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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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“MAMs further play a pivotal role in CMT, caused by mutated Mfn2, which does not only govern mitochondrial fusion but also seems to act as a tether between ER and mitochondria (de Brito and Scorrano 2008; Züchner et al. 2004).”
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“Strikingly, despite their similarity and overlapping functions, and even though Mfn1 and Mfn2 are able to replace one another under certain circumstances, mutations in Mfn2 alone have significant physiological consequences and can result in neurodegenerative diseases such as Charcot-Marie-Tooth Neuropathy type 2A (Tab…”
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“In the experiments reported here, we did not differentiate between OXPHOS- and glycolysis-related ATP production; however, our results would support the hypotheses that the concentrations of OPs evaluated did not compromise m or OXPHOS-dependent ATP production or that they drove mitochondrial fusion to maintain OXPHOS…”
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“Similarly, disruption of OPA1 in mammal cells by RNA interference (RNAi) blocked mitochondrial fusion, leading to poor cell growth and mitochondrial dysfunctions, including decreased mitochondrial membrane potential and reduced cellular respiration [58].”
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“Previous studies have proven that cellular repression of Mfn2 decreases the mitochondrial membrane potential and the cellular rate of glucose oxidation and represses mitochondrial proton leak, all occurring in the absence of changes in coupled respiration [18].”
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“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.”
BackgroundMolecular mechanism of mitochondrial membrane fusion
Griffin, E. E., Detmer, S. A., & Chan, D. C. (2006) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2006.02.003 · Cited by 73
“In addition, Mfn1-null mitochondria can fuse to Mfn2-null mitochondria, suggesting that a trans Mfn1/Mfn2 complex is also fusion-competent [5].”
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“The reduced expression of mitochondrial inner membrane fusion gene Opa1 in OE hearts could be part of the explanation, as Opa1 deficiency confers a mitochondrial dysfunction phenotype as strong as the combined deficiency of Mfn1 and Mfn2 in MEF cells 36 .”
Guo, Y., Wang, Z., Qin, X., Xu, J., Hou, Z., Yang, H., Mao, X., Xing, W., Li, X., Zhang, X., et al. (2018) · Cardiovascular Research · doi:10.1093/cvr/cvy052 · Cited by 73
Mitochondrial fragmentation enables localized signaling required for cell repair
Horn, A. J., Raavicharla, S., Shah, S., Cox, D., & Jaiswal, J. K. (2020) · The Journal of Cell Biology · doi:10.1083/jcb.201909154 · Cited by 73
“MEFs knocked out for Drp1 (Wakabayashi et al., 2009) and Mfn 1/2 (Chen et al., 2005), as well as Drp1 KO HeLa cells (Otera et al., 2016) and MiD49 patient cells (Bartsakoulia et al., 2018), were cultured as previously described.”
MAVS is energized by Mff which senses mitochondrial metabolism via AMPK for acute antiviral immunity
Hanada, Y., Ishihara, N., Wang, L., Otera, H., Ishihara, T., Koshiba, T., Mihara, K., Ogawa, Y., & Nomura, M. (2020) · Nature Communications · doi:10.1038/s41467-020-19287-7 · Cited by 69
Mechanism of PKM2 affecting cancer immunity and metabolism in Tumor Microenvironment
Chen, M., Liu, H., Li, Z., Ming, A. L., & Chen, H. (2021) · Journal of Cancer · doi:10.7150/jca.54430 · Cited by 76
“PKM2 expression can reinforce the utilization of oxygen and synthesis of growth substances in cancer cells by enhancing OXPHOS and the Warburg effect.”
InfluentialSelf-citationMitochondrial Dynamics in Heart Failure
Chen, L., & Knowlton, A. A. (2011) · Congestive Heart Failure · doi:10.1111/j.1751-7133.2011.00255.x · Cited by 73
“Respiration was restored by overexpression of MFN2 (10).”
BackgroundResultInfluentialMitochondrial Motility and Vascular Smooth Muscle Proliferation
Chalmers, S., Saunter, C. D., Wilson, C., Coats, P., Girkin, J. M., & McCarron, J. G. (2012) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.112.255174 · Cited by 74
Trichothecene Mycotoxins Inhibit Mitochondrial Translation—Implication for the Mechanism of Toxicity
Bin-Umer, M. A., McLaughlin, J. E., Basu, D., McCormick, S. P., & Tumer, N. E. (2011) · Toxins · doi:10.3390/toxins3121484 · Cited by 72
“cells show loss of mitochondrial membrane potential (ΔΨM) [29].”
Jou, M. (2008) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2008.06.004 · Cited by 73
Kislin, M., Sword, J., Fomitcheva, I. V., Croom, D., Pryazhnikov, E., Lihavainen, E., Toptunov, D., Rauvala, H., Ribeiro, A. S., Khiroug, L., et al. (2016) · Journal of Neuroscience · doi:10.1523/jneurosci.1510-16.2016 · Cited by 73
“Mitochondria are very dynamic organelles that can move within dendrites to the site of active synapses (Li et al., 2004; Chang et al., 2006) and undergo fusion and fission to maintain optimal morphology to match specific bioenergetic demands (Chen et al., 2005; Parone et al., 2008).”
BackgroundLoss of sirtuin 1 and mitofusin 2 contributes to enhanced ischemia/reperfusion injury in aged livers
Chun, S. K., Lee, S., Flores‐Toro, J., U, R. Y., Yang, M., Go, K. L., Biel, T. G., Miney, C. E., Louis, S. P., Law, B. K., et al. (2018) · Aging Cell · doi:10.1111/acel.12761 · Cited by 72
Mitochondrial alterations during oxidative stress in chronic obstructive pulmonary disease
Jiang, Y., Wang, X., & Hu, D. (2017) · International Journal of COPD · doi:10.2147/copd.s130168 · Cited by 75
Opa1 Is Required for Proper Mitochondrial Metabolism in Early Development
Rahn, J. J., Stackley, K. D., & Chan, S. S. L. (2013) · PLoS ONE · doi:10.1371/journal.pone.0059218 · Cited by 77
“showed that siRNA knockdown of OPA1 in mouse embryonic fibroblasts led to decreased basal respiration [6].”
BackgroundMitochondrial dynamics in the regulation of neuronal cell death
Cheung, E. C., McBride, H. M., & Slack, R. S. (2007) · APOPTOSIS · doi:10.1007/s10495-007-0745-5 · Cited by 70
“As with mitochondrial fission, the fusion machinery also plays an essential role in development and survival [35, 77, 78].”
BackgroundMitochondrial Dynamics and Motility Inside Living Vascular Endothelial Cells: Role of Bioenergetics
Giedt, R. J., Pfeiffer, D. R., Anastasios Matzavinos, A., Kao, C., & Alevriadou, B. R. (2012) · Annals of Biomedical Engineering · doi:10.1007/s10439-012-0568-6 · Cited by 75
Domain Interactions within Fzo1 Oligomers Are Essential for Mitochondrial Fusion
Griffin, E. E., & Chan, D. C. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m601847200 · Cited by 71
Self-citationKou, X., Li, J., Liu, X., Chang, J., Zhao, Q., Jia, S., Fan, J., & Chen, N. (2017) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00018.2017 · Cited by 73
“Although the disrupted dynamic balance of mitochondria is correlated with several physiological and pathological processes of aging and neurodegenerative diseases, the regulatory mechanisms involved in mitochondrial dynamics remain largely unknown (8, 32).”
BackgroundMitofusin 1 and optic atrophy 1 shift metabolism to mitochondrial respiration during aging.
Son, J. M., Sarsour, E. H., Kakkerla Balaraju, A., Fussell, J., Kalen, A. L., Wagner, B. A., Buettner, G. R., & Goswami, P. C. (2017) · Aging Cell · doi:10.1111/acel.12649 · Cited by 71
“Recent evidence suggests that mitochondrial dynamics contributes to mitochondrial respiration (Chen et al., 2005; Zorzano et al., 2010).”
BackgroundResultInfluentialRole of Mitochondria in Alcoholic Liver Disease
García‐Ruiz, C., Kaplowitz, N., & Fernández-Checa, J. C. (2013) · Current Pathobiology Reports · doi:10.1007/s40139-013-0021-z · Cited by 71
“Mitochondrial morphology and dynamics in living cells depend on membrane fusion and fission events, which not only determine the presence of an integrated mitochondrial reticular network or the appearance of dispersed organelles but also allow for the exchange of components from the inner and outer membrane and matrix…”
Mitochondrial death pathways in yeast and mammalian cells
Cheng, W., Leach, K. M., & Hardwick, J. M. (2008) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2008.04.012 · Cited by 73
Li, Z., Peng, Y., Hufnagel, R. B., Hu, Y., Zhao, C., Queme, L. F., Khuchua, Z. A., Driver, A. M., Dong, F., Lu, Q. R., et al. (2017) · Human Molecular Genetics · doi:10.1093/hmg/ddx262 · Cited by 70
Mitochondrial Membrane Dynamics—Functional Positioning of OPA1
Lee, H., & Yoon, Y. (2018) · Antioxidants · doi:10.3390/antiox7120186 · Cited by 73
Mitochondrial trafficking and morphology in neuronal injury
Rintoul, G. L., & Reynolds, I. J. (2009) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2009.09.005 · Cited by 70
“relatively unexplored; are smaller mitochondria functionally different from larger mitochondria? ie Do longer/shorter mitochondria have different membrane potentials, calcium sequestration ability, ATP production or motility? It has been reported that disruption of mitochondrial fusion in MEFs through knockout of Mfn1…”
BackgroundThe Complex Interaction of Mitochondrial Genetics and Mitochondrial Pathways in Psychiatric Disease
Cuperfain, A. B., Zhang, Z. L., Kennedy, J. L., & Gonçalves, V. F. (2018) · Complex Psychiatry · doi:10.1159/000488031 · Cited by 67
Capllonch-Amer, G., Lladó, I., Proenza, A. M., García-Palmer, F. J., & Gianotti, M. (2014) · Journal of Molecular Endocrinology · doi:10.1530/jme-13-0201 · Cited by 67
“…enables mitochondrial recruitment to critical subcellular compartments, mitochondria shape control, content exchange between mitochondria, mitochondrial communication with the cytosol, and mitochondrial quality control (Lee et al. 2004, Chen et al. 2005, 2010, Twig et al. 2008, Liesa et al. 2009).”
BackgroundMesquita, P. H. C., Lamb, D. A., Parry, H. A., Moore, J. H., Smith, M. A., Vann, C. G., Osburn, S. C., Fox, C. D., Ruple, B. A., Huggins, K. W., et al. (2020) · Physiological Reports · doi:10.14814/phy2.14526 · Cited by 66
The modified mitochondrial outer membrane carrier MTCH2 links mitochondrial fusion to lipogenesis
Labbè, K., Mookerjee, S. A., Vasseur, M. L., Gibbs, E., Lerner, C. A., & Nunnari, J. M. (2021) · The Journal of Cell Biology · doi:10.1083/jcb.202103122 · Cited by 70
Antonio Zorzano, A. (2009) · Applied Physiology, Nutrition, and Metabolism · doi:10.1139/h09-049 · Cited by 67
“Deficient activity of complexes I, II, and III is also detected in permeabilized Mfn double knockout cells (Chen et al. 2005).”
BackgroundDinámica mitocondrial: un potencial nuevo blanco terapéutico para la insuficiencia cardiaca
Kuzmicic, J., del Campo, A., López‐Crisosto, C., Morales, P. E., Pennanen, C., Bravo, R., Hechenleitner, J., Zepeda, R. J., Castro, P., Verdejo, H., et al. (2011) · Revista Española de Cardiología · doi:10.1016/j.recesp.2011.05.018 · Cited by 71
The regulation of tumor cell physiology by mitochondrial dynamics
Kashatus, D. F. (2017) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2017.06.192 · Cited by 69
“and excessive fragmentation can result in aneuploidy, DNA damage, disrupted proliferation and loss of normal tissue homeostasis [104-106].”
Metabolic Stress and Disorders Related to Alterations in Mitochondrial Fission or Fusion.
Babbar, M., & Sheikh, M. S. (2013) · PubMed · Cited by 70
Antonio Zorzano, A., Hernández‐Álvarez, M. I., Palacín, M., & Mingrone, G. (2010) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2010.02.017 · Cited by 69
“endogenous respiration, and an incapacity to increase respiration upon the addition of the ionophore 2,4-dinitrophenol [24].”
BackgroundZungu, M., Schisler, J. C., & Willis, M. S. (2011) · Circulation Journal · doi:10.1253/circj.cj-11-0967 · Cited by 66
Mitochondrially-targeted treatment strategies
Bozi, L. H. M., Campos, J. C., Zambelli, V. O., Ferreira, N. D., & Ferreira, J. C. B. (2019) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2019.100836 · Cited by 67
Mitochondrial Dynamics: a Potential New Therapeutic Target for Heart Failure
Kuzmicic, J., del Campo, A., López‐Crisosto, C., Morales, P. E., Pennanen, C., Bravo, R., Hechenleitner, J., Zepeda, R. J., Castro, P., Verdejo, H., et al. (2011) · Revista Española de Cardiología (English Edition) · doi:10.1016/j.rec.2011.05.022 · Cited by 86
“Whereas fusion of the external mitochondrial membrane requires a low concentration of GTP, fusion of the internal membrane requires hydrolysis of GTP and an intact mitochondrial membrane potential (Cmt) and, therefore, high ATP synthesis.33 Recent evidence shows that fusion directly regulates mitochondrial metabolism.…”
BackgroundInfluentialArnold, S., de Araújo, G. W., & Beyer, C. (2008) · Journal of Molecular Endocrinology · doi:10.1677/jme-08-0085 · Cited by 65
“…accepted role of fusion genes in anti-apoptotic processes and fission genes in proliferation and apoptosis (Yaffe 1999, James et al. 2003, Karbowski & Youle 2003, Olichon et al. 2003, Yoon et al. 2003, Lee et al. 2004, Stojanovski et al. 2004, Chen & Chan 2005, Chen et al. 2005, Chan 2007).”
BackgroundMitochondria and the Brain: Bioenergetics and Beyond
Belenguer, P., Duarte, J. M. N., Schuck, P. F., & Ferreira, G. C. (2019) · Neurotoxicity Research · doi:10.1007/s12640-019-00061-7 · Cited by 69
Context-Dependent Role of Mitochondrial Fusion-Fission in Clonal Expansion of mtDNA Mutations
Tam, Z. Y., Gruber, J., Halliwell, B. B., & Gunawan, R. (2015) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1004183 · Cited by 65
“Disruptions to the machinery of mitochondrial fusion-fission have been shown to affect mitochondria-related function, such as the electron transport chain [26] and apoptosis [27], and have been associated with neurodegenerative and metabolic diseases [28].”
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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