NCBI Summary:
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]
General function
Mitochondrial network maintenance
Comment
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 may play a role in the pathophysiology of obesity.
[url]http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene&cmd=Retrieve&dopt=full_report&list_uids=9927[/url]
Cellular localization
Cytoplasmic, Mitochondrial, Spindle
Comment
Mice born to females with oocyte-specific deletion of mitofusin 2 have increased weight gain and impaired glucose homeostasis. Garcia BM et al. (2020) Offspring born to obese and diabetic mothers are prone to metabolic diseases, a phenotype that has been linked to mitochondrial dysfunction and endoplasmic reticulum [ER] stress in oocytes. In addition, metabolic diseases impact the architecture and function of mitochondria-ER contact sites [MERCs], changes which associate with mitofusin 2 [MFN2] repression in muscle, liver and hypothalamic neurons. MFN2 is a potent modulator of mitochondrial metabolism and insulin signaling, with a key role in mitochondrial dynamics and tethering with the ER. Here, we investigated whether offspring born to mice with MFN2-deficient oocytes are prone to obesity and diabetes. Deletion of Mfn2 in oocytes resulted in a profound transcriptomic change, with evidence of impaired mitochondrial and ER function. Moreover, offspring born to females with oocyte-specific deletion of Mfn2 presented increased weight gain and glucose intolerance. This abnormal phenotype was linked to decreased insulinemia and defective insulin signaling, but not mitochondrial and ER defects in offspring liver and skeletal muscle. In conclusion, this study suggests a link between disrupted mitochondrial/ER function in oocytes and increased risk of metabolic diseases in the progeny. Future studies should determine whether MERC architecture and function are altered in oocytes from obese females, which might contribute toward transgenerational transmission of metabolic diseases.//////////////////
HSG mainly exhibited a submembrane distribution pattern in both oocytes and embryos. In GV oocytes, HSG was mainly distributed in cytoplasm, while in MII oocytes HSG accumulated in submembrane region and in the region of spindle and chromosomes.
Ovarian function
Oogenesis, Oocyte maturation, Early embryo development
Comment
Low MFN2 expression related to ageing in granulosa cells is associated with assisted reproductive technology outcome. Wang L et al. (2018) Is low MFN2 expression associated with ageing in granulosa cells as well as assisted reproductive technology (ART) outcome, and what is the underlying mechanism of action of MFN2? In a prospective study, fresh granulosa cells were obtained from 161 women aged 20-40 years who underwent IVF with embryo transfer and who were divided into two groups: the diminished ovarian reserve (DOR) group (n = 51) and the control group (n = 110). Patient characteristics including age, infertility duration, body mass index, FSH, anti-Müllerian hormone (AMH), antral follicle count (AFC) and husband's semen parameters and granulosa cell MFN2 expression levels, cell apoptosis, mitochondrial membrane potential (ΔΨm) and ATP levels were analysed. There were no significant differences between the DOR and control groups in terms of age, infertility duration and husband'' semen parameters; however, significant (P < 0.05) changes were found between the two groups in FSH, AMH and AFC levels. MFN2 expression was remarkably lower in granulosa cells from the DOR group and decreased in both groups as age increased. Furthermore, among young patients, MFN2 levels significantly increased in patients with pregnancy. MFN2 protein levels and cell apoptosis were lower in the MFN2 knockdown (MFN2-siRNA) group than in the control (Cy3-siRNA) group. ΔΨm and ATP levels were reduced in the MFN2-siRNA group compared with the Cy3-siRNA group. Low MFN2 expression levels in granulosa cells were related to ageing, which may be involved in the clinical outcome of ART by promoting cell apoptosis and affecting mitochondrial function.//////////////////
Mitofusin-2 is required for mouse oocyte meiotic maturation. Zhang JH et al. (2016) Mitofusin-2 (Mfn2) is essential for embryonic development, anti-apoptotic events, protection against free radical-induced lesions, and mitochondrial fusion in many cells. However, little is known about its mechanism and function during oocyte maturation. In this study, we found that Mfn2 was expressed in the cytoplasm during different stages of mouse oocyte maturation. Mfn2 was mainly associated with α-tubulin during oocyte maturation. Knockdown of Mfn2 by specific siRNA injection into oocytes caused the mitochondrial morphology and quantity to change, resulting in severely defective spindles and misaligned chromosomes. This led to metaphase I arrest and the failure of first polar body extrusion. Furthermore, Mfn2 depletion from GV stage oocytes caused the redistribution of p38 MAPK in oocyte cytoplasm. These findings provide insights into potential mechanisms of Mfn2-mediated cellular alterations, which may have significant implications for oocyte maturation.//////////////////
Granulosa Cell and Oocyte Mitochondrial Abnormalities in a Mouse Model of Fragile X Primary Ovarian Insufficiency. Dioguardi CC et al. (2016) We hypothesized that the mitochondria of granulosa cells (GC) and/or oocytes might be abnormal in a mouse model of Fragile X premutation (FXPM). Mice heterozygous and homozygous for the FXPM have increased death (atresia) of large ovarian follicles, fewer corpora lutea with a gene dosage effect manifesting in decreased litter size(s). Furthermore, granulosa cells (GC) and oocytes of FXPM mice have decreased mitochondrial content, structurally abnormal mitochondria, and reduced expression of critical mitochondrial genes. Because this mouse allele produces the mutant Fragile x mental retardation 1 (Fmr1) transcript and reduced levels of wild-type (WT) Fmr1 protein (FMRP), but does not produce a Repeat Associated Non-ATG Translation (RAN)-translation product, our data lend support to the idea that Fmr1 mRNA with large numbers of CGG-repeats is intrinsically deleterious in the ovary.What is known already: Mitochondrial dysfunction has been detected in somatic cells of human and mouse FX PM carriers and mitochondria are essential for oogenesis and ovarian follicle development, FX-associated primary ovarian insufficiency (FXPOI) is seen in women with FXPM alleles. These alleles have 55-200 CGG repeats in the 5' UTR of an X-linked gene known as FMR1. The molecular basis of the pathology seen in this disorder is unclear but is thought to involve either some deleterious consequence of overexpression of RNA with long CGG-repeat tracts or of the generation of a repeat-associated non-AUG translation (RAN translation) product that is toxic. Analysis of ovarian function in a knock-in FXPM mouse model carrying 130 CGG repeats was performed as follows on WT, PM/+, and PM/PM genotypes. Histomorphometric assessment of follicle and corpora lutea numbers in ovaries from 8-month-old mice was executed, along with litter size analysis. Mitochondrial DNA copy number was quantified in oocytes and GC using quantitative PCR, and cumulus granulosa mitochondrial content was measured by flow cytometric analysis after staining of cells with Mitotracker dye. Transmission electron micrographs were prepared of GC within small growing follicles and mitochondrial architecture was compared. Quantitative RT-PCR analysis of key genes involved in mitochondrial structure and recycling was performed. A defect was found in follicle survival at the large antral stage in PM/+ and PM/PM mice. Litter size was significantly decreased in PM/PM mice, and corpora lutea were significantly reduced in mice of both mutant genotypes. Mitochondrial DNA copy number was significantly decreased in GC and metaphase II eggs in mutants. Flow cytometric analysis revealed that PM/+ and PM/PM animals lack the cumulus GC that harbor the greatest mitochondrial content as found in wild-type animals. Electron microscopic evaluation of GC of small growing follicles revealed mitochondrial structural abnormalities, including disorganized and vacuolar cristae. Finally, aberrant mitochondrial gene expression was detected. Mitofusin 2 (Mfn2) and Optic atrophy 1 (Opa1), genes involved in mitochondrial fusion and structure, respectively, were significantly decreased in whole ovaries of both mutant genotypes. Mitochondrial fission factor 1 (Mff1) was significantly decreased in PM/+ and PM/PM GC and eggs compared to wild-type controls. Data from the mouse model used for these studies should be viewed with some caution when considering parallels to the human FXPOI condition. Our data lend support to the idea that Fmr1 mRNA with large numbers of CGG-repeats is intrinsically deleterious in the ovary. FXPM disease states, including FXPOI, may share mitochondrial dysfunction as a common underlying mechanism.Large scale data: Not applicable. Studies were supported by NIH R21 071873 (J.J./G.H), The Albert McKern Fund for Perinatal Research (J.J.), NIH Intramural Funds (K.U.), and a TUBITAK Research Fellowship Award (B.U.). No conflict(s) of interest or competing interest(s) are noted.//////////////////
Expression regulated by
Comment
Ovarian localization
Oocyte
Comment
Mitofusin 2 regulates the oocytes development and quality by modulating meiosis and mitochondrial function. Liu Q et al. (2016) Mitofusin-2 (Mfn2), one of the mitochondrial dynamic proteins plays a key role in maintaining the integrity of mitochondrial morphology and function. However, it is unknown if Mfn2 influences the quality of oocytes in the process of development by modulating mitochondrial function in vitro. In this study, immature oocytes were transfected with Mfn2-siRNA for 16 h. We found that the expression level of the Mfn2 gene was significantly lower than those of the control group. The rates of maturation and fertility were also found to have declined. Moreover, mitochondrial structure and function, especially the morphogenesis of spindles, were observed as abnormal during meiosis. Thus, the above findings indicate that down-regulation of Mfn2 may have an impact on the maturation and fertilization of immature oocytes in vitro by modulating meiosis and mitochondrial function.//////////////////
Follicle stages
Comment
Phenotypes
Mutations
2 mutations
Species: mouse
Mutation name: type: null mutation fertility: subfertile Comment: Mitofusin 2 plays a role in oocyte and follicle development, and is required to maintain ovarian follicular reserve during reproductive aging. Zhang M et al. (2019) Mitochondria change their shape through fusion and fission in order to adapt to their metabolic milieu. Mitofusin-2 (MFN2) is a key regulatory protein in this process, mediating mitochondrial fusion and interaction with endoplasmic reticulum. Targeted deletion of Mfn2 in oocytes resulted in mitochondrial dysfunction and female subfertility associated with impaired oocyte maturation and follicle development. Oocytes lacking MFN2 showed shortened telomeres and increased apoptosis, resulting in compromised oocyte quality and accelerated follicular depletion, consistent with a reproductive aging phenotype.//////////////////
Species: mouse
Mutation name: type: null mutation fertility: fertile Comment: Mitofusin 1 is required for oocyte growth and communication with follicular somatic cells. Carvalho KF et al. (2020) Mitochondrial function, largely regulated by the dynamics of this organelle, is inextricably linked to the oocyte health. In comparison with most somatic cells, mitochondria in oocytes are smaller and rounder in appearance, suggesting limited fusion. The functional implications of this distinct morphology, and how changes in the mitochondrial shape translate to mitochondrial function in oogenesis is little understood. We, therefore, asked whether the pro-fusion proteins mitofusins 1 (MFN1) and 2 (MFN2) are required for the oocyte development. Here we show that oocyte-specific deletion of Mfn1, but not Mfn2, prevents the oocyte growth and ovulation due to a block in folliculogenesis. We pinpoint the loss of oocyte growth and ovulation to impaired PI3K-Akt signaling and disrupted oocyte-somatic cell communication. In support, the double loss of Mfn1 and Mfn2 partially rescues the impaired PI3K-Akt signaling and defects in oocyte development secondary to the single loss of Mfn1. Together, this work demonstrates that the mitochondrial function influences the cellular signaling during the oocyte development, and highlights the importance of distinct, nonredundant roles of MFN1 and MFN2 in oogenesis.//////////////////