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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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InfluentialInnate Immune Pattern Recognition: A Cell Biological Perspective
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BackgroundInfluentialSelf-citationProteasome and p97 mediate mitophagy and degradation of mitofusins induced by Parkin
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InfluentialSelf-citationMitotic phosphorylation of dynamin-related GTPase Drp1 participates in mitochondrial fission.
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“Because the balance between fusion and fission controls mitochondrial morphology, genetic deletion of the fusion genes results in severe fragmentation of the mitochondrial network and abolishes content exchange between mitochondria (Hermann et al., 1998; Chen et al., 2003, 2005).”
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“Mfn1KO cells were used as a primary model since, unlike Opa1KO and Mfn1/2KO MEFs (Chen et al., 2005; Cogliati et al., 2013; Frezza et al., 2006) (Figure S5A), their respiration levels under fed conditions (Figures 5E and 5F) and mitophagy levels under starvation conditions (Figure S5B) were…”
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“Mfn1 (cid:2) / (cid:2) , Mfn2 (cid:2) / (cid:2) , Mfn1/2 (cid:2) / (cid:2) , and Opa1 (cid:2) / (cid:2) were generated as described (Chen et al , 2005; Song et al , 2007).”
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BackgroundBioenergetic role of mitochondrial fusion and fission
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“For example, 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).”
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“N IH -PA Author M anuscript N IH -PA Author M anuscript N IH -PA Author M anuscript MEF cells lacking the mitochondrial fusion proteins Mfn1 and Mfn2 have a mixed population of both healthy and damaged/depolarized mitochondria (Chen et al., 2005).”
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“Although the precise reason for mitochondrial fusion remains unclear, interruption of mitochondrial fusion (via loss of Opa1 or Mfn1/2) leads to loss of mitochondrial potential and diminished oxidative phosphorylation, indicating it is critical for maintaining mitochondrial function (Olichon et al., 2003; Chen et al.,…”
BackgroundInfluentialMitochondrial dysfunction in diabetic kidney disease
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BackgroundMitofusins and OPA1 mediate sequential steps in mitochondrial membrane fusion
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“Mitochondrial fusion protects against mitophagy (4, 45) and is thought to serve a repair function by allowing content mixing and by preventing the accumulation ofmitochondrial damage in cultured cells (46).”
BackgroundEmerging functions of mammalian mitochondrial fusion and fission
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“Oxygen electrode studies demonstrate that both endogenous and uncoupled respiration rates are reduced in Mfn-null cells and even more so in cells depleted of OPA1 by RNAi (OPA1–RNAi) (1).”
BackgroundSelf-citationMitochondrial-nuclear communications
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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).”
BackgroundQuality control of mitochondria: protection against neurodegeneration and ageing
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“In agreement with a protective function of mitochondrial fusion, a decline in respiratory activities has been observed in fusiondeficient murine fibroblasts lacking OPA1 or mitofusins (Chen et al, 2005, 2007).”
BackgroundEnergetics, epigenetics, mitochondrial genetics
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Mitochondrial Fusion is Essential for Organelle Function and Cardiac Homeostasis
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“Consistent with a critical role for mitochondrial fusion in regulating metabolism, inactivation of Mitofusin 1, Mitofusin 2, or Opa-1 inhibits oxidative metabolism and cell growth (68, 69).”
BackgroundMitofusins, from Mitochondria to Metabolism
Schrepfer, E., & Scorrano, L. (2016) · Molecular Cell · doi:10.1016/j.molcel.2016.02.022 · Cited by 504
Terman, A., Kurz, T., Navratil, M., Arriaga, E. A., & Brunk, U. T. (2010) · Antioxidants & Redox Signaling · doi:10.1089/ars.2009.2598 · Cited by 490
“For example, Mfn1 (mitofusin 1) and Mfn2 are closely related mammalian homologues, which play an important role in the fusion of the outer mitochondrial membrane (40, 41).”
InfluentialA common lipid links Mfn-mediated mitochondrial fusion and SNARE-regulated exocytosis
Choi, S., Huang, P., Jenkins, G. M., Chan, D. C., Schiller, J., & Frohman, M. A. (2006) · Nature Cell Biology · doi:10.1038/ncb1487 · Cited by 476
Self-citationMitochondrial Inner-Membrane Fusion and Crista Maintenance Requires the Dynamin-Related GTPase Mgm1
Meeusen, S., DeVay, R. M., Block, J., Cassidy-Stone, A., Wayson, S. M., McCaffery, J. M., & Nunnari, J. M. (2006) · Cell · doi:10.1016/j.cell.2006.09.021 · Cited by 474
Mitochondrial autophagy: molecular mechanisms and implications for cardiovascular disease
Li, A., Gao, M. Q., Liu, B., Qin, Y. H., Chen, L., Liu, H., Wu, H., & Gong, G. (2022) · Cell Death and Disease · doi:10.1038/s41419-022-04906-6 · Cited by 478
“For example, the reduction in fusion caused by OPA1 knockout also helps the elimination of dysfunctional mitochondria [87, 88].”
BackgroundMarsboom, G., Tóth, P. T., Ryan, J. J., Hong, Z., Wu, X., Fang, Y.-H., Thenappan, T., Piao, L. H., Zhang, H. J., Pogoriler, J. E., et al. (2012) · Circulation Research · doi:10.1161/circresaha.111.263848 · Cited by 476
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“Oxidative respiration studies were performed using a Clark oxygen electrode (Oxygraph; Hansatech Instruments, Norfolk, UK) similar to that described previously (Chen et al., 2005).”
MethodDavies, V. J., Hollins, A. J., Piechota, M. J., Yip, W., Davies, J. R., White, K. E., Nicols, P. P., Boulton, M. E., & Votruba, M. (2007) · Human Molecular Genetics · doi:10.1093/hmg/ddm079 · Cited by 449
“These proteins include pro-fusion GTPases: mitofusin (Mfn) 1 and 2; and pro-fission GTPases: dynamin related protein 1 (Drp1) and Fis 1 (17,23).”
BackgroundMitochondrial Dynamics in Regulating the Unique Phenotypes of Cancer and Stem Cells
Chen, H., & Chan, D. C. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.05.016 · Cited by 456
“MFN2, or of OPA1 (Chen et al., 2005) results in severe respiratory chain function, which is likely to be critical for cell differentiation.”
InfluentialSelf-citationMfn2 modulates the UPR and mitochondrial function via repression of PERK
Muñoz, J. P., Ivanova, S., Sánchez‐Wandelmer, J., Martínez‐Cristóbal, P., Noguera, E., Sancho, A., Díaz‐Ramos, A., Hernández‐Alvarez, M. I., Sebastián, D., Mauvezin, C., et al. (2013) · The EMBO Journal · doi:10.1038/emboj.2013.168 · Cited by 451
“All these alterations in mitochondrial function are coherent with previous reports (Bach et al , 2003; Chen et al , 2005; de Brito and Scorrano, 2008).”
SIRT3 Deacetylates and Activates OPA1 To Regulate Mitochondrial Dynamics during Stress
Samant, S. A., Zhang, H. J., Hong, Z., Pillai, V. B., Sundaresan, N. R., Wolfgeher, D., Archer, S. L., Chan, D. C., & Gupta, M. P. (2014) · Molecular and Cellular Biology · doi:10.1128/mcb.01483-13 · Cited by 446
“Consistent with earlier reports (13), OPA1null MEFs had reduced basal OCR, compared to their WT counterpart (Fig.”
BackgroundResultSelf-citationDuvezin‐Caubet, S., Jagasia, R., Wagener, J., Hofmann, S., Trifunović, A., Hansson, A., Chomyn, A., Bauer, M. F., Attardi, G. M., Larsson, N., et al. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m606059200 · Cited by 431
Self-citationHudson, G., Amati-Bonneau, P., Blakely, E. L., Stewart, J. D., He, L., Schaefer, A. M., Griffiths, P. G., Ahlqvist, K., Suomalainen, A., Reynier, P., et al. (2008) · Brain · doi:10.1093/brain/awm272 · Cited by 428
“Like opa 1, mitofusin (mfn) 1 and 2 are pro-fusion dynaminrelated GTPases whose function is balanced by the profission GTPases (Drp1) and Fis1 (Lee et al., 2004; Chen et al., 2005).”
BackgroundThe Layered Structure of Human Mitochondrial DNA Nucleoids
Bogenhagen, D. F., Rousseau, D. L., & Burke, S. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m708444200 · Cited by 426
Mitochondrial OPA1, apoptosis, and heart failure
Chen, L., Gong, Q., Stice, J. P., & Knowlton, A. A. (2009) · Cardiovascular Research · doi:10.1093/cvr/cvp181 · Cited by 435
“In the current study, OPA1 was decreased in the mitochondria in ischaemic HF, and based on the studies in the Drosophila and MEF cells, this might be expected to impair function, consistent with the decrease in ATP levels seen in HF.12,29 To better understand the function of OPA1, further studies are needed on the eff…”
BackgroundResultInfluentialLRRK2 regulates mitochondrial dynamics and function through direct interaction with DLP1
Wang, X., Ma, Y., Fujioka, H., Liu, J., Wilson‐Delfosse, A. L., Chen, S. G., Perry, G. L., Casadesús, G., & Zhu, X. (2012) · Human Molecular Genetics · doi:10.1093/hmg/dds003 · Cited by 437
Mitochondrial quality control: a matter of life and death for neurons
Rugarli, E. I., & Langer, T. (2012) · The EMBO Journal · doi:10.1038/emboj.2012.38 · Cited by 423
“The fusion of mitochondrial membranes allows exchange of genetic material and protects against accumulation of damage (Chen et al , 2005, 2010).”
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“electron transfer chain (ETC; [14]) and to reduce mitochondrial”
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“These alterations are accompanied by decreased cell growth and oxygen consumption, as well as the induction of apoptosis (Arnoult et al., 2005; Chen et al., 2005).”
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Mitochondria: diversity in the regulation of the NLRP3 inflammasome
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“Mice lacking either mitofusin 1 or mitofusin 2 are embryonic lethal, demonstrating the critical roles played by these proteins in vivo [51, 52].”
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Pharmacological approaches to restore mitochondrial function
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Mitochondrial Networking Protects β-Cells From Nutrient-Induced Apoptosis
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“Mitochondrial fusion is promoted by two dynamin-related, outer mitochondrial membrane proteins, mitofusin 1 and 2 (Mfn1 and Mfn2) (66, 68).”
BackgroundKrebiehl, G., Ruckerbauer, S., Burbulla, L. F., Kieper, N., Maurer, B., Waak, J., Wolburg, H., Gizatullina, Z. Z., Gellerich, F. N., Woitalla, D., et al. (2010) · PLoS ONE · doi:10.1371/journal.pone.0009367 · Cited by 381
“In general, the number and morphology of mitochondria is critically regulated by mediators of mitochondrial fission, such as Drp1 and Fis1, and by mediators of mitochondrial fusion, such as OPA1 and mitofusins (Mfn1 and Mfn2) [27].”
BackgroundInfluentialMitochondrial fusion/fission dynamics in neurodegeneration and neuronal plasticity
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“Mitochondrial fusion requires membrane potential, GTP hydrolysis, and the assembling activities of mitofusins 1 and 2 (Mfn-1 and Mfn-2, respectively) and optic atrophy protein 1 (Opa-1) (17, 18, 21, 43, 55, 74).”
BackgroundAxonal neuropathy with optic atrophy is caused by mutations in mitofusin 2
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“Mutations in OPA1 and mitofusins have been shown to disturb the balance between fusion and fission events in the highly dynamic mitochondrial network.(12) Thus, MFN2 is an excellent candidate gene for HSMN VI.”
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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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