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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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“EM For EM, cells were fixed in 4% PFA and 1% glutaraldehyde at 25°C for 30 min and analyzed as described previously (Eura et al., 2003).”
BackgroundMethodIshihara, N., Nomura, M., Jofuku, A., Kato, H., Suzuki, S. O., Masuda, K., Otera, H., Nakanishi, Y., Nonaka, I., Goto, Y.-I., et al. (2009) · Nature Cell Biology · doi:10.1038/ncb1907 · Cited by 1,066
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“Moreover, Mfn1 and Mfn2 form both homotypic and heterotypic complexes that can be detected by immunoprecipitation (Chen et al. 2003, Eura et al. 2003).”
BackgroundMitochondrial Dynamics in Mammalian Health and Disease
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“Reduction in the activity of these proteins by repression or by the presence of loss-of-function mutants or ablation of these proteins causes mitochondrial fragmentation or reduction in the extent of mitochondrial filaments (12, 16, 51, 92, 115, 223).”
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BackgroundMethodResultInfluentialSelf-citationThe dynamin-related GTPase Drp1 is required for embryonic and brain development in mice
Wakabayashi, J., Zhang, Z., Wakabayashi, N., Tamura, Y., Fukaya, M., Kensler, T. W., Iijima, M., & Sesaki, H. (2009) · Journal of Cell Biology · doi:10.1083/jcb.200903065 · Cited by 667
“We thank S. Gould, P. Watkinson, P. Espenshade, and M. Watanabe for antibodies, N. Ishihara and K. Mihara for Su9-GFP plasmids, A. Joyner, S. Dymecki,”
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Burté, F., Carelli, V., Chinnery, P. F., & Yu‐Wai‐Man, P. (2014) · Nature Reviews Neurology · doi:10.1038/nrneurol.2014.228 · Cited by 686
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BackgroundYoshii, S. R., Kishi, C., Ishihara, N., & Mizushima, N. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.209338 · Cited by 612
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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).”
BackgroundMitofusins, from Mitochondria to Metabolism
Schrepfer, E., & Scorrano, L. (2016) · Molecular Cell · doi:10.1016/j.molcel.2016.02.022 · Cited by 504
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BackgroundMolecular mechanisms of mitochondrial dynamics
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“Both proteins accumulate at contact sites between adjacent mitochondria 174 and form homotypic or heterotypic complexes, driving mitochondrial fusion 175 .”
Mitofusins 1/2 and ERRα expression are increased in human skeletal muscle after physical exercise
Cartoni, R., Léger, B., Hock, M. B., Praz, M., Crettenand, A., Pich, S., Ziltener, J., Luthi, F., Dériaz, O., Zorzano, A., et al. (2005) · The Journal of Physiology · doi:10.1113/jphysiol.2005.092031 · Cited by 406
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Papanicolaou, K. N., Khairallah, R. J., Ngoh, G. A., Chikando, A. C., Luptak, I., O’Shea, K. M., Riley, D. D., Lugus, J. J., Colucci, W. S., Lederer, W. J., et al. (2011) · Molecular and Cellular Biology · doi:10.1128/mcb.00911-10 · Cited by 371
“All of these mitochondrionshaping proteins are expressed in the mammalian heart (28, 32, 42, 73), but their roles in regulating organelle structure and function in this tissue remain to be elucidated.”
BackgroundMitofusin 2: from functions to disease
Filadi, R., Pendin, D., & Pizzo, P. (2018) · Cell Death and Disease · doi:10.1038/s41419-017-0023-6 · Cited by 373
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“134 Conversely, Mfns genetic deletion results in embryonic lethality, but the phenotypes of cellular models of individual Mfn ablation are not identical: mitochondria appear as short rods in Mfn2 (cid”
BackgroundDetmer, S. A., & Chan, D. C. (2007) · The Journal of Cell Biology · doi:10.1083/jcb.200611080 · Cited by 343
“The Mfn1–Mfn2 heterooligomeric complex is an important regulator of mitochondrial dynamics Previous immunoprecipitation studies indicated that Mfn1 and Mfn2 form heterooligomeric complexes (Chen et al., 2003; Eura et al., 2003).”
BackgroundInfluentialLevels of human Fis1 at the mitochondrial outer membrane regulate mitochondrial morphology
Stojanovski, D., Koutsopoulos, O. S., Okamoto, K., & Ryan, M. T. (2004) · Journal of Cell Science · doi:10.1242/jcs.01058 · Cited by 332
“Alternatively, they might be due to maintaining balances in opposed fusion events, given that differences in the levels of Mitofusins are also present in different cell types (Eura et al., 2003).”
BackgroundMitochondrial pathways in sarcopenia of aging and disuse muscle atrophy
Calvani, R., Joseph, A.-M., Adhihetty, P. J., Miccheli, A., Bossola, M., Leeuwenburgh, C., Bernabei, R., & Marzetti, E. (2013) · bchm · doi:10.1515/hsz-2012-0247 · Cited by 328
“…factors in mammals are the dynamin-related GTPases mitofusin 1 and 2 (Mfn1 and Mfn2), that are responsible for the tethering and fusion of outer mitochondrial membranes (OMMs) between two organelles (Eura et al. , 2003 ), and optic atrophy protein 1 (OPA1), that controls IMM fusion (Misaka et al.”
Determinants and Functions of Mitochondrial Behavior
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Yun, J., Puri, R., Yang, H., Lizzio, M. A., Wu, C., Sheng, Z.-H., & Guo, M. (2014) · eLife · doi:10.7554/elife.01958 · Cited by 303
“Mammals have two Mfn proteins, Mfn1 and Mfn2, both able to promote mitochondrial fusion (Chen et al., 2003; Eura et al., 2003).”
BackgroundDietrich, M. O., Liu, Z.-W., & Horvath, T. L. (2013) · Cell · doi:10.1016/j.cell.2013.09.004 · Cited by 306
“(Chen et al., 2003; Eura et al., 2003; Ishihara et al., 2004; Rojo et al., 2002; Santel and Fuller, 2001) and optic atrophy-1 (OPA1) (Cipolat et al.”
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MITOL Regulates Endoplasmic Reticulum-Mitochondria Contacts via Mitofusin2
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“In mammals, two Fzo1p homologues, Mitofusin (Mfn)1 and Mfn2 are widely expressed in many tissues (Rojo et al, 2002; Santel et al, 2003; Eura et al, 2003).”
BackgroundYamada, T., Murata, D., Adachi, Y., Itoh, K., Kameoka, S., Igarashi, A., Kato, T., Araki, Y., Huganir, R. L., Dawson, T. M., et al. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2018.06.014 · Cited by 292
Arnoult, D., Grodet, A., Lee, Y.-J., Estaquier, J., & Blackstone, C. D. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m505970200 · Cited by 265
The SUMO protease SENP5 is required to maintain mitochondrial morphology and function
Zunino, R., Schauss, A. C., Rippstein, P. U., Andrade-Navarro, M. A., & McBride, H. M. (2007) · Journal of Cell Science · doi:10.1242/jcs.03418 · Cited by 262
“…of many proteins that control mitochondrial dynamics in mammalian cells, including the GTPases such as mitofusin1 and mitofusin2 (Chen et al., 2003; Eura et al., 2003; Ishihara et al., 2004; Rojo et al., 2002; Santel and Fuller, 2001), DRP1 (Pitts et al., 1999; Smirnova et al., 2001), Opa1…”
BackgroundRecent advances into the understanding of mitochondrial fission
Elgass, K., Pakay, J. L., Ryan, M. T., & Palmer, C. S. (2012) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2012.05.002 · Cited by 274
Cyclin B1/CDK1-regulated mitochondrial bioenergetics in cell cycle progression and tumor resistance
Xie, B., Wang, S., Jiang, N., & Li, J. J. (2018) · Cancer Letters · doi:10.1016/j.canlet.2018.11.019 · Cited by 268
Listeria monocytogenes transiently alters mitochondrial dynamics during infection
Stavru, F., Bouillaud, F., Sartori-Rupp, A., Ricquier, D., & Cossart, P. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1100126108 · Cited by 252
“Key players in the fusion process include the outer mitochondrial membrane GTPases mitofusin 1 and 2 (Mfn1/2) (8, 9), and the inner membrane GTPase optic atrophy 1 (Opa1) (10, 11), but the molecular details of the fusion mechanism remain obscure (12, 13).”
BackgroundStructure, function, and regulation of mitofusin‐2 in health and disease
Chandhok, G., Lazarou, M., & Neumann, B. (2017) · Biological reviews/Biological reviews of the Cambridge Philosophical Society · doi:10.1111/brv.12378 · Cited by 263
“Mfn1 is ubiquitously expressed with higher expression levels in the heart and testis, whereas Mfn2 levels are increased in the heart, skeletal muscle, tongue, and brain (Santel & Fuller, 2001; Eura et al., 2003; Santel et al., 2003).”
BackgroundMitochondrial Homeostasis and Cellular Senescence
Vasileiou, P. V. S., Evangelou, K., Vlasis, K. G., Fildisis, G., Panayiotidis, M. I., Chronopoulos, E., Passias, P.-G., Kouloukoussa, M., Gorgoulis, V. G., & Havaki, S. (2019) · Cells · doi:10.3390/cells8070686 · Cited by 255
“MFN1 and MFN2 are transmembrane GTPases located in the outer mitochondrial membrane (OMM) and their primary function is to mediate the first step of mitochondrial fusion (fusion of the OMM), whereas OPA1 protein, a third GTPase of the dynamin family, is situated within the intermembrane space tightly associated with t…”
BackgroundInfluentialReciprocal Regulation of Mitochondrial Fission and Fusion
Sabouny, R., & Shutt, T. E. (2020) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2020.03.009 · Cited by 247
The Soluble Form of Bax Regulates Mitochondrial Fusion via MFN2 Homotypic Complexes
Hoppins, S. C., Edlich, F., Harwig, M. C., Banerjee, S., McCaffery, J. M., Youle, R. J., & Nunnari, J. M. (2011) · Molecular Cell · doi:10.1016/j.molcel.2010.11.030 · Cited by 253
“For example, MFN2 is the prevalent species in heart, skeletal muscle, and brain (Eura et al., 2003; Lein et al., 2007).”
BackgroundMitochondrial fission/fusion dynamics and apoptosis
Sheridan, C., & Martin, S. J. (2010) · Mitochondrion · doi:10.1016/j.mito.2010.08.005 · Cited by 247
“mammalian homologues of Fzo1 are Mfn1 and Mfn2, two large GTPases that are localised on the mitochondrial outer membrane (Eura et al., 2003; Santel et al., 2003).”
The mitochondrial protein MTP18 contributes to mitochondrial fission in mammalian cells
Tondera, D., Czauderna, F., Paulick, K., Schwarzer, R., Kaufmann, J., & Santel, A. (2005) · Journal of Cell Science · doi:10.1242/jcs.02415 · Cited by 239
“, 2003) and cells transfected with synthetic siRNA molecules for RNAi (Eura et al., 2003), whereas shRNA-Drp1 displayed the anticipated opposite effect of mitochondrial morphology.”
BackgroundOlichon, A., Elachouri, G., Baricault, L., Delettre, C., Belenguer, P., & Lenaers, G. (2006) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4402048 · Cited by 228
“Cell Death and Differentiation 2007; 2007 Apr;14(4):682-92 682-92”
BackgroundInfluentialmTORC1 as a Regulator of Mitochondrial Functions and a Therapeutic Target in Cancer
de la Cruz-López, K. G., Toledo-Guzmán, M. E., Sánchez, E. O., & Carrancá, A. G. (2019) · Frontiers in Oncology · doi:10.3389/fonc.2019.01373 · Cited by 223
“OM fusion is mediated by mitofusin 1 (MFN1) (115) and MNF2 (116), which are dynamin-related GTPases at the OM (117).”
BackgroundCausal roles of mitochondrial dynamics in longevity and healthy aging
Sharma, A., Smith, H. J., Yao, P., & Mair, W. B. (2019) · EMBO Reports · doi:10.15252/embr.201948395 · Cited by 222
“Of the two MFNs, MFN1 is the primary isoform expressed in liver and pancreas, whereas MFN2 is more abundant in skeletal muscle, brain, and brown adipose tissue [56,57].”
Yu, W., Sun, Y., Guo, S., & Lu, B. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddr235 · Cited by 219
“There are two Mfns in mammalian cells: Mfn1 and Mfn2, with Mfn1 showing general expression and Mfn2 more restricted expression (21,22).”
Mitochondrial Dynamics in Stem Cells and Differentiation
Seo, B. J., Yoon, S. H., & Tae, J. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19123893 · Cited by 208
“Mitochondrial fusion is a two-step process involving the 47 mitochondrial outer membrane (MOM) fusion, mediated by mitofusin proteins (Mfn1 and Mfn2) 48 [13-17] and mitochondrial inner membrane (MIM) fusion, mediated by Opa1, and could be possibly 49 coupled [18-20].”
BackgroundMitochondrial dynamics and transport in Alzheimer's disease
Flannery, P. J., & Trushina, E. V. (2019) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2019.06.009 · Cited by 203
Papanicolaou, K. N., Ngoh, G. A., Dabkowski, E. R., O’Connell, K. A., Júnior, R. F. R., Stanley, W. C., & Walsh, K. X. (2011) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00833.2011 · Cited by 208
“Similarly, the diminished GTPase activity of Mfn-2 may explain why Mfn-2 overexpression, in the presence of endogenous Mfn-1, induces the breakdown of mitochondrial tubules into small spherical structures relative to the WT condition (18, 25, 54, 57).”
BackgroundMitofusin 2 Triggers Vascular Smooth Muscle Cell Apoptosis via Mitochondrial Death Pathway
Guo, X., Chen, K., Guo, Y., Liao, H., Tang, J., & Xiao, R. (2007) · Circulation Research · doi:10.1161/circresaha.107.157644 · Cited by 201
Mitochondrial fusion proteins: Dual regulators of morphology and metabolism
Antonio Zorzano, A., Liesa, M., Sebastián, D., Segalés, J., & Palacín, M. (2010) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2010.01.002 · Cited by 204
Marzetti, E., Csiszár, A., Dutta, D., Balagopal, G., Calvani, R., & Leeuwenburgh, C. (2013) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00936.2012 · Cited by 198
Mitochondrial Dynamics in Mitochondrial Diseases
Suarez-Rivero, J. M., Paz, M. V., de la Cruz‐Ojeda, P., de la Mata, M., Cotán, D., Oropesa-Ávila, M., de Lavera, I., Álvarez-Córdoba, M., Luzón–Hidalgo, R., & Sánchez-Alcázar, J. A. (2016) · Diseases · doi:10.3390/diseases5010001 · Cited by 196
“Thus, studies where Mfn2 was overexpressed revealed a huge aggregation of mitochondria around the nucleus [71,72].”
BackgroundBaixauli, F., Martin-Cofreces, N. B., Morlino, G., Carrasco, Y. R., Calabia-Linares, C., Veiga, E., Serrador, J. M., & Sánchez‐Madrid, F. (2011) · The EMBO Journal · doi:10.1038/emboj.2011.25 · Cited by 191
Mitofusin 2 Protects Cerebellar Granule Neurons against Injury-induced Cell Death
Jahani‐Asl, A., Cheung, E. C., Neuspiel, M., MacLaurin, J. G., Fortin, A., Park, D. S., McBride, H. M., & Slack, R. S. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m703812200 · Cited by 187
Mitofusin-2 Is a Major Determinant of Oxidative Stress-mediated Heart Muscle Cell Apoptosis
Shen, T., Zheng, M., Cao, C., Chen, C., Tang, J., Zhang, W., Cheng, H., Chen, K., & Xiao, R. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m702657200 · Cited by 189
Morphological dynamics of mitochondria — A special emphasis on cardiac muscle cells
Hom, J., & Sheu, S. (2009) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2009.02.023 · Cited by 189
“Mfn1 and Mfn2 can form homo- and hetero-oligomers, or the coiled-coil domains of Mfn1 can interact in trans with Mfn1 on another mitochondrion which serves to tether adjacent mitochondria together [23,29].”
BackgroundAt the right distance: ER-mitochondria juxtaposition in cell life and death
Naon, D., & Scorrano, L. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2014.05.011 · Cited by 178
“Anyway, the ablation of either MFN1 or MFN2 results anyway in the inhibition of the fusion reaction [21,23,42].”
Nakamura, N., & Hirose, S. (2008) · Molecular Biology of the Cell · doi:10.1091/mbc.e07-11-1103 · Cited by 181
“The target sequences for Drp1 (Parone et al., 2006) and Mfn1 (Eura et al., 2003) RNAi were reported previously.”
BackgroundInfluentialEmerging role of mitophagy in cardiovascular physiology and pathology
Morales, P. E., Arias-Durán, C., Ávalos-Guajardo, Y., Aedo, G., Verdejo, H., Parra, V., & Lavandero, S. (2019) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2019.09.006 · Cited by 179
“Mitofusins (MFN) 1 and 2 are responsible for outer mitochondrial membrane (OMM) fusion (Santel and Fuller, 2001; Chen et al., 2003; Eura et al., 2003), while optic atrophy protein 1 (OPA1) mediates fusion of the inner mitochondrial membrane (IMM) (Olichon et al.”
BackgroundIs Mitochondrial Dysfunction a Common Root of Noncommunicable Chronic Diseases?
Díaz‐Vegas, A., Sánchez-Aguilera, P., Krycer, J. R., Morales, P. E., Monsalves‐Álvarez, M., Cifuentes, M., Rothermel, B. A., & Lavandero, S. (2020) · Endocrine Reviews · doi:10.1210/endrev/bnaa005 · Cited by 179
Axonal Transport and Mitochondrial Function in Neurons
Mandal, A., & Drerup, C. M. (2019) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2019.00373 · Cited by 174
Mitochondria and cancer: is there a morphological connection?
Alirol, E., & Martinou, J. (2006) · Oncogene · doi:10.1038/sj.onc.1209600 · Cited by 171
“In mammals, mitochondrial fusion is driven by two GTPases of the outer membrane named Mitofusins 1 and 2 (Mfn1, Mfn2) (Santel and Fuller, 2001; Chen et al., 2003; Eura et al., 2003).”
BackgroundMorpho-dynamic changes of mitochondria during ageing of human endothelial cells
Jendrach, M., Pohl, S., Vöth, M., Kowald, A., Hammerstein, P., & Bereiter‐Hahn, J. (2005) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2005.03.002 · Cited by 170
“Overexpression or downregulation of one of these proteins results in dramatic changes in mitochondrial morphology and organisation (Eura et al., 2003; Olichon et al., 2003; Frieden et al., 2004; Stojanovski et al., 2004).”
Structural insights of human mitofusin-2 into mitochondrial fusion and CMT2A onset
Li, Y.-J., Cao, Y.-L., Feng, J.-X., Qi, Y., Meng, S., Yang, J., Zhong, Y.-T., Kang, S., Chen, X., Lan, L., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-12912-0 · Cited by 182
Baker, N., Patel, J., & Khacho, M. (2019) · Mitochondrion · doi:10.1016/j.mito.2019.06.003 · Cited by 173
Onoue, K., Jofuku, A., Ban-Ishihara, R., Ishihara, T., Maeda, M., Koshiba, T., Itoh, T., Fukuda, M., Otera, H., Oka, T., et al. (2012) · Journal of Cell Science · doi:10.1242/jcs.111211 · Cited by 161
“These were applied and extracted from an SDS-PAGE gel, then used for immunizing rabbits as described (Eura et al., 2003).”
BackgroundMethodJoseph, A.-M., Adhihetty, P. J., Wawrzyniak, N. R., Wohlgemuth, S. E., Picca, A., Kujoth, G. C., Prolla, T. A., & Leeuwenburgh, C. (2013) · PLoS ONE · doi:10.1371/journal.pone.0069327 · Cited by 161
“Mitochondrial fusion is primarily regulated by members of the dynamin-related GTPases, mitofusin 1 and 2 (Mfn1 and Mfn2) and optic atrophy protein 1 (Opa1) that tether and fuse the outer and inner mitochondrial membranes, respectively [41,42].”
BackgroundMitochondrial dynamics and mitophagy in lung disorders
Sharma, A. K., Ahmad, S., Ahmad, T., Ali, S., & Syed, M. A. (2021) · Life Sciences · doi:10.1016/j.lfs.2021.119876 · Cited by 161
Mitochondrial coupling defect in Charcot–Marie–Tooth type 2A disease
Loiseau, D., Chevrollier, A., Verny, C., Guillet, V., Guéguen, N., de Crescenzo, M. P., Ferré, M., Malinge, M., Guichet, A., Nicolas, G., et al. (2007) · Annals of Neurology · doi:10.1002/ana.21086 · Cited by 156
Functional and morphological impact of ER stress on mitochondria
Vannuvel, K., Renard, P., Raes, M. J., & Arnould, T. (2013) · Journal of Cellular Physiology · doi:10.1002/jcp.24360 · Cited by 161
“MFN2 seems to preferentially participate in later steps of mitochondrial fusion (Eura et al., 2003; Santel et al., 2003; Ishihara et al., 2004), but the protein would be essential for the regulation of a number of cellular processes, related or not to its primary function as mitochondria-shaping…”
BackgroundRole of mitofusin 2 mutations in the physiopathology of Charcot–Marie–Tooth disease type 2A
Cartoni, R., & Martinou, J. (2009) · Experimental Neurology · doi:10.1016/j.expneurol.2009.05.003 · Cited by 157
“Importantly, Eura et al. (2003) reported the same mitochondrial collapse when both Mfn2 WT or GTPase mutants were overexpressed in HeLa cells.”
BackgroundMitofusin 2: A Mitochondria-Shaping Protein with Signaling Roles Beyond Fusion
de Brito, O. M., & Scorrano, L. (2007) · Antioxidants and Redox Signaling · doi:10.1089/ars.2007.1934 · Cited by 155
“MFN1 levels are higher in heart and testis; those of MFN2 are increased in heart, skeletal muscle, tongue, and brain (27, 77).”
Insulin Resistance and Mitochondrial Dysfunction
González-Franquesa, A., & Patti, M. (2017) · Advances in experimental medicine and biology · doi:10.1007/978-3-319-55330-6_25 · Cited by 160
Mitochondrial fusion is essential for steroid biosynthesis
Duarte, A., Poderoso, C., Cooke, M., Soria, G., Cornejo Maciel, F., Gottifredi, V., & Podestá, E. J. (2012) · PLoS ONE · doi:10.1371/journal.pone.0045829 · Cited by 149
“Mfn 1 and 2 are extensely expressed in tissues, as demonstrated in brain (mainly Mfn2), liver, adrenal glands and testis [21].”
BackgroundMitochondrial morphology—emerging role in bioenergetics
Galloway, C. A., Lee, H., & Yoon, Y. (2012) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2012.09.035 · Cited by 159
“At the protein level, however, Mfn2 is predominant in brain, whereas Mfn1 is abundant in heart and testis [14].”
Mitochondrial fission and fusion dynamics: the long and short of it
Berman, S., Pineda, F. J., & Hardwick, J. M. (2008) · Cell Death and Differentiation · doi:10.1038/cdd.2008.57 · Cited by 147
“Subsequently, the mammalian counterparts, Mfn1 and Mfn2, were reported to mediate mitochondrial fusion, though this conclusion was also based on short mitochondrial morphology when the function of Mfn1/Mfn2 was impaired.(29,30) While these studies in yeast are compelling, it remains possible that the effects of mutati…”
BackgroundThe molecular mechanism of mitochondrial fusion
Hoppins, S. C., & Nunnari, J. M. (2008) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2008.07.005 · Cited by 148
Jurcău, A. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222111847 · Cited by 152
“The process is regulated by two other proteins with GTPase activity, Mfn1 and Mfn2 (mitofusins 1 and 2) for fusion of the OMM, while fusion of the IMM is under control of another GTPase, OPA1 (optic atrophy 1) [95].”
BackgroundDengue Virus Impairs Mitochondrial Fusion by Cleaving Mitofusins
Yu, C.-Y., Liang, J., Li, J., Lee, Y.-L., Chang, B.-L., Su, C.-I., Huang, W.-J., Lai, M. M. C., & Lin, Y. (2015) · PLoS Pathogens · doi:10.1371/journal.ppat.1005350 · Cited by 138
“To explore whether DENV can affect mitochondrial dynamics, we performed a mitochondrial intermixing experiment, which has been used to investigate mitochondrial fusion/fission events by fusing two individual cells [37,38].”
MethodTamai, S., Iida, H., Yokota, S., Sayano, T., Kiguchiya, S., Ishihara, N., Hayashi, J.-I., Mihara, K., & Oka, T. (2008) · Journal of Cell Science · doi:10.1242/jcs.026625 · Cited by 138
“Electron microscopy was carried out as described previously (Eura et al., 2003).”
MethodFrom Structure to Function: Mitochondrial Morphology, Motion and Shaping in Vascular Smooth Muscle
McCarron, J. G., Wilson, C., Sandison, M. E., Olson, M. L., Girkin, J. M., Saunter, C. D., & Chalmers, S. (2013) · Journal of Vascular Research · doi:10.1159/000353883 · Cited by 144
The changing shape of mitochondrial apoptosis
Wasilewski, M., & Scorrano, L. (2009) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2009.03.007 · Cited by 135
Atkins, K., Dasgupta, A., Chen, K., Mewburn, J., & Archer, S. L. (2016) · Clinical Science · doi:10.1042/cs20160030 · Cited by 130
Nicotinamide enhances mitochondria quality through autophagy activation in human cells
Kang, H. T., & Hwang, E. S. (2009) · Aging Cell · doi:10.1111/j.1474-9726.2009.00487.x · Cited by 128
“The level of Mfn1, one of the mitochondria fusion proteins (Eura et al., 2003), increased slowly but reached a level over five-fold at later time points (Figs.”
BackgroundHuang, P., Yu, T., & Yoon, Y. (2007) · European Journal of Cell Biology · doi:10.1016/j.ejcb.2007.04.002 · Cited by 131
Liu, Y.-N., Yang, J., Huang, D.-J., Ni, H.-H., Zhang, C.-X., Zhang, L., He, J., Gu, J., Chen, H.-X., Mai, H., et al. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.01906 · Cited by 125
“In contrast, although MFN1 has been found to share some functional redundancy with MFN2 in mouse epithelial fibroblast (MEF)-based assays (20), ablation of MFN1 in HeLa cells is sufficient to induce mitochondrial fragmentation (49).”
BackgroundModulating mitofusins to control mitochondrial function and signaling
Zacharioudakis, E., Agianian, B., Vasantha Kumar, M. V., Biris, N., Garner, T. P., Rabinovich-Nikitin, I., Ouchida, A. T., Margulets, V., Nordstrøm, L. U., Riley, J. S., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-31324-1 · Cited by 137
Adaniya, S. M., O‐Uchi, J., Cypress, M. W., Kusakari, Y., & Jhun, B. S. (2019) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00523.2018 · Cited by 123
“Mfn1 is highly expressed in CMs (57), it should be noted that the investigation of PTMs of Mfn1 and their functional relevance in CMs may also be an important topic to explore in the future.”
BackgroundMitochondrial morphology and distribution in mammalian cells
Frazier, A. E., Kiu, C., Stojanovski, D., Hoogenraad, N. J., & Ryan, M. T. (2006) · Biological Chemistry · doi:10.1515/bc.2006.193 · Cited by 118
“Mitochondrial fusion assays showed that mitofusins must be present on adjacent mitochondrial membranes for membrane fusion to occur (Eura et al., 2003; Koshiba et al., 2004).”
Background
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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