Species Human Entrez 9927 | Human Mouse Ensembl ENSG00000116688 | |
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Aliases MFN2, CMT2A, CMT2A2, CPRP1, HSG, MARF, HMSN6A, mitofusin 2 External IDs OMIM: 608507 MGI: 2442230 HomoloGene: 8915 GeneCards: MFN2 | ||
Mitofusin-2 is a protein that in humans is encoded by the MFN2 gene. Mitofusins are GTPases embedded in the outer membrane of the mitochondria. In mammals MFN1 and MFN2 are essential for mitochondrial fusion. In addition to the mitofusins, OPA1 regulates inner mitochondrial membrane fusion, and DRP1 is responsible for mitochondrial fission.
Contents
Function
Mitofusin-2 is a mitochondrial membrane protein that participates in mitochondrial fusion and contributes to the maintenance and operation of the mitochondrial network. 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.
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.
Fusion is also important for mitochondrial transport and localization in neuronal processes. Conditional MFN2 knockout mice show degeneration in the Purkinje cells of the cerebellum, as well as improperly localized mitochondria in the dendrites. MFN2 also associates with the MIRO-Milton complex which links the mitochondria to the kinesin motor.
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. 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.
The MFN2 protein may play a role in the pathophysiology of obesity. Mitochondria arrest fusion by downregulating Mfn2 in obesity and diabetes, which leads to a fragmented mitochondrial network. This fragmentation is obvious in the pancreatic beta-cells in the Islets of Langerhaans and can inhibit mitochondrial quality control mechanisms such as mitophagy and autophagy - leading to a defect in insulin secretion and eventual beta-cell failure. The expression of MFN2 in skeletal muscle is proportional to insulin sensitivity in this tissue, and its expression is reduced in high-fat diet fed mice and Zucker fatty rats.
This protein is involved in the regulation of vascular smooth muscle cell proliferation.