Cited by 420Mitochondrial Function and PathologyAutophagy in Disease and TherapyDNA Repair Mechanisms

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Human cells are protected from mitochondrial dysfunction by complementation of DNA products in fused mitochondria

Ono, Tomoko, Isobe, Kotoyo, Nakada, Kazuto, Hayashi, Jun-Ichi·2001·Nature Genetics

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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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Mitochondrial dynamics and oxidative phosphorylation as critical targets in cancer
Punter, K. B., Chu, C., & Chan, E. Y. W. (2022) · Endocrine Related Cancer · doi:10.1530/erc-22-0229 · Cited by 21
Control of mitochondrial integrity in Parkinson’s disease
Vives-Bauzá, C., Tocilescu, M. A., deVries, R. L. A., Wolken, D. M. A., Jackson-Lewis, V. R., & Przedborski, S. (2010) · Progress in brain research · doi:10.1016/s0079-6123(10)83006-7 · Cited by 20
A Disturbance in the Force: Cellular Stress Sensing by the Mitochondrial Network
Gilkerson, R. (2018) · Antioxidants · doi:10.3390/antiox7100126 · Cited by 22
“In cells carrying heteroplasmic populations of mtDNA variants, the mitochondrial network frequently comprises a mixture of functional and non-functional organelles, in which organelles carrying different mtDNAs may transcomplement each other through fusion [14], while fission may isolate nonfunctional organelles for a…”
Background
Mitochondrial Dysfunction via Disruption of Complex II Activity during Iron Chelation—Induced Senescence‐like Growth Arrest of Chang Cells
Yoon, Y., Cho, H., Lee, J., & Yoon, G. (2004) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1293.013 · Cited by 21
Identification and Characterization of Unique Proline-rich Peptides Binding to the Mitochondrial Fission Protein hFis1
Serasinghe, M. N., Seneviratne, A. M. P. B., Smrcka, A. V., & Yoon, Y. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.027508 · Cited by 21
Mitochondria: Starving to reach quorum?
Picard, M. A., & Burelle, Y. (2012) · BioEssays · doi:10.1002/bies.201100179 · Cited by 20
“Microscopic evidence demonstrates that mitochondrial fusion is necessary to allow sharing of mtDNA and large proteins [8, 14].”
Signaling Role of Mitochondrial Enzymes and Ultrastructure in the Formation of Molecular Mechanisms of Adaptation to Hypoxia
Lukyanova, L. D., Germanova, E. L., Khmil, N. V., Pavlik, L. L., Mikheeva, I. B., Shigaeva, M. I., & Mironova, G. D. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22168636 · Cited by 20
Linkage between mitochondrial genome alterations, telomere length and aging population
Zole, E., Zadinane, K., Pliss, L., & Ranka, R. (2017) · Mitochondrial DNA Part A · doi:10.1080/24701394.2017.1303490 · Cited by 20
“Possibly, some mtDNA polymorphisms were selected with age, and such variants can compensate the defects induced by various types of mtDNA mutations, helping an individual to survive longer (Ono et al. 2001; Sondheimer et al. 2011).”
Background
Blockade of AMPA Receptor Regulates Mitochondrial Dynamics by Modulating ERK1/2 and PP1/PP2A-Mediated DRP1-S616 Phosphorylations in the Normal Rat Hippocampus
Kim, J.-E., Choi, H., Song, H., & Kang, T. (2019) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2019.00179 · Cited by 21
Increased ROS‐Dependent Fission of Mitochondria Causes Abnormal Morphology of the Cell Powerhouses in a Murine Model of Amyotrophic Lateral Sclerosis
Stein, J., Walkenfort, B., Cihankaya, H., Hasenberg, M., Bader, V., Winklhofer, K. F., Röderer, P., Matschke, J., Theiß, C., & Matschke, V. (2021) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2021/6924251 · Cited by 21
The ubiquitous role of mitochondria in Parkinson and other neurodegenerative diseases
Theocharopoulou, G. (2020) · AIMS neuroscience · doi:10.3934/neuroscience.2020004 · Cited by 19
Extraocular Muscle Reveals Selective Vulnerability of Type IIB Fibers to Respiratory Chain Defects Induced by Mitochondrial DNA Alterations
Oexner, R. R., Pla‐Martín, D., Paß, T., Wiesen, M. H. J., Zentis, P., Schauss, A. C., Baris, O. R., Kimoloi, S., & Wiesner, R. J. (2020) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.61.12.14 · Cited by 19
“40,41 In skeletal muscles, impaired mitochondrial fusion due to deletion of mitofusins 1 and 2 has particularly been shown to accelerate mtDNA mutagenesis and decreases mitochondrial DNA copy number.”
ATM-Mediated Mitochondrial Radiation Responses of Human Fibroblasts
Shimura, T. (2021) · Genes · doi:10.3390/genes12071015 · Cited by 19
Improvement of embryonic development and production of offspring by transferring meiosis-II chromosomes of senescent mouse oocytes into cytoplasts of young mouse oocytes
Mitsui, A., Yoshizawa, M., Matsumoto, H., & Fukui, E. (2008) · Journal of Assisted Reproduction and Genetics · doi:10.1007/s10815-008-9282-6 · Cited by 19
“Moreover, no defects in respiration have been observed in human somatic hybrids carrying heteroplasmic mtDNAs [17] or in mice carrying heteroplasmic mtDNAs derived from different individuals [18].”
Background
Circulating Cell-Free Mitochondrial DNA in Pregnancy
Bradshaw, J. L., Cushen, S. C., Phillips, N., & Goulopoulou, S. (2022) · Physiology · doi:10.1152/physiol.00037.2021 · Cited by 16
A Molecular Perspective on Mitochondrial Membrane Fusion: From the Key Players to Oligomerization and Tethering of Mitofusin
Vecchis, D. D., Brandner, A. F., Baaden, M., Cohen, M. M., & Taly, A. (2019) · The Journal of Membrane Biology · doi:10.1007/s00232-019-00089-y · Cited by 20
The acute and chronic influence of exercise on mitochondrial dynamics in skeletal muscle
Ritenis, E. J., Padilha, C. S., Cooke, M. B., Stathis, C. G., Philp, A., & CAMERA, D. M. (2024) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00311.2024 · Cited by 18
The Diagnostic Value of Mitochondrial Mass of Peripheral T Lymphocytes in Early Sepsis
Pang, L., Cai, W., Chen, L., Fu, J., Xia, C.-X., Li, J., & Li, Q. (2022) · Frontiers in Public Health · doi:10.3389/fpubh.2022.928306 · Cited by 17
“Animal experiments have confirmed that recombinant human mitochondrial transcription factor A stimulates mitochondrial regeneration, which can significantly increase the expression of mitochondrial DNA and improve mitochondrial function (38).”
BackgroundInfluential
Mitochondrial Tolerance to Drugs and Toxic Agents in Ageing and Disease
Suski, J. M., Lebiedzińska, M., Machado, N. G., Oliveira, P. J., Pinton, P., Duszyński, J., & Wieckowski, M. R. (2011) · Current Drug Targets · doi:10.2174/138945011795529029 · Cited by 16
“It seems that such elongated mitochondria enable exchange and distribution of correct copies of mtDNA along a fused mitochondrial network [102, 112, 113].”
Background
Mitochondrial DNA density homeostasis accounts for a threshold effect in a cybrid model of a human mitochondrial disease
Aryaman, J., Johnston, I. G., & Jones, N. S. (2017) · Biochemical Journal · doi:10.1042/bcj20170651 · Cited by 15
Altered mitochondrial homeostasis on bisphenol-A exposure and its association in developing polycystic ovary syndrome: A comprehensive review
Kodanch, S. M., Mukherjee, S., Prabhu, N. B., Kabekkodu, S. P., Bhat, S. K., & Rai, P. S. (2024) · Reproductive Toxicology · doi:10.1016/j.reprotox.2024.108700 · Cited by 17
Mitochondrial fusion in Chlamydomonas reinhardtii zygotes
Scholz, D., & Westermann, B. (2012) · European Journal of Cell Biology · doi:10.1016/j.ejcb.2012.10.004 · Cited by 15
Stimulation of mRNA Export by an F-box Protein, Mdm30p, in Vivo
Shukla, A., Durairaj, G., Schneider, J., Duan, Z., Shadle, T., & Bhaumik, S. R. (2009) · Journal of Molecular Biology · doi:10.1016/j.jmb.2009.04.018 · Cited by 15
Variations in mitochondrial membrane potential correlate with malic acid production by natural isolates ofSaccharomyces cerevisiaesake strains
Takahiro, O. B. A., Kusumoto, K., Kichise, Y., Izumoto, E., Nakayama, S., Tashiro, K., Kuhara, S., & Kitagaki, H. (2014) · FEMS Yeast Research · doi:10.1111/1567-1364.12170 · Cited by 15
“We believe that this hypothesis is supported by findings that the effects of detrimental mutations in the mitochondrial genome are removed by complementation between fused mitochondria (Ono et al., 2001).”
The mitochondrial plasmid of the true slime mold Physarum polycephalum bypasses uniparental inheritance by promoting mitochondrial fusion
Sakurai, R., Nomura, H., Moriyam, Y., & Kawano, S. (2004) · Current Genetics · doi:10.1007/s00294-004-0512-x · Cited by 15
“Recently, experiments with human cell lines suggested that mitochondrial fusion is a defense used by highly oxidative organelles to protect against the mito- chondrial dysfunction caused by the accumulation of mtDNA lesions with age (Ono et al. 2001; Nakada et al. 2002).”
Background
In Vivo Interaction Between Mitochondria Carrying mtDNAs From Different Mouse Species
Sato, A., Nakada, K., Shitara, H., Yonekawa, H., & Hayashi, J. (2004) · Genetics · doi:10.1534/genetics.103.021287 · Cited by 15
“Genetics 78: 415–437. supported by our previous reports (Hayashi et al. 1994; Hayashi, J.-I., Y. Tagashira and M. C. Yoshida, 1985 Absence of extensive recombination between inter- and intraspecies mito-Takai et al. 1999; Ono et al. 2001), which provided chondrial DNA in mammalian cells.”
BackgroundResultSelf-citation
Dual Regeneration of Muscle and Nerve by Intramuscular Infusion of Mitochondria in a Nerve Crush Injury Model
Sheu, M., Shen, C., Tsou, H., Yang, M., Su, H., Sheehan, J., Chang, M., Chen, H.-S., & Pan, H.-C. (2021) · Neurosurgery · doi:10.1093/neuros/nyab105 · Cited by 14
Mitochondrial metabolism in aging: Effect of dietary interventions
Cerqueira, F. M., & Kowaltowski, A. J. (2012) · Ageing Research Reviews · doi:10.1016/j.arr.2012.03.009 · Cited by 14
Mitohormesis and mitochondrial dynamics in the regulation of stem cell fate
Barzegari, A., Aboulhassanzadeh, S., Landon, R., Gueguen, V., Meddahi‐Pellé, A., Parvizpour, S., Anagnostou, F., & Pavon‐Djavid, G. (2022) · Journal of Cellular Physiology · doi:10.1002/jcp.30820 · Cited by 14
“mitochondrial biology, mtDNA integrity (Ono et al., 2001), mitochondrial respiration (Chen et al.”
Background
An interphase actin wave promotes mitochondrial content mixing and organelle homeostasis
Coscia, S. M., Moore, A. S., Thompson, C. P., Tirrito, C., Ostap, E. M., & Holzbaur, E. L. F. (2024) · Nature Communications · doi:10.1038/s41467-024-48189-1 · Cited by 14
“InordertoisolatecDNA,totalRNAfromcellswascollectedwithTRIzol reagent (ThermoFisher Scienti ﬁ c, 15596018).”
Influential
Role of mitofusin 2 in cardiovascular oxidative injury
Zheng, M., & Xiao, R. (2010) · Journal of Molecular Medicine · doi:10.1007/s00109-010-0675-5 · Cited by 14
“More recent studies in differentiated skeletal muscle have demonstrated that impaired mitochondrial fusion by deletion of mitofusins causes muscle atrophy and rapid accumulation of mtDNA mutations and deletions, implicating a protective role of mitochondrial fusion/mitofusins in human disorders associated with mtDNA m…”
Influential
Mitochondrial dynamics in neurodegeneration: from cell death to energetic states
Khacho, M., & Slack, R. S. (2015) · AIMS molecular science · doi:10.3934/molsci.2015.2.161 · Cited by 13
“The general belief being that dysregulation of mitochondrial fusion would lead to accumulation of defective mitochondria through loss of mtDNA complementation [96,97].”
Background
Mitochondrial unfolded protein response in regulatory T cell function: a protective mechanism in immune aging
Lewis, L., Valvi, D., Gedaly, R., & Martí, F. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1621759 · Cited by 12
Nutritional approaches targeting mitochondria for the prevention of sarcopenia
Hahm, J., Nirmala, F. S., Ha, T. Y., & Ahn, J. (2023) · Nutrition Reviews · doi:10.1093/nutrit/nuad084 · Cited by 13
The thankless task of playing genetics with mammalian mitochondrial DNA: a 30-year review
Bayona‐Bafaluy, M. P., Fernández‐Silva, P., & Enrı́quez, J. A. (2002) · Mitochondrion · doi:10.1016/s1567-7249(02)00044-2 · Cited by 12
Distal control of mitochondrial biogenesis and respiratory activity by extracellular lactate caused by large-scale deletion of mitochondrial DNA
Ogasawara, E., Nakada, K., & Ishihara, N. (2020) · Pharmacological Research · doi:10.1016/j.phrs.2020.105204 · Cited by 12
“Proportion of mtDNAs with A3243G mutation was estimated by restriction enzyme digestion as described previously [12].”
Self-citation
Substrate use and biochemical response to a 3,211-km bicycle tour in trained cyclists
Slivka, D. R., Dumke, C. L., Hailes, W. S., Cuddy, J. S., & Ruby, B. C. (2011) · European Journal of Applied Physiology · doi:10.1007/s00421-011-2129-3 · Cited by 12
“It has been suggested that fusion results in mtDNA recombination (Ono et al. 2001); however, direct evidence of this recombination does not yet exist.”
Background
Mitochondrial Network Branching Enables Rapid Protein Spread with Slower Mitochondrial Dynamics
Chuphal, P., Lanctôt, J. D., Cornelius, S. P., & Brown, A. I. (2024) · PRX Life · doi:10.1103/prxlife.2.043005 · Cited by 12

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
Publisher: Springer Science and Business Media LLC
Published: 2001-07
Volume: 28
Issue: 3
Pages: 272-275
ISSN: 1061-4036 (ISSN-L)
1546-1718
DOI: 10.1038/90116
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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Human cells are protected from mitochondrial dysfunction by complementation of DNA products in fused mitochondria

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