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Two Mitofusin Proteins, Mammalian Homologues of FZO, with Distinct Functions Are Both Required for Mitochondrial Fusion
Abstract
Mitochondria are dynamic organelles that undergo frequent fission and fusion or branching. Although these morphologic changes are considered crucial for cellular functions, the underlying mechanisms remain elusive, especially in mammalian cells. We characterized two rat mitochondrial outer membrane proteins, Mfn1 and Mfn2, with distinct tissue expressions, that are homologous to Drosophila Fzo, a GTPase involved in mitochondrial fusion. Expression of the GTPase-domain mutant of Mfn2 (Mfn2(K109T)) in HeLa cells induced mitochondrial fragmentation in which Mfn2(K109T) localized at the restricted domains. Immuno-electronmicroscopy revealed that Mfn2(K109T) was concentrated at the contact domains between adjacent mitochondria, suggesting that fusion of the outer membrane was arrested at some intermediate step. Mfn1 expression induced highly connected tubular network structures depending on the functional GTPase domain. The Mfn1-induced tubular networks were suppressed by co-expression with Mfn2. In vivo depletion of either isoform by RNA interference revealed that both are required to maintain normal mitochondrial morphology. The fusion of differentially-labeled mitochondria in HeLa cells subjected to depletion of either Mfn isoform and subsequent cell fusion by hemagglutinating virus of Japan revealed that both proteins have distinct functions in mitochondrial fusion. We conclude that the two Mfn isoforms cooperate in mitochondrial fusion in mammalian cells.
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“Despite some redundancies in their function, the two proteins possess several distinct properties, suggesting that they fulfill different roles in fusion (de Brito and Scorrano, 2008; Eura et al., 2003; Ishihara et al., 2004).”
From New insights into the role of mitochondria in aging: mitochondrial dynamics and more (2010) · cites this paper as Eura et al., 2003
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Expression of mitofusin 2R94Q in a transgenic mouse leads to Charcot–Marie–Tooth neuropathy type 2A
Cartoni, R., Arnaud, E., Médard, J., Poirot, O., Courvoisier, D. S., Chrast, R., & Martinou, J. (2010) · Brain · doi:10.1093/brain/awq082 · Cited by 115
“While potentially interesting, the relevance of MFN2-induced perinuclear mitochondrial aggregation for the pathophysiology of CMT2A disease is difficult to interpret since this phenomenon has been observed when the level of MFN2 overexpression was high (Eura et al., 2003; Detmer and Chan, 2007b).”
The Balance of MFN2 and OPA1 in Mitochondrial Dynamics, Cellular Homeostasis, and Disease
Zanfardino, P., Amati, A., Perrone, M., & Petruzzella, V. (2025) · Biomolecules · doi:10.3390/biom15030433 · Cited by 129
“While MFN1 is predominantly expressed in the heart and testis, MFN2 is abundant in the brain, underscoring its specialized role in neural tissue [19].”
Eura, Y., Ishihara, N., Oka, T., & Mihara, K. (2006) · Journal of Cell Science · doi:10.1242/jcs.03253 · Cited by 115
“…regions that are not conserved between rats and humans (RNAi-MIB-1, 5 -AGAUACUGCCAAGGGCUACTT-3 ; RNAiMIB-2, 5 -GUAGCCCUUGGCAGUAUCUTT-3 ). siRNAs for GFP were purchased from B-bridge (Mountain View, CA). siRNAs for Mfn (Eura et al., 2003) and Fis1 (Jofuku et al., 2005) were described previously.”
BackgroundMethodResultInfluentialSelf-citationOrganelle degradation in the lens by PLAAT phospholipases
Morishita, H., Eguchi, T., Tsukamoto, S., Sakamaki, Y., Takahashi, S., Saito, C., Koyama-Honda, I., & Mizushima, N. (2021) · Nature · doi:10.1038/s41586-021-03439-w · Cited by 111
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“…defects could arise from mitochondrial aggregation (Baloh et al., 2007, Detmer and Chan, 2007a), perhaps caused by mutant fusion complexes that prolong, or make permanent, the tethering of adjacent mitochondria (Eura et al., 2003, Huang et al., 2007, Koshiba et al., 2004, Rojo et al., 2002).”
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Keeping mitochondria in shape: a matter of life and death
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“Conversely, Mfn2 knockdown results in less fragmentation and produces mitochondria of varying sizes [29,37].”
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Simula, L., Nazio, F., & Campello, S. (2017) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2017.06.007 · Cited by 106
Viral degradasome hijacks mitochondria to suppress innate immunity
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“Mfn1 and Mfn2 are similar in their protein structures and functional domains, containing an N-terminal GTPase domain, two heptad-repeat regions (HR1 and HR2) and two transmembrane segments near the C-terminus.”
BackgroundInfluentialMitochondrial membrane dynamics, cristae remodelling and apoptosis
Heath-Engel, H. M., & Shore, G. C. (2006) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2006.02.006 · Cited by 104
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“The relative expression levels of Mfn1 and Mfn2 vary among different cell types: Mfn1 levels predominate in brain tissue, whereas Mfn2 levels are elevated in heart and testis [15 ,37 ].”
BackgroundUnraveling the Link Between Mitochondrial Dynamics and Neuroinflammation
de Oliveira, L. G., Angelo, Y. D. S., Iglesias, A. H., & Peron, J. P. S. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.624919 · Cited by 100
“The steps that orchestrate mitochondrial elongation are not fully understood, but a model suggests that the interaction of MFNs from two opposing mitochondrion is stabilized by coil-coil heptad repeat-2 (HR2) (36), increasing the surface of contact (37).”
BackgroundChan, E. Y. L., & McQuibban, G. A. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.399428 · Cited by 97
Highlighting the endoplasmic reticulum-mitochondria connection: Focus on Mitofusin 2
Filadi, R., Greotti, E., & Pizzo, P. (2018) · Pharmacological Research · doi:10.1016/j.phrs.2018.01.003 · Cited by 104
Mitofusin gain and loss of function drive pathogenesis in Drosophila models of CMT2A neuropathy
Fissi, N. E., Rojo, M., Aouane, A., Karataş, E., Poliacikova, G., David, C., Royet, J., & Rival, T. (2018) · EMBO Reports · doi:10.15252/embr.201745241 · Cited by 96
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“Expression plasmids for Mfn1- and Mfn2-FLAG were constructed as described previously (Eura et al., 2003).”
MethodMechanistic perspective of mitochondrial fusion: Tubulation vs. fragmentation
Escobar‐Henriques, M., & den Brave, F. (2012) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2012.07.016 · Cited by 100
Ushio‐Fukai, M., Ash, D., Nagarkoti, S., de Chantemèle, E. J. B., Fulton, D. J., & Fukai, T. (2021) · Antioxidants and Redox Signaling · doi:10.1089/ars.2020.8161 · Cited by 99
“Although Mfn gene-deleted embryos show developmental delays, expression of Mfn2 is increased in tissues under conditions of nutrient deprivation in the nervous system, skeletal muscle, and heart (6, 93).”
Yang, J., Xing, X., Luo, L., Zhou, X., Feng, J.-X., Huang, K., Liu, H., Jin, S., Liu, Y.-N., Zhang, S.-H., et al. (2023) · Science Immunology · doi:10.1126/sciimmunol.abq2424 · Cited by 101
“Mammals have two MFNs, MFN1 and MFN2, which share 80% sequence similarity and a certain extent of redundancy in catalyzing mitochondrial outer membrane fusion (20, 21).”
BackgroundUgo1 and Mdm30 act sequentially during Fzo1-mediated mitochondrial outer membrane fusion
den Brave, F., Fres, J. M., Schauss, A. C., Pinson, B., Praefcke, G. J. K., Langer, T., & Escobar‐Henriques, M. (2011) · Journal of Cell Science · doi:10.1242/jcs.073080 · Cited by 98
“Results Fzo1 dimerizes in the OM of mitochondria Mitofusins from yeast to mammals assemble in the mitochondrial OM to high molecular weight complexes of unknown composition (Eura et al., 2003; Rapaport et al., 1998).”
BackgroundDenzer, I., Münch, G. W., & Friedland, K. (2015) · Pharmacological Research · doi:10.1016/j.phrs.2015.11.019 · Cited by 91
Mitochondrial dynamics in cancer-induced cachexia
van der Ende, M., Grefte, S., Plas, R., Meijerink, J., Witkamp, R. F., Keijer, J., & van Norren, K. (2018) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2018.07.008 · Cited by 87
Thoudam, T., Jeon, J., Ha, C., & Lee, I. (2016) · Mediators of Inflammation · doi:10.1155/2016/1851420 · Cited by 91
“Mfn1 and Mfn2 form homotypic or heterotypic complexes during mitochondrial fusion in the mammalian cell [119, 120].”
BackgroundHomozygous mutations inMFN2cause multiple symmetric lipomatosis associated with neuropathy
Sawyer, S. L., Ng, A. C., Innes, A. M., Wagner, J. D., Dyment, D. A., Tétreault, M., Majewski, J., Boycott, K. M., Screaton, R. A., & Nicholson, G. A. (2015) · Human Molecular Genetics · doi:10.1093/hmg/ddv229 · Cited by 87
“Studies looking at the relative amounts ofMFN1 andMFN2proteins in various tissues demonstrated that although MFN1 is enriched in the heart, in agreementwithpreviousdata (12), itwas almostundetectable in brown fat (Fig.”
BackgroundMitophagy in the pathogenesis and management of disease
Wang, Q., Sun, Y., Li, T. Y., & Auwerx, J. (2026) · Cell Research · doi:10.1038/s41422-025-01203-7 · Cited by 103
“Mitochondrial fusion joins two mitochondria at the OMM and IMM, a process mediated by three membrane GTPases, namely MFN1, MFN2, 483,484 and OPA1.”
Role of Mitochondrial Dynamics in Heart Diseases
Tokuyama, T., & Yanagi, S. (2023) · Genes · doi:10.3390/genes14101876 · Cited by 92
“Mfns are prevalent at contact points between neighboring mitochondria, facilitating tethering, docking, and extension of OMM contacts through either homotypic or more effective heterotypic complexes [63] (Figure 2).”
BackgroundConnecting mitochondrial dynamics and life-or-death events via Bcl-2 family proteins
Aouacheria, A., Baghdiguian, S., Lamb, H. M., Huska, J. D., Pineda, F. J., & Hardwick, J. M. (2017) · Neurochemistry International · doi:10.1016/j.neuint.2017.04.009 · Cited by 81
“Consistent with high levels of Mfn2 expression in the brain, mutations in Mfn2 lead to neurological defects, corroborated by genetic studies in mice, where Mfn2-deficiency results in cerebellar degeneration, severe ataxia and death around 2-weeks of age (Chen et al., 2003, 2007; Eura et al., 2003).”
BOK controls apoptosis by Ca2+ transfer through ER-mitochondrial contact sites
Carpio, M. A., Means, R. E., Brill, A. L., Sainz, A. G., Ehrlich, B. E., & Katz, S. G. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.108827 · Cited by 89
“In addition, mitofusins are known to both regulate ER-mitochondrial contacts (de Brito and Scorrano, 2008) and mitochondrial morphology (Eura et al., 2003), the latter of which has been shown to affect susceptibility to apoptosis (Renault et al., 2015).”
Mitochondrial dynamics involves molecular and mechanical events in motility, fusion and fission
Green, A., Hossain, T., & Eckmann, D. M. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.1010232 · Cited by 86
“Both the N and C termini of DRPs face the cytosol (Hinshaw, 2000; Chen H. et al., 2003; Eura et al., 2003).”
BackgroundMitofusin 2 as a Driver That Controls Energy Metabolism and Insulin Signaling
Antonio Zorzano, A., Hernández‐Álvarez, M. I., Sebastián, D., & Muñoz, J. P. (2015) · Antioxidants and Redox Signaling · doi:10.1089/ars.2014.6208 · Cited by 83
“…tissues: Mfn1 predominates in the heart, liver, pancreas, adrenal glands, and testis, whereas Mfn2 is more abundant in the heart, skeletal muscle, brain, and brown adipose tissue (8, 29), and OPA1 shows the highest expression in the retina, brain, testis, liver, heart, and skeletal muscle (4, 24).”
How the Wnt signaling pathway protects from neurodegeneration: the mitochondrial scenario
Arrázola, M. S., Silva-Álvarez, C., & Inestrosa, N. C. (2015) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2015.00166 · Cited by 80
“By contrast, mitochondrial fusion is regulated by two proteins widely expressed in the OMM of the brain and other tissues, known as mitofusin (Mfn) 1 and 2 (Rojo et al., 2002; Eura et al., 2003).”
BackgroundDorn, G. W., & Scorrano, L. (2010) · Circulation Research · doi:10.1161/circresaha.110.225714 · Cited by 82
Miro: A molecular switch at the center of mitochondrial regulation
Eberhardt, E. L., Ludlam, A. V., Tan, Z., & Cianfrocco, M. A. (2020) · Protein Science · doi:10.1002/pro.3839 · Cited by 82
“In mitofusin knockout cells, mitochondria appear to be fragmented with small globular structures.(80,83) Overexpression of TRAK1 results in extensive clustering of mitochondria in these cells.”
BackgroundSmall molecule agonist of mitochondrial fusion repairs mitochondrial dysfunction
Guo, Y., Zhang, H., Chen, Y., Shen, B., Zhang, Y., Guo, X., Sun, S., Fan, Y., Yan, J., Liu, R., et al. (2023) · Nature Chemical Biology · doi:10.1038/s41589-022-01224-y · Cited by 82
Bioenergetic roles of mitochondrial fusion
Ramos, E. S., Larsson, N., & Mourier, A. (2016) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2016.04.002 · Cited by 79
Implications of mitochondrial dynamics on neurodegeneration and on hypothalamic dysfunction
Antonio Zorzano, A., & Claret, M. (2015) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2015.00101 · Cited by 83
“The N-terminal GTPase activity of Mfn2 is key for its function in mitochondrial fusion (Chen et al., 2003; Eura et al., 2003).”
BackgroundA time to reap, a time to sow: Mitophagy and biogenesis in cardiac pathophysiology
Andres, A. M., Stotland, A., Queliconi, B. B., & Gottlieb, R. A. (2015) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2014.10.003 · Cited by 78
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“Electron microscopy immunoelectron microscopy were carried out as described previously (Eura et al., 2003).”
MethodMitophagy is required for brown adipose tissue mitochondrial homeostasis during cold challenge
Lu, Y., Fujioka, H., Joshi, D., Li, Q., Sangwung, P., Hsieh, P., Zhu, J., Torio, J., Sweet, D., Wang, L., et al. (2018) · Scientific Reports · doi:10.1038/s41598-018-26394-5 · Cited by 76
Organellar vs cellular control of mitochondrial dynamics
Hyde, B. B., Twig, G., & Shirihai, O. S. (2010) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2010.01.003 · Cited by 81
Regulation and Physiologic Functions of GTPases in Mitochondrial Fusion and Fission in Mammals
Ishihara, N., Otera, H., Oka, T., & Mihara, K. (2012) · Antioxidants and Redox Signaling · doi:10.1089/ars.2012.4830 · Cited by 77
“These experiments revealed that mitochondrial fusion GTPases (Mfn1, Mfn2, and OPA1) and the active membrane potential are essential for mitochondrial fusion (11, 22).”
InfluentialMitochondrial Fission and Autophagy in the Normal and Diseased Heart
Iglewski, M., Hill, J. A., Lavandero, S., & Rothermel, B. A. (2010) · Current Hypertension Reports · doi:10.1007/s11906-010-0147-x · Cited by 75
“Fusion requires GTP hydrolysis, as it has been observed that mutation of the GTPase domain of MFN2 results in an accumulation of tethered but unfused mitochondria [ 21 ].”
Mitofusin 2 in Mature Adipocytes Controls Adiposity and Body Weight
Mancini, G., Pirruccio, K., Yang, X., Blüher, M., Rodeheffer, M. S., & Horváth, T. L. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.02.039 · Cited by 72
“In mammals, mitochondrial fusion of the outer membranes is mediated by mitofusins, including mitofusin 2 (mfn2) (Santel and Fuller, 2001; Santel et al., 2003; Rojo et al., 2002; Eura et al., 2003).”
BackgroundMolecular mechanism of mitochondrial membrane fusion
Griffin, E. E., Detmer, S. A., & Chan, D. C. (2006) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2006.02.003 · Cited by 73
“Co-immunoprecipitation studies have demonstrated that the mitofusins can interact to form three distinct molecular complexes: Mfn1 homotypic complexes, Mfn2 homotypic complexes and Mfn1/Mfn2 heterotypic complexes [4,29].”
BackgroundJofuku, A., Ishihara, N., & Mihara, K. (2005) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2005.05.154 · Cited by 73
Dürr, M., Escobar‐Henriques, M., Merz, S., Geimer, S., Langer, T., & Westermann, B. (2006) · Molecular Biology of the Cell · doi:10.1091/mbc.e06-01-0053 · Cited by 73
“These complexes might tether neighboring organelles, as it has been observed for mammalian cells expressing mutant forms of Mfn2 (Eura et al., 2003) or truncated forms of Mfn1 (Koshiba et al.”
BackgroundMAVS is energized by Mff which senses mitochondrial metabolism via AMPK for acute antiviral immunity
Hanada, Y., Ishihara, N., Wang, L., Otera, H., Ishihara, T., Koshiba, T., Mihara, K., Ogawa, Y., & Nomura, M. (2020) · Nature Communications · doi:10.1038/s41467-020-19287-7 · Cited by 69
Mitochondrial Fusion Protein Mfn2 and Its Role in Heart Failure
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Charcot-Marie-Tooth neuropathy type 2A: novel mutations in the mitofusin 2 gene (MFN2)
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“on the mitochondrial outer membrane [80–82].”
Domain Interactions within Fzo1 Oligomers Are Essential for Mitochondrial Fusion
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“Two MFN isoforms, MFN1 and MFN2, exist and cooperate in mitochondrial fusion in mammalian cells [27].”
BackgroundMitochondrial dynamics and mitophagy in Parkinson's disease: A fly point of view
von Stockum, S., Nardin, A., Schrepfer, E., & Ziviani, E. (2015) · Neurobiology of Disease · doi:10.1016/j.nbd.2015.11.002 · Cited by 70
Regulation of Mitochondrial Dynamics and Autophagy by the Mitochondria-Associated Membrane
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The regulation of tumor cell physiology by mitochondrial dynamics
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Targeting Drp1 and mitochondrial fission for therapeutic immune modulation
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Role of mitochondria in pathogenesis and therapy of renal fibrosis
Zhao, X., Li, Y., Yu, J., Teng, H., Wu, S., Wang, Y., Zhou, H., & Li, F. (2024) · Metabolism · doi:10.1016/j.metabol.2024.155913 · Cited by 71
Zika Virus-Induced Neuronal Apoptosis via Increased Mitochondrial Fragmentation
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“C. elegans fzo-1 and drp-1 genes are required for fusion and fission of mitochondria, respectively 24–28 , and encode GTPases of the dynamin family that are orthologues of the MFN1/FZO1 protein, which mediates mitochondrial fusion, and the DRP1 protein, which promotes mitochondrial fission 29–33 .”
Mfn2 localization in the ER is necessary for its bioenergetic function and neuritic development
Casellas‐Díaz, S., Larramona‐Arcas, R., Riqué‐Pujol, G., Tena‐Morraja, P., Müller‐Sánchez, C., Segarra‐Mondejar, M., Gavaldà‐Navarro, A., Villarroya, F., Reina, M., Martínez-Estrada, O. M., et al. (2021) · EMBO Reports · doi:10.15252/embr.202051954 · Cited by 68
“Mfn1 has been shown to be more efficient at mediating mitochondrial fusion; meanwhile, Mfn2 plays a more prominent role regulating mitochondrial metabolism (Bach et al , 2003; Chen et al , 2003; Eura et al , 2003; Ishihara et al , 2004; Pich et al , 2005).”
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FAM49B, a novel regulator of mitochondrial function and integrity that suppresses tumor metastasis
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The Effect of OPA1 on Mitochondrial Ca2+ Signaling
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“Knockdown of either the Mfn1 [26–28] or the OPA1 gene brings about the fragmentation of the mitochondria [19,29,30], moreover, knocking down of OPA1 (or Mgm1) gene also evokes drastic desorganisation of the cristae”
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Relationship between OPA1 and cardiolipin in mitochondrial inner-membrane fusion
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Atad3 Function Is Essential for Early Post-Implantation Development in the Mouse
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Mitochondrial functions and rare diseases
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The Emerging Role of Senescence in Ocular Disease
Sreekumar, P. G., Hinton, D. R., & Kannan, R. (2020) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2020/2583601 · Cited by 67
“The mitochondrial fusion is primarily regulated by Mitofusion proteins 1/2 (Mfn1/2), optic atrophy protein 1 (Opa1) [192, 193], and fission by dynamin-related protein 1 (Drp1) and fission 1 protein (Fis1).”
BackgroundRegulation of mitochondrial processes: A target for heart failure
Palaniyandi, S. S., Qi, X., Yogalingam, G., Ferreira, J. C. B., & Mochly‐Rosen, D. (2010) · Drug Discovery Today Disease Mechanisms · doi:10.1016/j.ddmec.2010.07.002 · Cited by 62
“mitochondrial fusion, through interactions of their coiled-coil domains, MFN1 and MFN2 form homo-oligometric and hetero-oligomeric complexes, and thus tether outer membranes of neighboring mitochondria together [32].”
BackgroundWinter, L., Kuznetsov, A. V., Grimm, M. F., Zeöld, A., Fischer, I., & Wiche, G. (2015) · Human Molecular Genetics · doi:10.1093/hmg/ddv184 · Cited by 59
“Similar to Mfn-2 (32), P1b was shown to be localized in the outer mitochondrial membrane, where it is anchored via its isoform-specific sequence that serves as a single-anchor domain (10).”
BackgroundMitochondrial fission and apoptosis: An ongoing trial
Parone, P. A., & Martinou, J. (2006) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2006.04.005 · Cited by 60
Lacombe, A., & Scorrano, L. (2024) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2024.02.001 · Cited by 65
Kim, S., Song, J., Erñst, P., Latimer, M. N., Ha, C., Goh, K. Y., Ma, W., Namakkal-Soorappan, R. N., Zhang, J., Liu, M., et al. (2020) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00617.2019 · Cited by 58
Mitochondria‐type GPAT is required for mitochondrial fusion
Ohba, Y., Sakuragi, T., Kage‐Nakadai, E., Tomioka, N. H., Kono, N., Imae, R., Inoue, A., Aoki, J., Ishihara, N., Inoué, T., et al. (2013) · The EMBO Journal · doi:10.1038/emboj.2013.77 · Cited by 62
“When mitochondrial fusion is reduced, mitochondria fragment due to ongoing fission; conversely, mitochondria are long and overly interconnected when this balance shifts towards fusion (Smirnova et al , 1998, 2001; Chen et al , 2003; Eura et al , 2003; Santel et al , 2003).”
New insights into mitochondrial fusion
Zhang, Y., & Chan, D. C. (2007) · FEBS Letters · doi:10.1016/j.febslet.2007.01.095 · Cited by 59
“Fzo1p in yeast functions as a homo-oligomeric complex, whereas Mfn1 and Mfn2 form both homo-oligomeric and hetero-oligomeric complexes [14,15,37,40].”
BackgroundZika Virus Neuropathogenesis: The Different Brain Cells, Host Factors and Mechanisms Involved
Komarasamy, T. V., Adnan, N. A. A., James, W., & Balasubramaniam, V. R. M. T. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.773191 · Cited by 58
“MFN2 is highly expressed in the brain (47) and it has been shown to be essential in embryonic development (48), neuronal maturation and synapse formation (138).”
BackgroundSun, D., Li, C., Liu, J., Wang, Z., Liu, Y., Luo, C., Chen, Y., & Wen, S. (2019) · DNA and Cell Biology · doi:10.1089/dna.2019.4731 · Cited by 56
Characterization of the mitofusin 2 R94W mutation in a knock‐in mouse model
Strickland, A. V., Rebelo, A. P., Zhang, F., Price, J. H., Bolon, B. N., Silva, J. P., Wen, R., & Zuchner, S. L. (2014) · Journal of the Peripheral Nervous System · doi:10.1111/jns5.12066 · Cited by 53
“Interestingly, P1 hearts did not show decreased ATP production, but heart tissue expresses higher levels of MFN1 than brain and it is possible that this paralogous protein might play a compensatory role for MFN2 functions (Eura et al., 2003).”
BackgroundGet the balance right: Mitofusins roles in health and disease
Santel, A. (2006) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2006.02.004 · Cited by 55
Vettori, A., Bergamin, G., Moro, E., Vazza, G., Polo, G., Tiso, N., Argenton, F., & Mostacciuolo, M. L. (2010) · Neuromuscular Disorders · doi:10.1016/j.nmd.2010.09.002 · Cited by 54
Molecular basis of axonal dysfunction and traffic impairments in CMT
Gentil, B. J., & Cooper, L. (2012) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2012.05.003 · Cited by 54
Activation of Mitofusin2 by Smad2-RIN1 Complex during Mitochondrial Fusion
Kumar, S., Pan, C. C., Shah, N. R., Wheeler, S. E., Hoyt, K. R., Hempel, N., Mythreye, K., & Lee, N. Y. (2016) · Molecular Cell · doi:10.1016/j.molcel.2016.04.010 · Cited by 54
“Previous studies have shown that loss of MFN2 leads to mitochondrial fragmentation that are heterogeneous in size and accumulate in perinuclear regions (Chen et al., 2003; Eura et al., 2003).”
BackgroundDaste, F., Sauvanet, C., Bavdek, A., Baye, J., Pierre, F., Borgne, R. L., David, C., Rojo, M., Fuchs, P., & Tareste, D. C. (2018) · EMBO Reports · doi:10.15252/embr.201643637 · Cited by 54
“Mutations in any of these functional domains impair Mitofusin function, but their exact role in mitochondrial fusion remains unknown [15,17 – 20].”
Mehta, K., Chacko, L. A., Chug, M. K., Jhunjhunwala, S., & Ananthanarayanan, V. (2019) · Journal of Biological Chemistry · doi:10.1074/jbc.ra118.006799 · Cited by 54
“Fusion of mitochondria requires two sets of proteins, namely Opa1 (6) for the inner membrane (Mgm1 in yeast (7)) and Mfn1/2 (8) for the outer membrane (Fzo1 in yeast (9)).”
BackgroundFowler, P. C., Garcia-Pardo, M. E., Simpson, J. C., & O’Sullivan, N. C. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.01051 · Cited by 53
“Once bound to MTs, Spastin can sever tubulin-tubulin interactions generating internal breaks in the MT network (Evans et al., 2005; Roll-Mecak and Vale, 2008).”
BackgroundMutational analysis of action of mitochondrial fusion factor mitofusin-2
Honda, S., Aihara, T., Hontani, M., Okubo, K., & Hirose, S. (2005) · Journal of Cell Science · doi:10.1242/jcs.02449 · Cited by 53
“In mammals, two isoforms, Mfn1 and Mfn2, have been reported to cooperate to fuse mitochondria (Chen et al., 2003; Santel et al., 2003; Eura et al., 2003).”
BackgroundMitochondrial Membrane Remodeling
Yang, Z., Wang, L., Yang, C., Pu, S., Guo, Z., Wu, Q., Zhou, Z., & Zhao, H. (2022) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2021.786806 · Cited by 54
“Both proteins accumulate at contact areas between two adjacent mitochondria and establish homo or heterotypic complexes leading to mitochondrial fusion (Eura et al., 2003; Hoppins et al., 2011a).”
BackgroundMolecular mechanisms of mitochondrial quality control
Li, W., Gui, Y., Guo, C., Huang, Y.-T., Liu, Y., Yu, X., Zhang, H., Wang, J., Liu, R., Mahaman, Y. A. R., et al. (2025) · Translational Neurodegeneration · doi:10.1186/s40035-025-00505-5 · Cited by 57
“During mitochondrial fusion, MFN proteins on the same mitochon-drion form oligomers, while the MFN protein complexes between adjacent mitochondria form connections, thus increasing the contact between adjacent mitochondria [45, 46].”
Mitochondrial regulation of airway smooth muscle functions in health and pulmonary diseases
Pan, S., Conaway, S., & Deshpande, D. A. (2019) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2019.01.002 · Cited by 51
“In fact, mitofusin (Mfn) 2, also called hyperplasia suppressor gene, is implicated not only in mitochondria fusion and tethering of mitochondrial and ER/SR membranes, but also in cell proliferation [99, 100].”
BackgroundRole of Mitofusins and Mitophagy in Life or Death Decisions
Joaquim, M., & Escobar‐Henriques, M. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.572182 · Cited by 50
Recent insights into the structure and function of Mitofusins in mitochondrial fusion
Cohen, M. M., & Tareste, D. C. (2018) · F1000Research · doi:10.12688/f1000research.16629.1 · Cited by 49
Nottia, M. D., Verrigni, D., Torraco, A., Rizza, T., Bertini, E., & Carrozzo, R. (2021) · Genes · doi:10.3390/genes12020247 · Cited by 51
Metadata
- Authors
- Eura, Y.
- Affiliations
- Kyushu University (JP)
- Corresponding author
- Eura, Y.
- ORCID
- Eura, Y.
- Venue
- Journal of Biochemistry
- Publisher
- Oxford University Press (OUP)
- Published
- 2003-09-01
- Volume
- 134
- Issue
- 3
- Pages
- 333-344
- ISSN
- 0021-924X (ISSN-L)
- OpenAlex
- W2001819241
- Cited by
- 445
- References
- 0
- Citations by year
- 2026: 7 · 2025: 25 · 2024: 24 · 2023: 33 · 2022: 28 · 2021: 35 · 2020: 34 · 2019: 27 · 2018: 21 · 2017: 17 · 2016: 19 · 2015: 16 · 2014: 16 · 2013: 26 · 2012: 22
- FWCI
- 3.54
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Biochemistry (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- mitofusin 1, mitofusin 2, mitochondrial fusion, mitochondrial fission, mitochondrial morphology, mitochondrial outer membrane, GTPase domain, mitochondrial fragmentation, mitochondrial contact sites, HeLa cells, RNAi knockdown, Sendai virus
- MeSH terms
- Animals, HeLa Cells, Humans, Membrane Fusion, Membrane Proteins, Mitochondria, Morphogenesis, Mutation, Tissue Distribution, Transfection, Protein Isoforms, GTP Phosphohydrolases, Mitochondrial Proteins, Sendai virus, Drosophila Proteins, RNA, Small Interfering, Rats
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