Inhibition of mitochondrial fission favours mutant over wild-type mitochondrial DNA
Abstract
Biased segregation of mitochondrial DNA variants has been widely documented, but little was known about its molecular basis. We set out to test the hypothesis that altering the balance between mitochondrial fusion and fission could influence the segregation of mutant and wild-type mtDNA variants, because it would modify the number of organelles per cell. Therefore human cells heteroplasmic for the pathological A3243G mitochondrial DNA mutation were transfected with constructs designed to silence Drp1 or hFis1, whose gene products are required for mitochondrial fission. Drp1 and hFis1 gene silencing were both associated with increased levels of mutant mitochondrial DNA. Thus, the extent of the mitochondrial reticular network appears to be an important factor in determining mutant load. The fact that the level of mutant and wild-type mitochondrial DNA can be manipulated by altering the expression of nuclear encoded factors involved in mitochondrial fission suggests new interventions for mitochondrial DNA disorders.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Silencing of Drp1 and Fis1 genes in a human cell line heteroplasmic for a pathological mtDNA mutation increases the levels of mutant mtDNA compared with wild-type mtDNA.
“Silencing of Drp1 and Fis1 genes in a human cell line heteroplasmic for a pathological mtDNA mutation increased the levels of mutant mtDNA compared with wild-type mtDNA (Malena et al., 2009).”
From New insights into the role of mitochondria in aging: mitochondrial dynamics and more (2010) · cites this paper as Malena et al., 2009
Cites
Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans
Fire, A., Xu, S., Montgomery, M. K., Kostas, S. A., Driver, S. E., & Mello, C. C. (1998) · Nature · doi:10.1038/35888 · Cited by 15,429 · see citing works
Parkin is recruited selectively to impaired mitochondria and promotes their autophagy
Narendra, D., Tanaka, A., Suen, D.-F., & Youle, R. J. (2008) · The Journal of Cell Biology · doi:10.1083/jcb.200809125 · Cited by 4,026 · see citing works
Mitochondrial free radical generation, oxidative stress, and aging
Cadenas, E., & Davies, K. J. A. (2000) · Free Radical Biology and Medicine · doi:10.1016/s0891-5849(00)00317-8 · Cited by 3,010 · see citing works
Mitofusin 2 tethers endoplasmic reticulum to mitochondria
de Brito, O. M., & Scorrano, L. (2008) · Nature · doi:10.1038/nature07534 · Cited by 2,442 · see citing works
Mitochondrial DNA mutation associated with Leber’s hereditary optic neuropathy
Wallace, D. C., Singh, G., Lott, M. T., Hodge, J. A., Schurr, T. G., Lezza, A. M. S., Elsas, L. J., & Nikoskelainen, E. K. (1988) · Science · doi:10.1126/science.3201231 · Cited by 2,440 · see citing works
Goto, Y.-I., Nonaka, I., & Horai, S. (1990) · Nature · doi:10.1038/348651a0 · Cited by 2,070 · see citing works
OPA1 Controls Apoptotic Cristae Remodeling Independently from Mitochondrial Fusion
Frezza, C., Cipolat, S., Martins de Brito, O., Micaroni, M., Beznoussenko, G. V., Rudka, T., Bartoli, D., Polishuck, R. S., Danial, N. N., De Strooper, B., et al. (2006) · Cell · doi:10.1016/j.cell.2006.06.025 · Cited by 1,673 · see citing works
Human Cells Lacking mtDNA: Repopulation with Exogenous Mitochondria by Complementation
King, M. P., & Attardi, G. M. (1989) · Science · doi:10.1126/science.2814477 · Cited by 1,659 · see citing works
Gene silencing in mammals by small interfering RNAs
McManus, M. T., & Sharp, P. A. (2002) · Nature Reviews Genetics · doi:10.1038/nrg908 · Cited by 1,400 · see citing works
Oxidant signals and oxidative stress
Finkel, T. (2003) · Current Opinion in Cell Biology · doi:10.1016/s0955-0674(03)00002-4 · Cited by 1,393 · see citing works
Human cells lacking mtDNA: repopulation with exogenous mitochondria by complementation
(1990) · Trends in Genetics · doi:10.1016/0168-9525(90)90040-d · Cited by 1,386 · see citing works
Disruption of Fusion Results in Mitochondrial Heterogeneity and Dysfunction
Chen, H., Chomyn, A., & Chan, D. C. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m503062200 · Cited by 1,376 · see citing works
OPA1 requires mitofusin 1 to promote mitochondrial fusion
Cipolat, S., de Brito, O. M., Dal Zilio, B., & Scorrano, L. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0407043101 · Cited by 1,300 · see citing works
van den Ouweland, J. M. W., Lemkes, H. H. P. J., Ruitenbeek, W., Sandkuijl, L. A., de Vijlder, M. F., Struyvenberg, P. A. A., van de Kamp, J. J. P., & Maassen, J. A. (1992) · Nature Genetics · doi:10.1038/ng0892-368 · Cited by 1,127 · see citing works
Roles of the mammalian mitochondrial fission and fusion mediators Fis1, Drp1, and Opa1 in apoptosis
Lee, Y.-J., Jeong, S.-Y., Karbowski, M., Smith, C. L., & Youle, R. J. (2004) · Molecular Biology of the Cell · doi:10.1091/mbc.e04-04-0294 · Cited by 1,042 · see citing works
Mitochondrial fusion protects against neurodegeneration in the cerebellum
Chen, H., McCaffery, J. M., & Chan, D. C. (2007) · Cell · doi:10.1016/j.cell.2007.06.026 · Cited by 924 · see citing works
Mitofusin-2 Determines Mitochondrial Network Architecture and Mitochondrial Metabolism
Bach, D., Pich, S., Soriano, F. X., Vega, N., Baumgartner, B., Oriola, J., Daugaard, J. R., Lloberas, J., Camps, M., Zierath, J. R., et al. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m212754200 · Cited by 832 · see citing works
The Machines that Divide and Fuse Mitochondria
Hoppins, S., Lackner, L., & Nunnari, J. (2007) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.76.071905.090048 · Cited by 790 · see citing works
Cipolat, S., Rudka, T., Hartmann, D., Costa, V., Serneels, L., Craessaerts, K., Metzger, K., Frezza, C., Annaert, W. G., D'adamio, L., et al. (2006) · Cell · doi:10.1016/j.cell.2006.06.021 · Cited by 735 · see citing works
Frank-Kamenetsky, M. D., Grefhorst, A., Anderson, N. N., Racie, T., Bramlage, B., Akinc, A., Butler, D., Charissé, K., Dorkin, J. R., Fan, Y., et al. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0805434105 · Cited by 635 · see citing works
Jenuth, J. P., Peterson, A. C., Fu, K., & Shoubridge, E. A. (1996) · Nature Genetics · doi:10.1038/ng1096-146 · Cited by 591 · see citing works
Hayashi, J., Ohta, S., Kikuchi, A., Takemitsu, M., Goto, Y., & Nonaka, I. (1991) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.88.23.10614 · Cited by 552 · see citing works
Strong Purifying Selection in Transmission of Mammalian Mitochondrial DNA
Stewart, J. B., Freyer, C., Elson, J. L., Wredenberg, A., Cansu, Z., Trifunović, A., & Larsson, N. (2008) · PLoS Biology · doi:10.1371/journal.pbio.0060010 · Cited by 525 · see citing works
OPA1 mutations induce mitochondrial DNA instability and optic atrophy 'plus' phenotypes
Amati-Bonneau, P., Valentino, M. L., Reynier, P., Gallardo, M. E., Bornstein, B., Boissiere, A., Campos, Y., Rivera, H., de la Aleja, J. G., Carroccia, R., et al. (2008) · Brain · doi:10.1093/brain/awm298 · Cited by 520 · see citing works
A mouse model of mitochondrial disease reveals germline selection against severe mtDNA mutations
Fan, W., Waymire, K. G., Narula, N., Li, P., Rocher, C., Coskun, P. E., Vannan, M. A., Narula, J., MacGregor, G. R., & Wallace, D. C. (2008) · Science · doi:10.1126/science.1147786 · Cited by 466 · see citing works
Hudson, 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 · see citing works
Coupled Leading- and Lagging-Strand Synthesis of Mammalian Mitochondrial DNA
Holt, I. J., Lorimer, H. E., & Jacobs, H. T. (2000) · Cell · doi:10.1016/s0092-8674(00)80688-1 · Cited by 418 · see citing works
Self-citationParone, P. A., Da Cruz, S., Tondera, D., Mattenberger, Y., James, D. I., Maechler, P., Barja, F., & Martinou, J.-C. (2008) · PLoS ONE · doi:10.1371/journal.pone.0003257 · Cited by 415 · see citing works
Tissue-specific selection for different mtDNA genotypes in heteroplasmic mice
Jenuth, J. P., Peterson, A. C., & Shoubridge, E. A. (1997) · Nature Genetics · doi:10.1038/ng0597-93 · Cited by 415 · see citing works
Inoue, K., Nakada, K., Ogura, A., Isobe, K., Goto, Y., Nonaka, I., & Hayashi, J.-I. (2000) · Nature Genetics · doi:10.1038/82826 · Cited by 393 · see citing works
Herlan, M., Vogel, F., Bornhövd, C., Neupert, W., & Reichert, A. S. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m211311200 · Cited by 378 · see citing works
Moreno‐Loshuertos, R., Acín‐Pérez, R., Fernández‐Silva, P., Movilla, N., Martos, A. P., de Córdoba, S. R., Gallardo, M. E., & Enrı́quez, J. A. (2006) · Nature Genetics · doi:10.1038/ng1897 · Cited by 325 · see citing works
Yoneda, M., Chomyn, A., Martinuzzi, A., Hurko, O., & Attardi, G. M. (1992) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.89.23.11164 · Cited by 291 · see citing works
Boldogh, I., Nowakowski, D. W., Yang, H.-C., Chung, H., Karmon, S., Royes, P., & Pon, L. (2003) · Molecular Biology of the Cell · doi:10.1091/mbc.e03-04-0225 · Cited by 283 · see citing works
Regulation of mitochondrial fusion and division
Cerveny, K. L., Tamura, Y., Zhang, Z., Jensen, R. E., & Sesaki, H. (2007) · Trends in Cell Biology · doi:10.1016/j.tcb.2007.08.006 · Cited by 261 · see citing works
The inheritance of mitochondrial DNA heteroplasmy: random drift, selection or both?
Chinnery, P. F., Thorburn, D. R., Samuels, D. C., White, S. L., Dahl, H.-H. M., Turnbull, D. M., Lightowlers, R. N., & Howell, N. (2000) · Trends in Genetics · doi:10.1016/s0168-9525(00)02120-x · Cited by 253 · see citing works
Yasukawa, T., Reyes, A., Cluett, T. J., Yang, M., Bowmaker, M., Jacobs, H. T., & Holt, I. J. (2006) · The EMBO Journal · doi:10.1038/sj.emboj.7601392 · Cited by 251 · see citing works
Self-citationHe, J., Mao, C.-C., Reyes, A., Sembongi, H., Re, M. D., Granycome, C., Clippingdale, A. B., Fearnley, I. M., Harbour, M. E., Robinson, A. J., et al. (2007) · The Journal of Cell Biology · doi:10.1083/jcb.200609158 · Cited by 241 · see citing works
Self-citationHess, J. F., Parisi, M. A., Bennett, J. L., & Clayton, D. A. (1991) · Nature · doi:10.1038/351236a0 · Cited by 234 · see citing works
Hobbs, A. E. A., Srinivasan, M., McCaffery, J., & Jensen, R. (2001) · Journal of Cell Biology · doi:10.1083/jcb.152.2.401 · Cited by 223 · see citing works
Minczuk, M. A., Papworth, M. A., Miller, J. C., Murphy, M. P., & Klug, A. (2008) · Nucleic Acids Research · doi:10.1093/nar/gkn313 · Cited by 215 · see citing works
Random genetic drift determines the level of mutant mtDNA in human primary oocytes
Brown, D. T., Samuels, D. C., Michael, E. M., Turnbull, D. M., & Chinnery, P. F. (2001) · The American Journal of Human Genetics · doi:10.1086/318190 · Cited by 196 · see citing works
Dunbar, D. R., Moonie, P., Jacobs, H. T., & Holt, I. J. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.14.6562 · Cited by 193 · see citing works
Self-citationManipulating mitochondrial DNA heteroplasmy by a mitochondrially targeted restriction endonuclease
Srivastava, S. (2001) · Human Molecular Genetics · doi:10.1093/hmg/10.26.3093 · Cited by 187 · see citing works
Evidence for a two membrane–spanning autonomous mitochondrial DNA replisome
Meeusen, S., & Nunnari, J. M. (2003) · The Journal of Cell Biology · doi:10.1083/jcb.200304040 · Cited by 177 · see citing works
Suzuki, M., Jeong, S.-Y., Karbowski, M., Youle, R. J., & Tjandra, N. (2003) · Journal of Molecular Biology · doi:10.1016/j.jmb.2003.09.064 · Cited by 161 · see citing works
Clinical aspects of mitochondrial disorders
Münnich, A., Rustin, P., Rötig, A., Chrétien, D., Bonnefont, J., Nuttin, C., Cormier‐Daire, V., Vassault, A. J., Parvy, P., Bardet, J., et al. (1992) · Journal of Inherited Metabolic Disease · doi:10.1007/bf01799603 · Cited by 154 · see citing works
Youngman, M. J., Hobbs, A. E. A., Burgess, S. M., Srinivasan, M., & Jensen, R. E. (2004) · The Journal of Cell Biology · doi:10.1083/jcb.200308012 · Cited by 148 · see citing works
Hyvärinen, A. K., Pohjoismäki, J., Reyes, A., Wanrooij, S., Yasukawa, T., Karhunen, P. J., Spelbrink, J. N., Holt, I. J., & Jacobs, H. T. (2007) · Nucleic Acids Research · doi:10.1093/nar/gkm676 · Cited by 132 · see citing works
Self-citationHori, A., Yoshida, M., Shibata, T., & Ling, F. (2008) · Nucleic Acids Research · doi:10.1093/nar/gkn993 · Cited by 129 · see citing works
Bourgeron, T., Chrétien, D., Rötig, A., Münnich, A., & Rustin, P. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)36524-x · Cited by 103 · see citing works
A tRNA suppressor mutation in human mitochondria
Meziane, A. E., Lehtinen, S. K., Hance, N., Nijtmans, L. G. J., Dunbar, D. R., Holt, I. J., & Jacobs, H. T. (1998) · Nature Genetics · doi:10.1038/ng0498-350 · Cited by 101 · see citing works
Self-citationHolt, I. J. (1997) · Human Molecular Genetics · doi:10.1093/hmg/6.8.1251 · Cited by 99 · see citing works
Self-citationKasahara, A., Ishikawa, K., Yamaoka, M., Ito, M., Watanabe, N., Akimoto, M., Sato, A., Nakada, K., Endo, H., Suda, Y., et al. (2006) · Human Molecular Genetics · doi:10.1093/hmg/ddl005 · Cited by 75 · see citing works
Jofuku, A., Ishihara, N., & Mihara, K. (2005) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2005.05.154 · Cited by 73 · see citing works
DELETIONS OF MUSCLE MITOCHONDRIAL DNA
Holt, I. J., Cooper, J. M., MORGAN-HUGHES, J. A., et al. (1988) · The Lancet · doi:10.1016/s0140-6736(88)92273-8 · Cited by 73 · see citing works
Self-citationThyroid hemiagenesis and elevated thyrotropin levels in a child with Williams syndrome
Cammareri, V., Vignati, G., Nocera, G., Beck‐Peccoz, P., & Persani, L. (1999) · American Journal of Medical Genetics · doi:10.1002/(sici)1096-8628(19990827)85:5 · Cited by 41 · see citing works
Cultured muscle cells display defects of mitochondrial myopathy ameliorated by anti-oxidants
Vergani, L., Malena, A., Sabatelli, P., Loro, E., Cavallini, L., Magalhães, P. M. R., Valente, L., Bragantini, F., Carrara, F., Léger, B., et al. (2007) · Brain · doi:10.1093/brain/awm151 · Cited by 13 · see citing works
Self-citationVergani, L., Prescott, A. R., & Holt, I. J. (2000) · Neuromuscular Disorders · doi:10.1016/s0960-8966(00)00096-1 · Cited by 12 · see citing works
Self-citationSembongi, H., Re, M. D., Bokori‐Brown, M., & Holt, I. J. (2007) · Human Molecular Genetics · doi:10.1093/hmg/ddm182 · Cited by 11 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Mitochondrial DNA stress primes the antiviral innate immune response
West, A. P., Khoury-Hanold, W., Staron, M., Tal, M. C., Pineda, C. M., Lang, S. M., Bestwick, M., Duguay, B. A., Raimundo, N., MacDuff, D. A., et al. (2015) · Nature · doi:10.1038/nature14156 · Cited by 1,975 · see citing works
Mitochondrial dynamics and apoptosis
Suen, D.-F., Norris, K. L., & Youle, R. J. (2008) · Genes & Development · doi:10.1101/gad.1658508 · Cited by 1,270 · see citing works
Haem oxygenase is synthetically lethal with the tumour suppressor fumarate hydratase
Frezza, C., Zheng, L., Folger, O., Rajagopalan, K. N., MacKenzie, E. D., Jerby, L., Micaroni, M., Chaneton, B., Adam, J., Hedley, A., et al. (2011) · Nature · doi:10.1038/nature10363 · Cited by 503 · see citing works
New insights into the role of mitochondria in aging: mitochondrial dynamics and more
Seo, A. Y., Joseph, A.-M., Dutta, D., Hwang, J. C. Y., Aris, J. P., & Leeuwenburgh, C. (2010) · Journal of Cell Science · doi:10.1242/jcs.070490 · Cited by 522 · see citing works
DeBalsi, K. L., Hoff, K. E., & Copeland, W. C. (2017) · Ageing Research Reviews · doi:10.1016/j.arr.2016.04.006 · Cited by 180 · see citing works
Spelbrink, J. N. (2010) · IUBMB Life · doi:10.1002/iub.282 · Cited by 171 · see citing works
Busch, K. B., Kowald, A., & Spelbrink, J. N. (2014) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2013.0442 · Cited by 87 · see citing works
Kasashima, K., Sumitani, M., & Endo, H. (2011) · Experimental Cell Research · doi:10.1016/j.yexcr.2010.10.008 · Cited by 54 · see citing works
De Toni, L., Strapazzon, G., Gianesello, L., Caretta, N., Pilon, C., Bruttocao, A., & Foresta, C. (2011) · Journal of Endocrinological Investigation · doi:10.1007/bf03346724 · Cited by 25 · see citing works
- Authors
- Malena, A., Loro, E., Di Re, M., Holt, I. J., & Vergani, L.
- Affiliations
- University of Padua (IT)
- MRC Mitochondrial Biology Unit (GB)
- Corresponding author
- Holt, Ian J.
- Vergani, Lodovica
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2009-06-27
- Volume
- 18
- Issue
- 18
- Pages
- 3407-3416
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2131594084
- Cited by
- 107
- References
- 60
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 12 · 2023: 2 · 2022: 8 · 2021: 7 · 2020: 8 · 2019: 7 · 2018: 2 · 2017: 5 · 2016: 5 · 2015: 6 · 2014: 4 · 2013: 9 · 2012: 9
- FWCI
- 3.47
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Padua Research Archive (University of Padova) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › ATP Synthase and ATPases Research
- Keywords
- mitochondrial fission, mitochondrial fusion, mitochondrial DNA segregation, heteroplasmy, A3243G mutation, Drp1, gene silencing, mitochondrial DNA disorders
- MeSH terms
- Base Sequence, DNA, Mitochondrial, Humans, Membrane Proteins, Mitochondria, Molecular Sequence Data, Mutation, Down-Regulation, Gene Dosage, GTP Phosphohydrolases, Mitochondrial Proteins, Cell Line, Tumor
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review