MFN2

Official Full Name

mitofusin 2

Organism

Homo sapiens

GeneID

9927

Background

This gene encodes a mitochondrial membrane protein that participates in mitochondrial fusion and contributes to the maintenance and operation of the mitochondrial network. This protein is involved in the regulation of vascular smooth muscle cell proliferation, and it may play a role in the pathophysiology of obesity. Mutations in this gene cause Charcot-Marie-Tooth disease type 2A2, and hereditary motor and sensory neuropathy VI, which are both disorders of the peripheral nervous system. Defects in this gene have also been associated with early-onset stroke. Two transcript variants encoding the same protein have been identified. [provided by RefSeq, Jul 2008]

Synonyms

HSG; MSL; MARF; CMT2A; CPRP1; CMT2A2; HMSN6A; CMT2A2A; CMT2A2B;

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Detailed Information

Mfn2 consists of 758 amino acid residues and is a multi-domain protein containing a hydrophobic transmembrane region (599644 aa), a p21ras consensus motif (77-92 aa), a GTP-binding region (P-ring, 98-117 aa) and PKA/PKG phosphorylation site (serine at position 442). Mfn2 has a GTPase domain at the N-terminus, a transmembrane region at the C-terminus, and a hydrophobic region on each side of the transmembrane region, similar to coiled-coil, which play an important role in triggering mitochondrial fusion. Mfn2 was transmembrane twice in the mitochondrial outer membrane and evenly distributed. Both the GTPase domain at the N-terminus and the coiled-coil domain at the C-terminus are directed toward the cytoplasm. The middle portion of the two transmembrane regions is located in the intermembrane space and mediates the attachment of the inner and outer membranes. This linkage is important for the function of Mfn2.

The Role of MFN2

Tibial muscle atrophy Type 2A disease is a dominant hereditary peripheral neuropathy caused by mutations in Mfn2. The role of Mfn2 in hypertension and proliferation-suppressing diseases cannot be ignored. Studies in rat cell culture and In vivo studies have shown that overexpression of Mfn2 can inhibit vascular smooth muscle cell proliferation. Inhibition of M fn2 expression in myotubes is associated with mitochondrial oxidative network cleavage, decreased glucose oxidation and mitochondrial membrane potential. Mfn2 not only controls mitochondrial fusion in the form of perinuclear mitochondria, but also exhibits insulin-dependent relationships in vitro. From the expression of Mfn2 in skeletal muscle of obese rats, it can be shown that Mfn2 can be used as an anti-obesity gene, and the Mfn2 in obese people is also less than that in lean.

Mitochondria are fragmented in cells lacking Mfn1 or Mfn2, and tubular structures are missing, which in turn affects function. Mfn1 or Mfn2 knockout mice are fragmented due to decreased fusion efficiency, and mitochondrial mobility is reduced. Studies have suggested that the interaction of mouse Mfn1 and Mfn2 is beneficial to protect mutations in CMT2A disease caused by mitochondrial fusion defects. The study found that in obese and non-obese patients with type 2 diabetes, low expression of Mfn2 was accompanied by a decrease in mitochondrial Cox-III and a moderate decrease in citrate-synthesized mRNA, indicating functional impairment.

MFN2 Fusion with Mitochondria

Mfn1/2 is the main molecule that regulates mitochondrial fusion, plays an important role in mitochondrial fusion, and Mfn1 and Mfn2 may play different roles in mitochondrial fusion. Mfn1 promotes the binding of mitochondria mainly in the early stage of fusion, and Mfn2 mainly plays a role in the late stage of mitochondrial fusion reaction, such as promoting mitochondrial fusion and facilitating intimal docking. Studies have shown that Mfn1 or Mfn2 knockout mice have mitochondrial fragmentation due to decreased mitochondrial fusion efficiency, mitochondrial mobility is reduced, and mitochondrial morphology is also significantly different.

Figure 1. Alternative models for MFN2-mediated ER−mitochondria tethering. (Filadi, R., et al. 2018)

MFN2 and Tumor

HSG expression was also observed in breast cancer cell lines. Some scholars correctly cloned the ORF sequence of Mfn2 into vector pEGFP-C2, and successfully constructed the e-nucleic expression vector pEGFP-mfn2 of Mfn2 gene. The proliferation of MCF-7 cells was significantly inhibited after transfection of exogenous Mfn2 gene, and MCF-7 cells were arrested in S phase. This apoptosis may be related to the obvious changes of mitochondrial morphology. The above studies also demonstrated that the exogenous Mfn2 gene enhances the sensitivity of MCF-7 to camptothecin-based chemotherapy drugs. In vivo studies on the inhibitory effect of Mfn2 on the proliferation of xenografted tumors in nude mice showed that Mfn2 can significantly inhibit the tumor formation of human breast cancer cells, and can be used for the treatment of human breast cancer after tumor formation, which has certain effects on the proliferation and metastasis of transplanted tumors.

References:

Oanh, N. T. K. , Park, Y. Y. , & Cho, H. . (2017). Mitochondria elongation is mediated through sirt1-mediated mfn1 stabilization. Cellular Signalling, 38, 67-75.
Cao, Y. L. , Meng, S. , Chen, Y. , Feng, J. X. , Gu, D. D. , & Yu, B. , et al. (2017). Mfn1 structures reveal nucleotide-triggered dimerization critical for mitochondrial fusion. Nature,542(7641), 372-376.
Formosa, L E. , Ryan, M T.. (2016) Mitochondrial fusion: Reaching the end of mitofusin's tether. The Journal of cell biology, 5(215), 597-598.

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