PDBe-KB.