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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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The social nature of mitochondria: Implications for human health
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Mitochondrial dynamics following global cerebral ischemia
Kumar, R., Bukowski, M. J., Wider, J. M., Reynolds, C. A., Calo, L., Lepore, B., Tousignant, R. N., Jones, M., Przyklenk, K., & Sanderson, T. H. (2016) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2016.08.010 · Cited by 102
“For example, Drp1 reportedly co-localizes with members of the Bcl-2 family proteins (Bax and tBid) (Arnoult et al., 2005a) at the level of the mitochondria, and blocking this attenuates fission and enhances cell survival (Chen et al., 2005).”
Zeng, K., Wang, J., Wang, L., Guo, Q., Liu, T., Wang, F., Feng, N., Zhang, X., Liao, L., Zhao, M., et al. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-00447-6 · Cited by 105
Vimentin supports mitochondrial morphology and organization
Tang, H. L., Lung, H. L., Wu, K. C., Le, A.-H., Tang, H. M., & Fung, M. C. (2008) · Biochemical Journal · doi:10.1042/bj20071072 · Cited by 101
Regulation of mitochondrial morphology by APC/CCdh1-mediated control of Drp1 stability
Horn, S. R. G.-V., Thomenius, M. J., Johnson, E. S., Freel, C. D., Wu, J. Q., Coloff, J. L., Yang, C., Tang, W., An, J., Ilkayeva, O., et al. (2011) · Molecular Biology of the Cell · doi:10.1091/mbc.e10-07-0567 · Cited by 100
“The persistently fragmented mitochondrial morphology that results in the absence of Cdh1-mediated Drp1 degradation (and the subsequent decreases in cyclin E and alterations in lipid-derived metabolites) may have cumulative deleterious effects on mitochondrial function, comparable to the severe defects in cell growth,…”
BackgroundThyroid hormones and mitochondria: With a brief look at derivatives and analogues
Cioffi, F., Senese, R., Lanni, A., & Goglia, F. (2013) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2013.06.006 · Cited by 100
“…outer mitochondrial membrane and form homo- and heterooligomeric complexes between apposing mitochondria (Koshiba et al., 2004; Meeusen et al., 2004; Chen et al., 2005; Detmer in the regulation of mitochondrial functions (biogenesis, oxygen consumption, and plasma membrane into the cytoplasm…”
Mitochondrial membrane dynamics, cristae remodelling and apoptosis
Heath-Engel, H. M., & Shore, G. C. (2006) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2006.02.006 · Cited by 104
“Downregulation of mitofilin 1 affects cristae morphology without a concomitant effect on fission/fusion [107], while OPA1 is involved in both maintenance of IMM structure and in the fusion process [35,49,50,58,61,62,68,69].”
Regulation of mitochondrial dynamics: convergences and divergences between yeast and vertebrates
Zhao, J., Lendahl, U., & Nistér, M. (2012) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-012-1066-6 · Cited by 105
“Mfn1 and Mfn2 are required for outer-membrane fusion, and Mfn1/2-null embryonic fibroblast cell lines (lacking both Mfn1 and 2) display a loss of fusion-competence and a fragmented mitochondrial phenotype [119].”
BackgroundInfluentialMitochondria in heart failure: the emerging role of mitochondrial dynamics
Marín-García, J., Akhmedov, A. T., & Moe, G. W. P. L. (2012) · Heart Failure Reviews · doi:10.1007/s10741-012-9330-2 · Cited by 105
“Reduction in either MFN1 or 2 can be compensated in part by the other MFN protein, suggesting the existence of overlap in their function [87].”
BackgroundJežek, P., & Plecitá‐Hlavatá, L. (2009) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2009.02.014 · Cited by 106
Kumari, S., Anderson, L., Farmer, S., Mehta, S. L., & Li, P. A. (2012) · Translational Stroke Research · doi:10.1007/s12975-012-0158-9 · Cited by 100
Tanaka, A. (2010) · FEBS Letters · doi:10.1016/j.febslet.2010.02.060 · Cited by 100
“(d) Mitochondria in MEF cells derived from Mfn1 / , Mfn2 / [53] mice, which are showing heterogenic mitochondrial membrane potential.”
BackgroundLackner, L. L., & Nunnari, J. M. (2010) · Chemistry & Biology · doi:10.1016/j.chembiol.2010.05.016 · Cited by 101
“…mitochondrial fusion in mammalian cells can rescue the longer term defects associated with loss of fusion: decreased ology 17, June 25, 2010 ª2010 Elsevier Ltd All rights reserved 581 respiratory capacity, reduction in mtDNA levels, and increased rates of mtDNA mutation (Chen et al., 2005, 2010).”
BackgroundHasnat, M., Yuan, Z., Naveed, M., Asifullah, K., Raza, F., Xu, D., Ullah, A., Sun, L., Zhang, L., & Jiang, Z. (2018) · Cell Biology and Toxicology · doi:10.1007/s10565-018-9447-8 · Cited by 100
Calì, C., Agus, M., Kare, K., Boges, D. J., Lehväslaiho, H., Hadwiger, M., & Magistretti, P. J. (2019) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2019.101696 · Cited by 99
Béraud, N., Pelloux, S., Usson, Y., Kuznetsov, A. V., Ronot, X., Tourneur, Y., & Saks, V. A. (2009) · Journal of Bioenergetics and Biomembranes · doi:10.1007/s10863-009-9214-x · Cited by 105
“Many recent works have shown that mitochondrial fusion and fission are potentially important for cell differentiation and pathophysiology (Yaffe 1999; Dimmer and Scorrano 2006; Kuznetsov 2007; Chan 2006; Chen et al. 2005; Benard and Rossignol 2008; Karbowski and Youle 2003; Twig et al. 2008a, b).”
BackgroundMuscle choline kinase beta defect causes mitochondrial dysfunction and increased mitophagy
Mitsuhashi, S., Hatakeyama, H., Karahashi, M., Koumura, T., Nonaka, I., Hayashi, Y. K., Noguchi, S., Sher, R. B., Nakagawa, Y., Manfredi, G., et al. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddr305 · Cited by 95
“Disequilibrium of mitochondrial fusion and fission can cause alterations of mitochondrial morphology with mitochondrial dysfunction (9,10).”
BackgroundHeart Failure and Mitochondrial Dysfunction
Knowlton, A. A., Chen, L., & Malik, Z. A. (2013) · Journal of Cardiovascular Pharmacology · doi:10.1097/01.fjc.0000432861.55968.a6 · Cited by 100
“Correspondingly, Mfn2 is upregulated in conditions of high-energy demand, such as exercise, and in response to proapoptotic stimuli.(59) Thus, mitochondrial fusion and Mfn1/2 have important effects on mitochondrial energetics and respiration.”
BackgroundInfluentialYoshinaka, T., Kosako, H., Yoshizumi, T., Furukawa, R., Hirano, Y., Kuge, O., Tamada, T., & Koshiba, T. (2019) · iScience · doi:10.1016/j.isci.2019.08.056 · Cited by 96
Ushio‐Fukai, M., Ash, D., Nagarkoti, S., de Chantemèle, E. J. B., Fulton, D. J., & Fukai, T. (2021) · Antioxidants and Redox Signaling · doi:10.1089/ars.2020.8161 · Cited by 99
“Loss of Mfn2 reduces mitochondrial membrane potential, O 2 consumption, and activity of the ETC and the TCA cycle whereas anaerobic respiration increases as a compensatory mechanism (44, 241).”
Mitochondrial dysfunction in glaucoma: Understanding genetic influences
Lascaratos, G., Garway‐Heath, D. F., Willoughby, C. E., Chau, K., & Schapira, A. H. V. (2011) · Mitochondrion · doi:10.1016/j.mito.2011.11.004 · Cited by 97
Mitochondrial fusion provides an ‘initial metabolic complementation’ controlled by mtDNA
Yang, L., Long, Q., Liu, J., Tang, H., Li, Y., Bao, F., Qin, D., Pei, D., & Liu, X. (2015) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-015-1863-9 · Cited by 95
“Defects in mitochondrial fusion can result in heterogeneity in (DWm) and mtDNA nucleoids, which encode components of the electron transport chain [21].”
BackgroundMechanistic perspective of mitochondrial fusion: Tubulation vs. fragmentation
Escobar‐Henriques, M., & den Brave, F. (2012) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2012.07.016 · Cited by 100
“Only simultaneous deletion of Mfn1 and Mfn2 completely inhibits mitochondrial OM fusion, clearly demonstrating their redundant nature.”
InfluentialXu, L., Wu, Z., He, Y., Chen, Z., Xu, K., Yu, W., Fang, W., Ma, C., Moqbel, S. A. A., Ran, J., et al. (2020) · Osteoarthritis and Cartilage · doi:10.1016/j.joca.2019.11.011 · Cited by 87
Mitofusin gain and loss of function drive pathogenesis in Drosophila models of CMT2A neuropathy
Fissi, N. E., Rojo, M., Aouane, A., Karataş, E., Poliacikova, G., David, C., Royet, J., & Rival, T. (2018) · EMBO Reports · doi:10.15252/embr.201745241 · Cited by 96
Giant mitochondria do not fuse and exchange their contents with normal mitochondria
Navratil, M., Terman, A., & Arriaga, E. A. (2007) · Experimental Cell Research · doi:10.1016/j.yexcr.2007.09.013 · Cited by 94
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Vallat, J., Ouvrier, R., Pollard, J. D., Magdelaine, C., Zhu, D., Nicholson, G. A., Grew, S., Ryan, M. M., & Funalot, B. (2008) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e31818b6cbc · Cited by 98
Inácio, Â. S., Costa, G. N., Domingues, N. S., Santos, M. S., Moreno, A. J., Vaz, W. L. C., & Vieira, O. V. (2013) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.02437-12 · Cited by 93
“Although the physiological significance of the dynamics of mitochondrial morphology is not completely understood, there is growing evidence to suggest that these dynamics, regulated by fission and fusion events, reflects mitochondrial energetic status (33, 34), and is crucial for key cellular functions (31, 35).”
BackgroundDynamin-Related Protein 1 at the Crossroads of Cancer
Lima, A. R., Santos, L., Correia, M., Soares, P., Sobrinho-Simões, M. A., Melo, M., & Máximo, V. (2018) · Genes · doi:10.3390/genes9020115 · Cited by 96
Kondadi, A. K., Anand, R., & Reichert, A. S. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20174311 · Cited by 94
“Also, depletion of Mfn1, Mfn2, Opa1 or Mfn1 & Mfn2 together in MEFs clearly showed loss of mitochondrial nucleoids when compared to control MEFs [150] which could have accounted for loss of membrane potential, decreased growth rates, and reduced mitochondrial oxygen consumption [151].”
BackgroundScheffer, D. D. L., Garcia, A. A., Lee, L., Mochly‐Rosen, D., & Ferreira, J. C. B. (2022) · Antioxidants and Redox Signaling · doi:10.1089/ars.2021.0145 · Cited by 96
“Mitofusins are responsible for regulating many cellular processes, including mitochondrial number and morphology (12, 40), biogenesis (152), calcium homeostasis (27), protein turnover (35), and apoptosis (118).”
Galloway, C. A., Lee, H., Nejjar, S., Jhun, B. S., Yu, T., Hsu, W., & Yoon, Y. (2012) · Diabetes · doi:10.2337/db11-1640 · Cited by 92
“Previous studies with cell lines indicated that mitochondria become dysfunctional upon knockout or knockdown of fusion or fission proteins (35,36).”
BackgroundFu, H., Zhou, H., Yu, X., Xu, J., Zhou, J., Meng, X., Zhao, J., Zhou, Y., Chisholm, A. D., & Xu, S. (2020) · Nature Communications · doi:10.1038/s41467-020-14885-x · Cited by 91
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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