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Disruption of Fusion Results in Mitochondrial Heterogeneity and Dysfunction
Open accessAbstract
Mitochondria undergo continual cycles of fusion and fission, and the balance of these opposing processes regulates mitochondrial morphology. Paradoxically, cells invest many resources to maintain tubular mitochondrial morphology, when reducing both fusion and fission simultaneously achieves the same end. This observation suggests a requirement for mitochondrial fusion, beyond maintenance of organelle morphology. Here, we show that cells with targeted null mutations in Mfn1 or Mfn2 retained low levels of mitochondrial fusion and escaped major cellular dysfunction. Analysis of these mutant cells showed that both homotypic and heterotypic interactions of Mfns are capable of fusion. In contrast, cells lacking both Mfn1 and Mfn2 completely lacked mitochondrial fusion and showed severe cellular defects, including poor cell growth, widespread heterogeneity of mitochondrial membrane potential, and decreased cellular respiration. Disruption of OPA1 by RNAi also blocked all mitochondrial fusion and resulted in similar cellular defects. These defects in Mfn-null or OPA1-RNAi mammalian cells were corrected upon restoration of mitochondrial fusion, unlike the irreversible defects found in fzodelta yeast. In contrast, fragmentation of mitochondria, without severe loss of fusion, did not result in such cellular defects. Our results showed that key cellular functions decline as mitochondrial fusion is progressively abrogated.
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“fibroblasts lacking Mfn1 and Mfn2 completely lack mitochondrial fusion and show severe cellular defects, including poor growth, heterogeneity of mitochondrial membrane potential, and decreased respiration (11).”
From Mitochondrial Fission Contributes to Mitochondrial Dysfunction and Insulin Resistance in Skeletal Muscle (2012) · cites this paper as [11]
In the citing paper
“This is of particular importance since it is now established that mitochondrial morphology and function are interrelated, with changes in mitochondrial morphology affecting mitochondrial function (Chen et al., 2005; Jahani-Asl et al., 2007; Yu et al., 2008; Ong et al., 2010; Gomes et al., 2011) and vice versa (Benard et al., 2007).”
From Effects of Aging and Caloric Restriction on Fiber Type Composition, Mitochondrial Morphology and Dynamics in Rat Oxidative and Glycolytic Muscles (2019) · cites this paper as Chen et al., 2005
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“Repression of Mfn2 in cells decreases oxygen consumption, glucose oxidation, mitochondrial membrane potential and the expression of oxidative phosphorylation proteins (Bach et al., 2003; Chen et al., 2005; Pich et al., 2005).”
From New insights into the role of mitochondria in aging: mitochondrial dynamics and more (2010) · cites this paper as Chen et al., 2005
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“Loss of OPA1 disrupts mitochondrial integrity leading to cytochrome-c release (Olichon et al., 2003) and intriguingly, OPA1 functionally cooperates specifically with MFN1 to mediate the fusion of the inner mitochondrial membrane (Chen et al., 2005; Cipolat et al., 2004).”
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BackgroundMitochondrial morphology controls fatty acid utilization by changing CPT1 sensitivity to malonyl‐CoA
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Mitochondrial fusion is frequent in skeletal muscle and supports excitation–contraction coupling
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“In Mfn1 and Mfn2 2/2, we observed two additional cell populations, on the basis of their mitochondrial morphology (see Figure S4), which we named ‘‘fragmented’’, given that most mitochondria from these cells were spherical (similar percentages as previously reported, [3]) , and ‘‘perinuclear’’, for which almost all mi…”
BackgroundH2O2-induced mitochondrial fragmentation in C2C12 myocytes
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BackgroundMitochondrial dysfunction in glaucoma and emerging bioenergetic therapies
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“Changes in mitochondrial fusion and fission are tightly linked to DJm (Chen et al., 2005; Legros et al., 2002) as well as mitochondrial homogeneity (Chan and Marshall, 2012).”
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BackgroundInfluentialMul1 restrains Parkin-mediated mitophagy in mature neurons by maintaining ER-mitochondrial contacts
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BackgroundMitoguardin regulates mitochondrial fusion through MitoPLD and is required for neuronal homeostasis.
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“…noted elsewhere and above, mitochondria are in a constant state of dynamic flux between fusion and fission events, with mitochondrial respiration and metabolism spatially and temporally regulated by the morphology and positioning of the organelle (Chen et al., 2005; McBride et al., 2006).”
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“We have observed thatmurine embryonic fibroblasts (MEFs) deficient in bothMfn1 andMfn2 (derived fromMfn1/Mfn2 double null mouse embryos [27]) exhibit prolonged doubling times associated with mitochondrial fragmentation, whereas MEFs lacking one or the other Mfn alone have less pronounced mitochondrial morphometric ab-”
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“Mfn1, 2, or OPA1 results in mitochondrial fission and cellular dysfunction.(15,16) Mitochondrial division is a normal physiological process;”
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“PD mouse models exhibit various alterations in dopaminergic neuron function prior to the degeneration of dopaminergic brain areas (Goldberg et al. 2003; Yavich et al. 2004; Chen et al. 2005b).”
BackgroundThe role of mitochondria in neurodegenerative diseases
Filosto, M., Scarpelli, M., Cotelli, M. S., Vielmi, V., Todeschini, A., Gregorelli, V., Tonin, P., Tomelleri, G., & Padovani, A. (2011) · Journal of Neurology · doi:10.1007/s00415-011-6104-z · Cited by 142
“OPA1 should be involved in inner membrane fusion [71, 72].”
Sandoval, H., Yao, C., Chen, K., Jaiswal, M., Donti, T., Lin, Y. Q., Bayat, V., Xiong, B., Zhang, K., David, G., et al. (2014) · eLife · doi:10.7554/elife.03558 · Cited by 143
“…obvious developmental defects at NMJs (Figure 2—source data 2, Figure 3C and Figure 5B) (Drp1 IR knockdown of Drp1 mRNA is 82% using a ubiquitous driver Actin-Gal4), we tested whether loss of Opa1, another fusion protein (Cipolat et al., 2004; Chen et al., 2005), in RGs causes a bouton phenotype.”
BackgroundPi, H., Xu, S., Zhang, L., Guo, P., Li, Y., Xie, J., Tian, L., He, M., Lu, Y., Li, M., et al. (2013) · Autophagy · doi:10.4161/auto.25665 · Cited by 139
“Mitochondrial morphological dynamics are linked to the regulation of many specific cell functions, such as apoptosis regulation,(51-53) Catransfer(45) and mitochondrial quality control.(46) Very recently, mitochondrial morphological changes were revealed to participate in autophagosome biogenesis, but mitochondrial mo…”
BackgroundThe many shapes of mitochondrial death
Cereghetti, G. M., & Scorrano, L. (2006) · Oncogene · doi:10.1038/sj.onc.1209605 · Cited by 140
“…ablation of Opa1 by short interfering RNA has a profound impact on cell viability, causing mitochondrial fragmentation, dissipation of mitochondrial membrane potential, ultrastructural changes and cell death (Olichon et al., 2003; Cipolat et al., 2004; Griparic et al., 2004; Chen et al., 2005).”
BackgroundMechanisms and roles of mitochondrial localisation and dynamics in neuronal function
Seager, R., Lee, L. J., Henley, J. M., & Wilkinson, K. A. (2020) · Neuronal Signaling · doi:10.1042/ns20200008 · Cited by 152
Bess, A. S., Crocker, T. L., Ryde, I. T., & Meyer, J. N. (2012) · Nucleic Acids Research · doi:10.1093/nar/gks532 · Cited by 138
“Loss of fusion capacity increases susceptibility to loss of MP (105), respiratory deficiency (105,106), oxidative stress (61,107), apoptosis and cell death (61,108,109).”
BackgroundCell cycle–dependent regulation of mitochondrial preprotein translocase
Harbauer, A. B., Opalińska, M., Gerbeth, C., Herman, J. S., Rao, S., Schönfisch, B., Guiard, B., Schmidt, O., Pfanner, N., & Meisinger, C. (2014) · Science · doi:10.1126/science.1261253 · Cited by 134
Yan, T., & Zhao, Y. (2019) · Redox Biology · doi:10.1016/j.redox.2019.101381 · Cited by 141
“The balance of fission and fusion is critical for maintaining the normal structure and function of mitochondria [5[12]].”
BackgroundMARF and Opa1 Control Mitochondrial and Cardiac Function in Drosophila
Dorn, G. W., Clark, C. F., Eschenbacher, W. H., Kang, M., Engelhard, J. T., Warner, S. J., Matkovich, S. J., & Jowdy, C. C. (2010) · Circulation Research · doi:10.1161/circresaha.110.236745 · Cited by 139
Hypoxic enlarged mitochondria protect cancer cells from apoptotic stimuli
Chiche, J., Rouleau, M., Gounon, P., Brahimi-Horn, M. C., Pouysségur, J., & Mazure, N. M. (2009) · Journal of Cellular Physiology · doi:10.1002/jcp.21984 · Cited by 139
“Moreover, cells lacking mitochondrial fusion showed changes in mitochondrial shape associated with a loss of their membrane potential, a reduced growth rate, and a lower activity of respiratory complexes (Chen et al., 2005).”
BackgroundPINK1 function in health and disease
Deas, E., Plun‐Favreau, H., & Wood, N. W. (2009) · EMBO Molecular Medicine · doi:10.1002/emmm.200900024 · Cited by 154
“In the case of mfn-1 or mfn-2 knockout mice, cells show severe mitochondrial fragmentation (Chen et al, 2003, 2005).”
BackgroundFrom 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
Mitochondrial fission‐fusion as an emerging key regulator of cell proliferation and differentiation
Mitra, K. (2013) · BioEssays · doi:10.1002/bies.201300011 · Cited by 134
“Consistently, mouse embryonic fibroblasts derived from double knockout of the fusion proteins, MFN1 and 2, have been found to proliferate significantly more slowly than their corresponding wild type counterparts [50].”
BackgroundInfluentialVillavicencio-Tejo, F., & Quintanilla, R. A. (2021) · Antioxidants · doi:10.3390/antiox10071069 · Cited by 143
“Fis1, Mfn1, and Mfn2 are mitochondrial transmembrane proteins placed on the outer mitochondrial membrane [257], while OPA1 is located on the inner mitochondrial membrane [260].”
BackgroundCrosstalk between mitochondrial (dys)function and mitochondrial abundance
Michel, S., Wanet, A., Pauw, A. D., Rommelaere, G., Arnould, T., & Renard, P. (2011) · Journal of Cellular Physiology · doi:10.1002/jcp.23021 · Cited by 138
“Moreover, human MSC also reprogram adult cardiomyocytes into progenitors through partial cell fusion and mitochondria transfer (Acquistapace et al., 2011).”
BackgroundInfluentialMitochondrial-mediated antiviral immunity
Koshiba, T. (2012) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2012.03.005 · Cited by 134
Human NADH:ubiquinone oxidoreductase deficiency: radical changes in mitochondrial morphology?
Koopman, W. J. H., Verkaart, S., Visch, H.-J., Vries, S. E. V. E., Nijtmans, L. G. J., Smeitink, J. A. M., & Willems, P. H. G. M. (2007) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00194.2006 · Cited by 134
“When not appropriately counterbalanced by the cell’s endogenous antioxidant systems (68), ROS can damage proteins like CI, lipids, and mitochondrial DNA, thereby further compromising mitochondrial function (12, 13, 18).”
BackgroundHigh Glucose Disrupts Mitochondrial Morphology in Retinal Endothelial Cells
Trudeau, K. M., Molina, A. J. A., Guo, W., & Roy, S. (2010) · American Journal Of Pathology · doi:10.2353/ajpath.2010.091029 · Cited by 132
Mitoconfusion: Noncanonical Functioning of Dynamism Factors in Static Mitochondria of the Heart
Song, M., & Dorn, G. W. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2014.12.019 · Cited by 128
“…and can interact either homotypically (Mfn1-Mfn1, Mfn2-Mfn2) or heterotypically (Mfn1-Mfn2), although differences in their GTPase activity (Ishihara et al., 2004) likely underlie the modest differences in mitochondrial morphology exhibited by MEFs lacking one or the other Mfn (Chen et al., 2005).”
InfluentialMarques‐Aleixo, I., Oliveira, P. J., Moreira, P. I., Magalhães, J., & Ascensão, A. A. M. R. (2012) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2012.08.002 · Cited by 134
Mitochondrial quality control pathways as determinants of metabolic health
Held, N. M., & Houtkooper, R. H. (2015) · BioEssays · doi:10.1002/bies.201500013 · Cited by 133
Twig, G., Graf, S. A., Wikström, J. D., Mohamed, H., Haigh, S. E., Elorza, Á. A., Deutsch, M., Zurgil, N., Reynolds, N., & Shirihai, O. S. (2006) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00348.2005 · Cited by 129
“Moreover, converting the mitochondrial networks to separate units (fragmentation) has been shown to impair Ca(2) wave propagation through the mitochondrial web (28) and alter the susceptibility of the cell to apoptosis (5, 16, 26).”
BackgroundKumari, S., Mehta, S. L., & Li, P. A. (2012) · PLoS ONE · doi:10.1371/journal.pone.0039382 · Cited by 134
“Mitochondrial fusion regulates calcium buffering capacity, the electron transfer chain (ETC) activity and mitochondrial metabolism [7].”
BackgroundOettinghaus, B., Schulz, J. M., Restelli, L. M., Licci, M., Savoia, C., Schmidt, A., Schmitt, K., Grimm, A., Morè, L., Hench, J., et al. (2015) · Cell Death and Differentiation · doi:10.1038/cdd.2015.39 · Cited by 130
“In addition, elaborate quality-control mechanisms also rely on mitochondrial dynamics: whereas defective organelles are sequestered by fission, enabling their removal from the mitochondrial network,(3,4) fusion supports qualitative homogeneity of the syncytium through complementation.(5) Mitochondrial fusion and fissi…”
Pilsl, A., & Winklhofer, K. F. (2011) · Acta Neuropathologica · doi:10.1007/s00401-011-0902-3 · Cited by 131
Mcl-1 involvement in mitochondrial dynamics is associated with apoptotic cell death
Morciano, G., Giorgi, C., Balestra, D., Marchi, S., Perrone, D., Pinotti, M., & Pinton, P. (2015) · Molecular Biology of the Cell · doi:10.1091/mbc.e15-01-0028 · Cited by 134
“Although mitochondrial fusion has been associated with a healthy cell state because of matrix content exchanges (Chen et al., 2005), it has recently been shown that fusion can also favor cell death (Westrate et al., 2014).”
Oxidative stress-induced mitochondrial fragmentation and movement in skeletal muscle myoblasts
Iqbal, S., & Hood, D. A. (2014) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00017.2014 · Cited by 129
“(10) reported that impaired mitochondrial fusion as a result of mitofusin 1/2 or optic atrophy 1 deficiency resulted in lower rates of respiration (10), resembling the effects found in our H2O2-treated cells.”
BackgroundWang, X., Su, B., Liu, W., He, X., Gao, Y., Castellani, R. J., Perry, G. L., Smith, M. A., & Zhu, X. (2011) · Aging Cell · doi:10.1111/j.1474-9726.2011.00721.x · Cited by 134
“Indeed, cells with fragmented mitochondria because of a deficiency in Mfn1 ⁄ 2 or OPA1 have greatly reduced endogenous and uncoupled respiratory rates caused by compromised electron transport in respiration complexes I, III, and IV (Chen et al., 2005, 2003).”
BackgroundBoscolo, A., Milanović, D., Starr, J. A., Sanchez, V., Oklopcic, A., Moy, L., Ori, C., Erişir, A., & Jevtović‐Todorović, V. (2013) · Anesthesiology · doi:10.1097/aln.0b013e318289bc9b · Cited by 128
Mitochondrial Structure, Function and Dynamics Are Temporally Controlled by c-Myc
Graves, J. A., Wang, Y., Sims‐Lucas, S., Cherok, E., Rothermund, K. D., Branca, M. F., Elster, J. D., Beer–Stolz, D., Houten, B. V., Vockley, J. E., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0037699 · Cited by 128
“The same cells were stained with MitoTrackerH Deep Red which also measures mitochondrial mass, but does so in a manner that is more dependent on the maintenance of mitochondrial membrane potential ([25,37,38]; Figure 2a).”
BackgroundInfluentialRegulation of mitochondrial fission by intracellular Ca2+ in rat ventricular myocytes
Hom, J., Yu, T., Yoon, Y., Porter, G. A., & Sheu, S. (2010) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2010.03.018 · Cited by 130
Alirol, E., James, D. I., Huber, D., Marchetto, A., Vergani, L., Martinou, J., & Scorrano, L. (2006) · Molecular Biology of the Cell · doi:10.1091/mbc.e06-05-0377 · Cited by 128
“Mfn-null and Opa1-RNAi cells display reduced respiration, loss of mitochondrial membrane potential, and inhibition of cell growth (Chen et al., 2005).”
BackgroundMitochondrial Dysfunction—A Pharmacological Target in Alzheimer's Disease
Eckert, G. P., Renner, K., Eckert, S. H., Eckmann, J., Hagl, S., Abdel-Kader, R. M., Kurz, C., Leuner, K., & Muller, W. E. (2012) · Molecular Neurobiology · doi:10.1007/s12035-012-8271-z · Cited by 127
Mitochondrial Dynamics and Peripheral Neuropathy
Baloh, R. H. (2007) · The Neuroscientist · doi:10.1177/1073858407307354 · Cited by 127
Cooper, J. F., Machiela, E., Dues, D. J., Spielbauer, K. K., Senchuk, M. M., & Raamsdonk, J. M. V. (2017) · Scientific Reports · doi:10.1038/s41598-017-16637-2 · Cited by 129
Modulating 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
“2-(2-((5-cyclopropyl-4-phenyl-4H-1,2,4-triazol-3-yl)thio)propanamido) −5,6-dihydro-4H-cyclopenta[b]thiophene-3-carboxamide (8).”
Park, Y.-Y., Nguyen, T. K. O., Kang, H. C., & Cho, H. (2014) · Cell Death and Disease · doi:10.1038/cddis.2014.142 · Cited by 125
“Mitochondrial fusion activity is generally beneficial to cells and it contributes to dilution of mutant mitochondrial DNA and excess ROS.8 In fact, mitochondrial fusion is required for the maintenance of the mitochondrial genome.9 In addition, transient mitochondrial hyperfusion is observed in cells exposed to differe…”
BackgroundInfluentialLiu, W., & Zhou, C. (2012) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2011.12.003 · Cited by 129
“Disruption of fusion results in mitochondrial heterogeneity and dysfunction (Chen et al., 2005).”
BackgroundKuznetsov, A. V., Troppmair, J., Sucher, R., Hermann, M., Saks, V. A., & Margreiter, R. (2006) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2006.03.014 · Cited by 124
“Interestingly, cells with targeted null mutations in Mfn1 or Mfn2 and lacking ability for mitochondrial fusion show high degree of mitochondrial functional heterogeneity [26].”
Marine Natural Product Aurilide Activates the OPA1-Mediated Apoptosis by Binding to Prohibitin
Sato, S., Murata, A., Orihara, T., Shirakawa, T., Suenaga, K., Kigoshi, H., & Uesugi, M. (2011) · Chemistry & Biology · doi:10.1016/j.chembiol.2010.10.017 · Cited by 127
“both of which work together to achieve controlled mitochondrial fusion (Chen et al., 2005; Cipolat et al., 2004; Griparic et al., 2004).”
Background
Metadata
- Authors
- Chen, H., Chomyn, A., & Chan, D. C.
- Affiliations
- California Institute of Technology (US)
- Corresponding author
- Chan, David C.
- ORCID
- Chan, David C.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2005-07
- Volume
- 280
- Issue
- 28
- Pages
- 26185-26192
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2124140045
- Cited by
- 1,376
- References
- 28
- Citations by year
- 2026: 32 · 2025: 53 · 2024: 55 · 2023: 61 · 2022: 63 · 2021: 77 · 2020: 84 · 2019: 79 · 2018: 95 · 2017: 89 · 2016: 56 · 2015: 74 · 2014: 78 · 2013: 70 · 2012: 92
- FWCI
- 15.69
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion)
- Funders
- Muscular Dystrophy Association
- United Mitochondrial Disease Foundation
- National Institutes of Health
- National Institute of General Medical Sciences (GM11726, 1 R01 GM62967-01, R01GM062967)
- 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
- mitochondrial fusion, mitochondrial fission, Mfn1, mitofusin 2, OPA1, mitochondrial heterogeneity, mitochondrial membrane potential, cellular respiration, mitochondrial morphology, mitochondrial dysfunction
- MeSH terms
- Alleles, Animals, Fibroblasts, Genotype, Membrane Potentials, Microscopy, Fluorescence, Mitochondria, Mutation, Oxygen, Oxygen Consumption, Polyethylene Glycols, Recombinant Fusion Proteins, RNA, Time Factors, Blotting, Western, Microscopy, Confocal, GTP Phosphohydrolases, RNA Interference, Cell Proliferation, Green Fluorescent Proteins, Mice
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