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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
In the citing paper
“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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Mitochondrial morphology and function: two for the price of one!
Faitg, J., Davey, T., Turnbull, D. M., White, K., & Vincent, A. E. (2020) · Journal of Microscopy · doi:10.1111/jmi.12891 · Cited by 45
“Furthermore it is now well-established that changes in mitochondrial morphology affect the mitochondrial function and vice versa (Chen et al., 2005; Yu et al., 2006; Jahani-Asl et al., 2007; Chen & Chan, 2009; Romanello et al., 2010; Picard et al., 2013).”
BackgroundZhang, Z., Cui, D., Zhang, T., Sun, Y., & Ding, S. (2020) · Diabetes Metabolic Syndrome and Obesity · doi:10.2147/dmso.s243024 · Cited by 39
Kim, J., & Cheong, J. (2020) · Cells · doi:10.3390/cells9071691 · Cited by 40
Morphological control of mitochondrial bioenergetics
Yoon, Y. (2015) · Frontiers in bioscience · doi:10.2741/4306 · Cited by 41
“Fragmented mitochondria in cells lacking both Mfn1 and Mfn2 showed reduced respiration (110).”
BackgroundBandaru, L. J. M., Ayyalasomayajula, N., Murumulla, L., & Challa, S. (2022) · BioMetals · doi:10.1007/s10534-021-00360-7 · Cited by 39
Mitochondrial Bioenergetics and Dynamics in Secretion Processes
Martínez, J., Marmisolle, I., Tarallo, D., & Quijano, C. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.00319 · Cited by 41
Li, J., Chang, X., Shang, M., Niu, S., Zhang, W., Li, Y., Sun, Z., Wu, T., Kong, L., Zhang, T., et al. (2021) · Nanoscale · doi:10.1039/d1nr02153b · Cited by 38
Axonal Charcot–Marie–Tooth disease
Shy, M. E., & Patzkó, Á. (2011) · Current Opinion in Neurology · doi:10.1097/wco.0b013e32834aa331 · Cited by 38
The role of PTEN-induced kinase 1 in mitochondrial dysfunction and dynamics
Craig, K. J. T., & Cookson, M. (2009) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2009.02.018 · Cited by 37
Kao, S., Yen, M., Wang, A.-G., Yeh, Y.-L., & Lin, A.-L. (2015) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.14-16288 · Cited by 36
Genetic axonal neuropathies and neuronopathies of pre‐natal and infantile onset
Yiu, E. M., & Ryan, M. M. (2012) · Journal of the Peripheral Nervous System · doi:10.1111/j.1529-8027.2012.00412.x · Cited by 37
“It is important for mitochondrial fusion, axonal mitochondrial transport, and tethering of mitochondria to the endoplasmic reticulum (Chen et al., 2005; Baloh et al., 2007; de Brito and Scorrano, 2008).”
BackgroundMitochondria: Signaling with phosphatidic acid
Yang, C., & Frohman, M. A. (2012) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2012.05.006 · Cited by 40
“The heart, for example, elies strongly on oxidative phosphorylation to generate ATP and n this tissue, mitochondria are not fused.”
BackgroundInfluentialHagenbuchner, J., Scholl‐Buergi, S., Karall, D., & Ausserlechner, M. J. (2018) · Scientific Reports · doi:10.1038/s41598-018-21519-2 · Cited by 38
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“The disruption of this delicate balance results in altered mitochondrial fragmentation, mitochondrial membrane potential (MMP) heterogeneity, and apoptosis [16 – 18].”
Identification of a mitofusin specificity region that confers unique activities to Mfn1 and Mfn2
Sloat, S. R., Whitley, B. N., Engelhart, E. A., & Hoppins, S. C. (2019) · Molecular Biology of the Cell · doi:10.1091/mbc.e19-05-0291 · Cited by 41
“This is underscored by the relatively low fusion efficiency of mitochondria that possess solely Mfn1 or Mfn2 (Chen et al., 2003; Chen et al., 2005).”
BackgroundZheng, L., Rao, Z., Guo, Y., Chen, P., & Xiao, W. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.00561 · Cited by 39
Yu, R., Liu, T., Jin, S., Ankarcrona, M., Lendahl, U., Nistér, M., & Zhao, J. (2021) · BMC Biology · doi:10.1186/s12915-021-01161-7 · Cited by 37
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“Two of these, mitofusin 1 (Mfn1) and mitofusin 2 (Mfn2), facilitate outer membrane fusion (Chen et al., 2005; Chen et al., 2003a; Song et al., 2009) whereas optic atrophy 1 (Opa1) is necessary for inner membrane fusion (Chen et al.”
BackgroundInfluentialCharcot-Marie-tooth disease type 2A: An update on pathogenesis and therapeutic perspectives
Alberti, C., Rizzo, F., Anastasia, A., Comi, G. P., Corti, S. P., & Abati, E. (2024) · Neurobiology of Disease · doi:10.1016/j.nbd.2024.106467 · Cited by 39
“Essentially, an excessive level of mitochondrial fragmentation leads to a depletion of mitochondrial DNA (mtDNA) (Chen et al., 2005).”
Wolken, G. G., & Arriaga, E. A. (2014) · Analytical Chemistry · doi:10.1021/ac403849x · Cited by 36
Pendin, D., Filadi, R., & Pizzo, P. (2017) · Frontiers in Oncology · doi:10.3389/fonc.2017.00102 · Cited by 35
“On the same line, inactivation of pro-fusion proteins inhibits oxidative metabolism (24, 25), though the mechanism is not completely clear and may involve unbalanced partitioning of mtDNA.”
BackgroundLee, C. A., Chin, L., & Li, L. (2017) · Protein & Cell · doi:10.1007/s13238-017-0469-4 · Cited by 36
“As reported previously (Chen et al., 2003, 2005), A B C CTRL WT hyrt WT O f M ito (% ) Mito length (μm) <1 >41– 2 2– 3 3– 4 O f M ito (% ) 0 20 40 60 100 80 ** * * * * * * CTRL Trak1 WT Trak1 hyrt <0 .5 0.”
Rossetti, A., Togliatto, G., Rolo, A. P., Teodoro, J. S., Granata, R., Ghigo, E., Columbano, A., Palmeira, C. M., & Brizzi, M. F. (2017) · Cell Death Discovery · doi:10.1038/cddiscovery.2017.77 · Cited by 37
Jeong, H. Y., Kang, J. M., Jun, H. H., Kim, D., Park, S. H., Sung, M. J., Heo, J. H., Yang, D. H., Lee, S. H., & Lee, S. (2018) · Scientific Reports · doi:10.1038/s41598-018-26858-8 · Cited by 37
Cho, S.-G., Xiao, X., Wang, S., Gao, H., Rafikov, R., Black, S. M., Huang, S., Ding, H., Yoon, Y., Kirken, R. A., et al. (2019) · Journal of the American Society of Nephrology · doi:10.1681/asn.2018111117 · Cited by 35
Mitochondrial biology and dysfunction in secondary mitochondrial disease
Baker, M. J., Crameri, J. J., Thorburn, D. R., Frazier, A. E., & Stojanovski, D. (2022) · Open Biology · doi:10.1098/rsob.220274 · Cited by 39
Dirks‐Naylor, A. J., Kouzi, S. A., Bero, J. D., Phan, D. T., Taylor, H. N., Whitt, S. D., & Mabolo, R. (2014) · Fundamental and Clinical Pharmacology · doi:10.1111/fcp.12073 · Cited by 36
Darwesh, A. M., Jamieson, K. L., Wang, C., Samokhvalov, V., & Seubert, J. M. (2018) · Canadian Journal of Physiology and Pharmacology · doi:10.1139/cjpp-2018-0480 · Cited by 35
“Often IR injury is associated with a marked reduction in mitochondrial Opa-1 levels leading to a significant reduction in oxygen consumption rates and cardiomyocyte cell death (Chen et al. 2005; Chen et al. 2009; Le Page et al. 2016).”
Background‘Inside Out’– a dialogue between mitochondria and bacteria
Han, B., Lin, C.-C., Hu, G., & Wang, M. C. (2018) · FEBS Journal · doi:10.1111/febs.14692 · Cited by 37
Maternal transmission of mitochondrial diseases
Chiaratti, M. R., Macabelli, C. H., Neto, J. D. A., Grejo, M. P., Pandey, A. K., Perecin, F., & del Collado, M. (2020) · Genetics and Molecular Biology · doi:10.1590/1678-4685-gmb-2019-0095 · Cited by 37
RNA-Binding Proteins Implicated in Mitochondrial Damage and Mitophagy
Ravanidis, S., & Doxakis, E. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.00372 · Cited by 37
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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