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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Mfn1 and Mfn2 possess several distinct properties, suggesting that they fulfill different roles in fusion.
“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).”
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The mitochondrial protein MTP18 contributes to mitochondrial fission in mammalian cells
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“OM fusion is mediated by mitofusin 1 (MFN1) (115) and MNF2 (116), which are dynamin-related GTPases at the OM (117).”
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“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].”
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“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).”
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Guo, X., Chen, K., Guo, Y., Liao, H., Tang, J., & Xiao, R. (2007) · Circulation Research · doi:10.1161/circresaha.107.157644 · Cited by 199 · see citing works
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“Thus, studies where Mfn2 was overexpressed revealed a huge aggregation of mitochondria around the nucleus [71,72].”
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Mitofusin 2 Protects Cerebellar Granule Neurons against Injury-induced Cell Death
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Mitofusin-2 Is a Major Determinant of Oxidative Stress-mediated Heart Muscle Cell Apoptosis
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“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].”
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Naon, D., & Scorrano, L. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2014.05.011 · Cited by 178 · see citing works
“Anyway, the ablation of either MFN1 or MFN2 results anyway in the inhibition of the fusion reaction [21,23,42].”
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“The target sequences for Drp1 (Parone et al., 2006) and Mfn1 (Eura et al., 2003) RNAi were reported previously.”
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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 178 · see citing works
“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 174 · see citing works
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 167 · see citing works
Mitochondria and cancer: is there a morphological connection?
Alirol, E., & Martinou, J. (2006) · Oncogene · doi:10.1038/sj.onc.1209600 · Cited by 169 · see citing works
“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 · see citing works
“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 167 · see citing works
Baker, N., Patel, J., & Khacho, M. (2019) · Mitochondrion · doi:10.1016/j.mito.2019.06.003 · Cited by 168 · see citing works
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 158 · see citing works
“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 · see citing works
“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 157 · see citing works
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 · see citing works
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 155 · see citing works
“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 152 · see citing works
“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 152 · see citing works
“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 154 · see citing works
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 · see citing works
“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 150 · see citing works
“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. B., Pineda, F. J., & Hardwick, J. M. (2008) · Cell Death and Differentiation · doi:10.1038/cdd.2008.57 · Cited by 146 · see citing works
“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 141 · see citing works
Jurcău, A. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222111847 · Cited by 150 · see citing works
“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 136 · see citing works
“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 134 · see citing works
“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 133 · see citing works
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 129 · see citing works
Atkins, K., Dasgupta, A., Chen, K., Mewburn, J., & Archer, S. L. (2016) · Clinical Science · doi:10.1042/cs20160030 · Cited by 125 · see citing works
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 125 · see citing works
“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 123 · see citing works
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 · see citing works
“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 127 · see citing works
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 115 · see citing works
“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 · see citing works
“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
- 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
- Health Sciences › Medicine › Epidemiology › 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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