Cited by 445Mitochondrial Function and PathologyAutophagy in Disease and TherapyCell death mechanisms and regulation

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Two Mitofusin Proteins, Mammalian Homologues of FZO, with Distinct Functions Are Both Required for Mitochondrial Fusion

Eura, Y.·2003·Journal of Biochemistry

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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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Background
Time-of-Day Circadian Modulation of Grape-Seed Procyanidin Extract (GSPE) in Hepatic Mitochondrial Dynamics in Cafeteria-Diet-Induced Obese Rats
Rodríguez, R. M., Cortés-Espinar, A. J., Soliz‐Rueda, J. R., Feillet‐Coudray, C., Casas, F., Colom‐Pellicer, M., Aragonès, G., Ávila‐Román, J., Muguerza, B., Mulero, M., et al. (2022) · Nutrients · doi:10.3390/nu14040774 · Cited by 23
“On the other hand, the GTPase dynamin-related protein 1 (Drp1), together with OMM-located mitochondrial fission 1 protein (Fis1), conducts the fission events.”
Background
Mitochondrial targeted nanomaterials for alleviating inflammation
Cheng, S., Wang, W., Wang, K., Sun, Z., & Zhang, L. (2024) · Nano Today · doi:10.1016/j.nantod.2024.102323 · Cited by 23
High expression of Mfn1 promotes early development of bovine SCNT embryos: Improvement of mitochondrial membrane potential and oxidative metabolism
Hua, S., Zhang, H., Song, Y., Li, R., Liu, J., Wang, Y., Quan, F., & Zhang, Y. (2012) · Mitochondrion · doi:10.1016/j.mito.2011.12.002 · Cited by 22
“Chen et al. (2003) found that mice deficient in either Mfn1 or Mfn2 died in midgestation and that embryonic fibroblasts lacking Mfn1 or Mfn2 displayed distinct types of fragmented mitochondria, which was attributable to a severe reduction in mitochondrial fusion.”
BackgroundInfluential
Long-Chain Acyl-Carnitines Interfere with Mitochondrial ATP Production Leading to Cardiac Dysfunction in Zebrafish
Park, D.-D., Gahr, B. M., Krause, J., Rottbauer, W., Zeller, T., & Just, S. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22168468 · Cited by 21
“To determine whether high LCAC uptake in mitochondria affects mitochondrial morphology and structure, thereby leading to defective ATP production, we first conducted quantitative real-time PCR (qRT-PCR) analyses to investigate the expression of mfn1, encoding the mitochondrial membrane protein involved in regulating m…”
Method
Regulation of dynamin family proteins by post-translational modifications
Kar, U. P., Dey, H., & Rahaman, A. (2017) · Journal of Biosciences · doi:10.1007/s12038-017-9680-y · Cited by 20
“Althoughboth Mfn1 and Mfn2 are essential, they play distinct roles in mitochondrial fusion (Eura et al. 2003; Chen et al. 2003).”
Monitoring the Mitochondrial Dynamics in Mammalian Cells
Simula, L., & Campello, S. (2018) · Methods in molecular biology · doi:10.1007/978-1-4939-7831-1_15 · Cited by 22
ELMOD2 regulates mitochondrial fusion in a mitofusin-dependent manner, downstream of ARL2
Schiavon, C. R., Turn, R. E., Newman, L. E., & Kahn, R. (2019) · Molecular Biology of the Cell · doi:10.1091/mbc.e18-12-0804 · Cited by 21
“MFN1/2 are essential for outer mitochondrial membrane (OMM) fusion by tethering apposing mitochondria (Chen et al., 2003; Eura, 2003; Koshiba et al., 2004).”
Background
Identification and Characterization of Unique Proline-rich Peptides Binding to the Mitochondrial Fission Protein hFis1
Serasinghe, M. N., Seneviratne, A. M. P. B., Smrcka, A. V., & Yoon, Y. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.027508 · Cited by 21
Mitochondrial fission and fusion in neurodegenerative diseases:Ca2+ signalling
Liu, X., Li, T., Tu, X., Xu, M., & Wang, J. (2025) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2025.103992 · Cited by 22
Guanxinning Injection Combined With Ischemic Postconditioning Attenuate Myocardial Ischemic Reperfusion Injury in Chronic Renal Failure Rats by Modulating Mitochondrial Dynamics
Wang, A., Zhang, D., Liu, J., Yan, H., Zhang, P., Yuan, H., & Ma, X. (2022) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2022.905254 · Cited by 21
“MFN2 is reportedly the most abundant protein in the brain, whereas MFN1 is highly expressed in the heart (36).”
Background
Mitofusin 2 Sustains the Axonal Mitochondrial Network to Support Presynaptic Ca 2+ Homeostasis and the Synaptic Vesicle Cycle in Rat Hippocampal Axons
Vevea, J., & Chapman, E. R. (2023) · Journal of Neuroscience · doi:10.1523/jneurosci.1356-22.2023 · Cited by 19
“We then evaluated whether axonal mitochondrial fusion is critical for the function of the SV cycle by knocking down the main neuronal mitochondrial outer membrane fusion protein, mitofusin 2 (MFN2) (Eura et al., 2003).”
Mitochondrial hyperfusion induces metabolic remodeling in lung endothelial cells by modifying the activities of electron transport chain complexes I and III
Yegambaram, M., Sun, X., Lü, Q., Jin, Y., Ornatowski, W., Soto, J. E., Aggarwal, S., Wang, T., Tieu, K., Gu, H., et al. (2023) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2023.11.008 · Cited by 23
Dynamic properties of mitochondria during human corticogenesis
Baum, T., & Gama, V. (2021) · Development · doi:10.1242/dev.194183 · Cited by 20
What is the biological significance of the two mitofusin proteins present in the outer mitochondrial membrane of mammalian cells?
Zorzano, A., & Pich, S. (2006) · IUBMB Life · doi:10.1080/15216540600644838 · Cited by 20
“The relative mRNA or protein expression levels of Mfn1 and Mfn2 vary between tissues: Mfn1 predominates in heart, liver, pancreas, adrenal glands and testis ( 2, 3 ), whereas Mfn2 is more abundant in heart, skeletal muscle, brain, adrenal glands and brown adipose tissue ( 3, 4 ).”
Background
Current Studies of Mitochondrial Quality Control in the Preeclampsia
Peng, X., Hou, R., Yang, Y., Luo, Z., & Cao, Y. (2022) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2022.836111 · Cited by 20
“However, in MFN1-deficient Hela cells, mitochondrion failed to bind to each other and resulted in fragmentation of mitochondrion (92).”
Background
OPA1 supports mitochondrial dynamics and immune evasion to CD8 + T cell in lung adenocarcinoma
Wang, Y., Li, Y., Jiang, X., Gu, Y., Zheng, H., Wang, X., Zhang, H., Wu, J., & Yang, C. (2022) · PeerJ · doi:10.7717/peerj.14543 · Cited by 18
“Mitofusins (MFN1/2) ( Eura et al., 2003 ; Santel et al., 2003 ) and optic atrophy 1 (OPA1) ( Ehses et al., 2009 ) mediate mitochondrial fusions of outer and inner mitochondrial membrane (IMM) respectively.”
Relationship between mitofusin 2 and cancer
Allegra, A., Innao, V., Allegra, A. G., & Musolino, C. (2018) · Advances in protein chemistry and structural biology · doi:10.1016/bs.apcsb.2018.11.009 · Cited by 21
The abundance of the ARL2 GTPase and its GAP, ELMOD2, at mitochondria are modulated by the fusogenic activity of mitofusins and stressors
Newman, L. E., Schiavon, C. R., Zhou, C., & Kahn, R. (2017) · PLoS ONE · doi:10.1371/journal.pone.0175164 · Cited by 20
“The partial rescue by MFN2[K109A]myc in mfn2 MEFs, compared to the lack of any rescue of fragmentation in mfn1mfn2 MEFs, is likely due to the presence of endogenous MFN1 in mfn2 MEFs, as MFN1 and MFN2 can hetero-oligomerize to promote fusion [6, 7, 36].”
Background
An emerging role of mitochondrial quality control in bone metabolism: from molecular mechanisms to targeted therapeutic interventions
Qin, Z., Zhu, X., Shen, Y., Ling, H., Ruan, N., Ye, W., Xu, Y., & Gan, X. (2025) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-025-05802-w · Cited by 25
Molecular Mechanisms behind Inherited Neurodegeneration of the Optic Nerve
Maresca, A., & Carelli, V. (2021) · Biomolecules · doi:10.3390/biom11040496 · Cited by 20
Blocking AMPKαS496 phosphorylation improves mitochondrial dynamics and hyperglycemia in aging and obesity
Pearah, A., Ramatchandirin, B., Liu, T., Wolf, R. M., Ikeda, A., Radovick, S., Sesaki, H., Wondisford, F. E., O'Rourke, B. P., & He, L. (2023) · Cell chemical biology · doi:10.1016/j.chembiol.2023.09.017 · Cited by 19
Deterioration of mitochondrial function in the human intercostal muscles differs among individuals with sarcopenia, obesity, and sarcopenic obesity
Kim, K. W., Baek, M., Yoon, M., & Son, K. H. (2021) · Clinical Nutrition · doi:10.1016/j.clnu.2021.03.009 · Cited by 20
Contributions of Bcl-xL to acute and long term changes in bioenergetics during neuronal plasticity
Jonas, E. A. (2013) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2013.11.007 · Cited by 18
“Similar molecular players overlap in the two systems such as endophilin family members (Farsad et al., 2001).”
Background
Structural insights into vesicle amine transport-1 (VAT-1) as a member of the NADPH-dependent quinone oxidoreductase family
Kim, S., Mori, T., Chek, M. F., Furuya, S., Matsumoto, K., Yajima, T., Ogura, T., & Hakoshima, T. (2021) · Scientific Reports · doi:10.1038/s41598-021-81409-y · Cited by 17
Mfn2 is responsible for inhibition of the RIG-I/IRF7 pathway and activation of NLRP3 inflammasome in Seneca Valley virus-infected PK-15 cells to promote viral replication
Deng, H., Zhu, S., Zhu, L., Sun, J., Ding, Y., Li, F., Jian, Z., Zhao, J., Deng, L., Deng, J., et al. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.955671 · Cited by 18
“Mitofusin2 (Mfn2), a mitochondrial outer membrane that participates in the initial step of mitochondrial fusion and promotes the maintenance of cellular homeostasis (17, 18), regulates various other biological processes such as cell proliferation and cell death (19–21).”
Background
Mitofusin-mediated contacts between mitochondria and peroxisomes regulate mitochondrial fusion
Alsayyah, C., Singh, M. K., Morcillo-Parra, M. Á., Cavellini, L., Shai, N., Schmitt, C., Schuldiner, M., Zalckvar, E., Mallet, A., Belgareh‐Touzé, N., et al. (2024) · PLoS Biology · doi:10.1371/journal.pbio.3002602 · Cited by 18
“This process is mediated by 2 distinct mitofusins (Mfn1 and Mfn2) in mammalian cells and a single one (Fzo1) in the yeast Saccharomyces cerevisiae (from hereon simply yeast) [4–7].”
Background
Defective nucleotide-dependent assembly and membrane fusion in Mfn2 CMT2A variants improved by Bax
Samanas, N. B., Engelhart, E. A., & Hoppins, S. C. (2020) · Life Science Alliance · doi:10.26508/lsa.201900527 · Cited by 16
“Mfn1 and Mfn2 are functionally related but nonredundant paralogs in mammalian cells (Santel & Fuller, 2001; Chen et al, 2003; Eura, 2003; Ishihara et al, 2004).”
Background
Pharmacophore-Based Design of Phenyl-[hydroxycyclohexyl] Cycloalkyl-Carboxamide Mitofusin Activators with Improved Neuronal Activity
Dang, X., Williams, S. B., Devanathan, S., Franco, A., Fu, L., Bernstein, P. R., Walters, D., & Dorn, G. W. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.1c00163 · Cited by 18
“N-(4-hydroxycyclohexyl)-2-(3-phenylpropyl)cyclopropane-1-carboxamide (5).”
Mitochondrial quality control: a pathophysiological mechanism and potential therapeutic target for chronic obstructive pulmonary disease
Xu, M., Feng, P., Yan, J., & Li, L. (2025) · Frontiers in Pharmacology · doi:10.3389/fphar.2024.1474310 · Cited by 19
The molecular mechanisms of mitochondrial dynamics and mitophagy and their complex association with cancer drug resistance
Zhao, Z., Ren, Y., Yuan, M., Liu, G., & Sun, J. P. (2025) · Journal of Translational Medicine · doi:10.1186/s12967-025-07078-x · Cited by 23
“Moreover, these two proteins have a synergistic effect on the fusion of the OMM [34].”
Physics-based oligomeric models of the yeast mitofusin Fzo1 at the molecular scale in the context of membrane docking
Brandner, A. F., Vecchis, D. D., Baaden, M., Cohen, M. M., & Taly, A. (2019) · Mitochondrion · doi:10.1016/j.mito.2019.06.010 · Cited by 18
Mitofusin 2 but not mitofusin 1 mediates Bcl-XL-induced mitochondrial aggregation
Du, M., Si, Y., Su, W., Zhao, M., Yang, F., Liu, Y., Mai, Z., Wang, Y., Wang, X., & Chen, T. (2020) · Journal of Cell Science · doi:10.1242/jcs.245001 · Cited by 16
Effects of Mitochondrial Dynamics in the Pathophysiology of Obesity
Wang, J., Lin, X., Zhao, N., Dong, G., Wu, W., Huang, K., & Fu, J. (2022) · Frontiers in Bioscience-Landmark · doi:10.31083/j.fbl2703107 · Cited by 16
“On the other hand, mitochondrial dynamin like GTPase optic atrophy 1 (Opa1) leads to the mitochondrial fusion of mitochondrial inner membrane [23], while mitofusin 1 (Mfn1) and mitofusin 2 (Mfn2) are responsible for the fusion of mitochondrial outer membrane [24].”
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)
DOI: 10.1093/jb/mvg150
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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Two Mitofusin Proteins, Mammalian Homologues of FZO, with Distinct Functions Are Both Required for Mitochondrial Fusion

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