Disease relevance of MFN2

• It is intriguing that MFN2 shows functional overlap with optic atrophy 1 (OPA1), the protein underlying the most common form of autosomal dominant optic atrophy, and mitochondrial encoded oxidative phosphorylation components as seen in Leber's hereditary optic atrophy [1].
• We conclude that autosomal dominant HMSN VI is caused by mutations in MFN2, emphasizing the important role of mitochondrial function for both optic atrophies and peripheral neuropathies [1].
• The aim of this study was to verify whether MFN2 might be implicated in the metabolic inflexibility of obesity [2].
• CONCLUSIONS/INTERPRETATION: We propose that the significant increase in MFN2 mRNA levels may explain the increase in glucose oxidation observed in morbid obesity following bariatric surgery [2].
• Axonal neuropathy with optic atrophy is caused by mutations in mitofusin 2 [1].

High impact information on MFN2

• Moreover, mutations in the mitochondrial fusion genes Mitofusin-2 and OPA1 lead to the peripheral neuropathy Charcot-Marie-Tooth type 2A and dominant optic atrophy [3].
• These studies indicate that orally administered HSG can survive passage in the gastrointestinal tract in an immunologically active form, and that the oral administration of immunoglobulins with specific reactivities has potential for the prevention or treatment of gastrointestinal infections [4].
• We examined the pharmacokinetics and immunological activity of human serum immunoglobulins (HSG) possessing anti-rota-virus activity which were orally administered to three children with primary immunodeficiency syndromes and prolonged gastrointestinal excretion of rotavirus [4].
• Spatial and temporal association of Bax with mitochondrial fission sites, Drp1, and Mfn2 during apoptosis [5].
• Mitofusin-2 (Mfn2) is a mitochondrial membrane protein that participates in mitochondrial fusion in mammalian cells and mutations in the Mfn2 gene cause Charcot-Marie-Tooth neuropathy type 2A [6].

Chemical compound and disease context of MFN2

• EXPERIMENTAL DESIGN: Salivary gland adenocarcinoma cell lines HSG and HSY were used to study the effect of diarylpropionitrile and estrogen on the nongenomic signaling of ERbeta, cytoskeletal remodeling, and cell motility [7].
• Dopamine dose-dependently reduced the viable cell number of both human salivary gland tumor HSG and oral squamous cell carcinoma HSC-2, HSC-4, and NA cells [8].
• We have found that reversible differentiation into the myoepithelial cells of a human salivary gland adenocarcinoma cell line (HSG) occurs in growth medium containing dibutyryl cAMP (dB-cAMP) [9].
• Their cytotoxicity against a human submandibular gland adenocarcinoma cell line (HSG) declined in the order curcumin > isoeugenol > bis-eugenol > eugenol [10].
• Compound 23 (5-(2-hydroxylbenzoyl)-2-phenylimidazole) showed the highest cytotoxic activity against both human oral tumor cell lines (human squamous cell carcinoma HSC-2, human salivary gland tumor HSG) and normal human gingival fibroblast (HGF) [11].

Biological context of MFN2

• METHODS: The authors performed a standardized neuromuscular and nerve conduction examination, genotyped known CMT loci, and analyzed the MFN2 gene by direct sequencing in three pedigrees and 10 additional probands affected by axonal CMT [12].
• Upon staurosporine-stimulated cell death, activated Bax is recruited to the Mfn2-containing puncta; however, Bax activation and cytochrome c release are inhibited in the presence of the dominant active mutants of Mfn2 [13].
• Mitochondrial fusion is stimulated dramatically within heterokaryons expressing this mutant, demonstrating that hydrolysis is not requisite for the fusion event, and supporting a role for Mfn2 as a signaling GTPase [13].
• The potential for regulation of human Mfn2 gene expression in vivo is largely unknown [14].
• The mitofusins (Mfn1 and Mfn2) are homologs of the Drosophila protein fuzzy onion (Fzo) that associate with mitochondria and alter mitochondrial morphology when expressed by transient transfection in tissue culture cells [15].

Anatomical context of MFN2

• INTERPRETATION: MFN2 is a mitochondrial membrane protein that was recently reported to cause axonal CMT type 2A [1].
• Overexpression of MARCH-V promoted the formation of long tubular mitochondria in a manner that depends on MFN2 activity [16].
• This is the first evidence that Mfn2 is a signaling GTPase regulating mitochondrial fusion and that the nucleotide-dependent activation of Mfn2 concomitantly protects the organelle from permeability transition [13].
• Obesity-induced Mfn2 deficiency in rat skeletal muscle was also associated with a decrease in the subunits of complexes I, II, III and V [6].
• In vitro experiments revealed an inhibitory effect of TNFalpha or interleukin-6 on Mfn2 expression in cultured cells [14].

Associations of MFN2 with chemical compounds

• The percentage changes in MFN2 mRNA were positively correlated with the percentage change in glucose oxidation during the clamp (glucose oxidation percent (%) change=0.3 MFN2 mRNA percent (%) change+153.2; R2=0.61, p<0.001) [2].
• Estrogen stimulation also induced long cytoplasmic extensions, filopodia formation, and abnormal outgrowths in both HSG and HSY cells [7].
• Vitamin K3 induced internucleosomal DNA fragmentation in HL-60 cells, but not in HSC-2 or HSG cells [17].
• The cytotoxic activity of CGA against human oral tumor cells (HSC-2, HSG) was completely eliminated by lower concentrations of sodium ascorbate or NAC, whereas that of sodium ascorbate or NAC was only slightly reduced by CGA [18].
• Dopamine produced DNA fragments (demonstrated by TUNEL method) and induced degradation of cytokeratin by activated caspase in HSG cells (detected by an immunocytochemical method, using a specific M30 monoclonal antibody) [8].

Enzymatic interactions of MFN2

• Immunoprecipitation studies demonstrated that MARCH-V interacts with mitofusin 2 (MFN2) and ubiquitinated forms of Drp1 [16].

Other interactions of MFN2

• Mitochondrial fusion in higher eukaryotes requires at least two essential GTPases, Mitofusin 1 and Mitofusin 2 (Mfn2) [13].
• BACKGROUND: Axonal neuropathy linked to the CMT2A locus was originally associated with a mutation in the KIF1B gene [12].
• Surprisingly, Drp1 and Mfn2, but not other proteins implicated in the regulation of mitochondrial morphology, colocalize with Bax in these foci [5].
• The PGC-1alpha/ERRalpha-mediated induction of Mfn2 suggests a role of these two factors in mitochondrial fusion [19].
• The cytotoxic activity against human oral tumor cell lines (HSC-2, HSG) and human gingival fibroblast cells (HGF) declined in the order of DBP >> bisDBP = TBP = TBP-OOH (2,4,6-tri-t-butyl-4-hydroperoxy-2,5-cyclohexadiene-1-one) [20].

Analytical, diagnostic and therapeutic context of MFN2

• To determine the effect of weight loss on Mfn2 mRNA expression, six morbidly obese subjects were subjected to weight loss by bilio-pancreatic diversion [14].
• Two human Fzo-homologs, mitofusins Mfn1 and Mfn2, are shown by RT-PCR and western blot to be ubiquitous mitochondrial proteins [21].
• Transplantation of HSG cells into nude mice resulted in the establishment of a nude mouse system with malignant characteristics such as invasion and metastasis [22].
• In addition, functional differentiation was determined by indirect immunofluorescence and immunoblot analysis for cystatin, a salivary gland acinar cell-specific protein found to be produced by differentiated HSG cells [23].
• Linkage mapping of the gene for Charcot-Marie-Tooth disease type 2 to chromosome 1p (CMT2A) and the clinical features of CMT2A [24].

References