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Human cells are protected from mitochondrial dysfunction by complementation of DNA products in fused mitochondria
Abstract
Extensive complementation between fused mitochondria is indicated by recombination of 'parental' mitochondrial (mt) DNA (ref. 1,2) of yeast and plant cells. It has been difficult, however, to demonstrate the occurrence of complementation between fused mitochondria in mammalian species through the presence of recombinant mtDNA molecules, because sequence of mtDNA throughout an individual tends to be uniform owing to its strictly maternal inheritance. We isolated two types of respiration-deficient cell lines, with pathogenic mutations in mitochondrial tRNAIle or tRNALeu(UUR) genes from patients with mitochondrial diseases. The coexistence of their mitochondria within hybrids restored their normal morphology and respiratory enzyme activity by 10-14 days after fusion, indicating the presence of an extensive and continuous exchange of genetic contents between the mitochondria. This complementation between fused mitochondria may represent a defence of highly oxidative organelles against mitochondrial dysfunction caused by the accumulation of mtDNA lesions with age.
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“This process enables the redistribution of energy in the form of mitochondrial potential, metabolites, proteins, and mtDNA, improving calcium handling, and ATP synthesis [24, 54–57].”
From The connection between the dynamic remodeling of the mitochondrial network and the regulation of muscle mass (2021) · cites this paper as [57]
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The Mitochondrial Response to DNA Damage
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“Mitochondrial fusion allows the mitochondria with normal mtDNA to compensate for defects in the mitochondria with damaged mtDNA (Nakada et al., 2001; Ono et al., 2001; Yang et al., 2015).”
BackgroundMargineantu, D. H., Cox, W. G., Sundell, L., Sherwood, S. W., Beechem, J., & Capaldi, R. (2002) · Mitochondrion · doi:10.1016/s1567-7249(02)00006-5 · Cited by 173
Duvezin‐Caubet, S., Koppen, M., Wagener, J., Zick, M., Israel, L., Bernacchia, A., Jagasia, R., Rugarli, E. I., Imhof, A., Neupert, W., et al. (2007) · Molecular Biology of the Cell · doi:10.1091/mbc.e07-02-0164 · Cited by 175
“, 2005) and functional complementation of mitochondrial DNA (mtDNA) mutations by content mixing (Nakada et al., 2001; Ono et al., 2001) depend on dynamics of mitochondria.”
Huang, P., Kuo, C.-C., Lee, H.-C., Shen, C.-I., Cheng, F.-C., Wu, S.-F., Chang, J., Pan, H.-C., Lin, S., Liu, C., et al. (2016) · Cell Transplantation · doi:10.3727/096368915x689785 · Cited by 174
Cho, Y. M., Kim, J. H., Kim, M., Park, S. J., Koh, S. H., Ahn, H. S., Kang, G. H., Lee, J.-B., Park, K. S., & Lee, H. K. (2012) · PLoS ONE · doi:10.1371/journal.pone.0032778 · Cited by 173
“However, it has been suggested that mitochondrial diseases elicited by mtDNA mutations could be treated by exploiting the intermitochondrial complementation through exchange of genetic materials between mitochondria with normal and mutant mtDNAs [14,15] In this regard, the elucidation of the mechanism of the mitochond…”
Gene therapy for progeny of mito-mice carrying pathogenic mtDNA by nuclear transplantation
Sato, A., Kono, T., Nakada, K., Ishikawa, K., Inoue, S.-I., Yonekawa, H., & Hayashi, J.-I. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0506197102 · Cited by 171
Morpho-dynamic changes of mitochondria during ageing of human endothelial cells
Jendrach, M., Pohl, S., Vöth, M., Kowald, A., Hammerstein, P., & Bereiter‐Hahn, J. (2005) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2005.03.002 · Cited by 170
“In cell culture systems, mitochondrial fusion can complement mtDNA mutations by exchange of mtDNA or transcripts (Ono et al., 2001).”
Mitochondrial nucleoids maintain genetic autonomy but allow for functional complementation
Gilkerson, R., Schon, E. A., Hernández, E., & Davidson, M. M. (2008) · The Journal of Cell Biology · doi:10.1083/jcb.200712101 · Cited by 163
“…in respiratorydefi cient backgrounds. mtDNA transcomplementation has been demonstrated previously, both between two complementing point mutations ( Ono et al., 2001 ) and between a point mutation and a large-scale deletion ( Takai et al., 1999 ), but has never been shown at nucleoid…”
BackgroundResultChu, C. T. (2010) · Human Molecular Genetics · doi:10.1093/hmg/ddq143 · Cited by 177
The ageing neuromuscular system and sarcopenia: A mitochondrial perspective
Rygiel, K. A., Picard, M., & Turnbull, D. M. (2016) · The Journal of Physiology · doi:10.1113/jp271212 · Cited by 165
“Although sarcopenia eventually affects everyone, the time point at which it begins shows substantial inter-individual variability – some experience only modest changes in old age, while others become severely disabled as early as in their seventh decade of life.”
BackgroundMitochondrial biogenesis in the axons of vertebrate peripheral neurons
Amiri, M., & Hollenbeck, P. J. (2008) · Developmental Neurobiology · doi:10.1002/dneu.20668 · Cited by 165
“which mitochondria must dilute the products of their error-prone DNA replication (Scharpira, 1993) by fission and fusion (Ono et al., 2001; Chan, 2006; Chang and Reynolds, 2006; Hoppins et al., 2007) and renew themselves through biogenesis (Schmitz et al.”
BackgroundHoitzing, H., Johnston, I. G., & Jones, N. S. (2015) · BioEssays · doi:10.1002/bies.201400188 · Cited by 159
“mitochondria to synchronize gene expression [1, 88] or improve the health of the mitochondrial population by allowing mitochondria to complement each other’s deficiencies [89, 90] (functional complementation).”
BackgroundStaying cool in difficult times: Mitochondrial dynamics, quality control and the stress response
Shutt, T. E., & McBride, H. M. (2012) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2012.05.024 · Cited by 167
Baker, N., Patel, J., & Khacho, M. (2019) · Mitochondrion · doi:10.1016/j.mito.2019.06.003 · Cited by 173
Mitochondrial structural and functional dynamics in Huntington's disease
Reddy, P. H., Mao, P., & Mańczak, M. (2009) · Brain Research Reviews · doi:10.1016/j.brainresrev.2009.04.001 · Cited by 164
Mai, S., Muster, B., Bereiter‐Hahn, J., & Jendrach, M. (2012) · Autophagy · doi:10.4161/auto.8.1.18174 · Cited by 162
Frequency and Selectivity of Mitochondrial Fusion Are Key to Its Quality Maintenance Function
Mouli, P. K., Twig, G., & Shirihai, O. S. (2009) · Biophysical Journal · doi:10.1016/j.bpj.2008.12.3959 · Cited by 164
“A solid body of in vitro (8,9) and in vivo (10) data support this view.”
BackgroundMarongiu, R., Spencer, B. J., Crews, L. A., Adame, A., Patrick, C., Trejo, M., Dallapiccola, B., Valente, E. M., & Masliah, E. (2009) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2009.05932.x · Cited by 157
“2006) and eventually to selective autophagic degradation of mitochondria—a process known as mitophagy (Nakada et al. 2001; Ono et al. 2001; Priault et al. 2005).”
BackgroundMitochondria in vascular disease
Yu, E., Mercer, J. R., & Bennett, M. R. (2012) · Cardiovascular Research · doi:10.1093/cvr/cvs111 · Cited by 153
“Fusion allows mixing of the mitochondrial genomes, diluting and so protecting against damaged DNA.(53) Fission is also required for”
BackgroundRole of mitofusin 2 mutations in the physiopathology of Charcot–Marie–Tooth disease type 2A
Cartoni, R., & Martinou, J. (2009) · Experimental Neurology · doi:10.1016/j.expneurol.2009.05.003 · Cited by 157
“Such a function has been previously demonstrated by a very elegant experiment (Ono et al., 2001).”
BackgroundMitochondrial fission and fusion dynamics: the long and short of it
Berman, S., Pineda, F. J., & Hardwick, J. M. (2008) · Cell Death and Differentiation · doi:10.1038/cdd.2008.57 · Cited by 147
“For reasons that remain unclear, the maintenance of mtDNA cannot take place without mitochondrial fusion,(10) and fusion of mitochondria has been directly implicated in preventing the accumulation of damaged mtDNA.(11,12) In the special case of neurons, mitochondrial dynamics”
BackgroundPicca, A., Lezza, A. M. S., Leeuwenburgh, C., Pesce, V., Calvani, R., Bossola, M., Manes-Gravina, E., Landi, F., Bernabei, R., & Marzetti, E. (2018) · Rejuvenation Research · doi:10.1089/rej.2017.1989 · Cited by 144
“mtDNA and preserving mtDNA integrity.(10,11) Mitochondrial fission, instead, segregates defective or unnecessary organelles for their subsequent removal through mitophagy.”
BackgroundYuan, H., Gerencser, A. A., Liot, G., Lipton, S. A., Ellisman, M. H., Perkins, G. A., & Bossy‐Wetzel, E. (2006) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4402046 · Cited by 140
“Furthermore, bioenergetically highly active mitochondria are associated with the filamentous phenotype.(28,29) In support of this notion, we show here that by blockage of glycolysis using 2DG or triggering low energy level signaling via AICAR, neuronal mitochondria increased in length.”
BackgroundWestermann, B. (2002) · EMBO Reports · doi:10.1093/embo-reports/kvf113 · Cited by 149
“Fusion of mitochondria might contribute to the maintenance of respiratory activity by allowing trans-complementation of somatic mutations that accumulate in mitochondrial chromosomes over time (Ono et al., 2001), and thus mitochondrial fusion may be a crucial defence mechanism against cellular aging.”
BackgroundInfluentialMdm30 Is an F-Box Protein Required for Maintenance of Fusion-competent Mitochondria in Yeast
Fritz, S., Weinbach, N., & Westermann, B. (2003) · Molecular Biology of the Cell · doi:10.1091/mbc.e02-12-0831 · Cited by 140
“Furthermore, fusion is required for the formation of intracellular mitochondrial networks that allow the dissipation of energy in the cell (Skulachev, 2001) and for complementation of mitochondrial gene products, a mechanism thought to constitute a defense against cellular aging (Ono et al., 2001).”
BackgroundMitochondrial dynamics in Parkinson's disease
Laar, V. S. V., & Berman, S. (2009) · Experimental Neurology · doi:10.1016/j.expneurol.2009.03.019 · Cited by 141
“, 1998), and fusion of mitochondria has been directly implicated in preventing the accumulation of damaged mtDNA (Nakada et al., 2001; Ono et al., 2001).”
BackgroundWilkens, V., Kohl, W., & Busch, K. B. (2012) · Journal of Cell Science · doi:10.1242/jcs.108852 · Cited by 139
“In general, the balance between fusion and fission determines the mitochondrial morphology and facilitates the exchange of metabolites, mtDNA and proteins (Nakada et al., 2001; Ono et al., 2001; Malka et al., 2005; Twig et al., 2006).”
BackgroundBess, A. S., Crocker, T. L., Ryde, I. T., & Meyer, J. N. (2012) · Nucleic Acids Research · doi:10.1093/nar/gks532 · Cited by 138
“Fusion provides protection against the effects of mtDNA mutations by facilitating ‘functional complementation’ (111,112), the mixing of lipids, proteins and mtDNA to compensate for mutated DNA (80) and this mechanism may explain the lack of phenotypic expression of mtDNA mutations until the occurrence is high (>40–90%…”
Background
Metadata
- Authors
- Ono, T., Isobe, K., Nakada, K., & Hayashi, J.-I.
- Affiliations
- University of Tsukuba (JP)
- Corresponding author
- Hayashi, Jun-Ichi
- ORCID
- Nakada, Kazuto
- Venue
- Nature Genetics
- Published
- 2001-07
- Volume
- 28
- Issue
- 3
- Pages
- 272-275
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W1554250492
- Cited by
- 420
- References
- 29
- Citations by year
- 2026: 7 · 2025: 14 · 2024: 14 · 2023: 10 · 2022: 16 · 2021: 24 · 2020: 18 · 2019: 15 · 2018: 10 · 2017: 24 · 2016: 13 · 2015: 21 · 2014: 21 · 2013: 11 · 2012: 28
- FWCI
- 5.94
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- 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 › DNA Repair Mechanisms
- Keywords
- mitochondrial fusion, mitochondrial recombination, mitochondrial dysfunction, mitochondrial tRNA mutations, mitochondrial disease, respiratory deficiency, oxidative stress, human cell lines
- MeSH terms
- DNA, Mitochondrial, Genetic Complementation Test, Humans, Hybrid Cells, Intracellular Membranes, Membrane Fusion, Mitochondria, Oxygen Consumption, RNA, Transfer, Ile, RNA, Transfer, Leu, Mitochondrial Myopathies
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