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Selective inhibition of mutant human mitochondrial DNA replication in vitro by peptide nucleic acids
Abstract
Mitochondrila DNA (mtDNA) is the only extrachromosomal DNA in humans. It is a small (16.5 kb) genome which encodes 13 essential peptides of the respiratory chain, two rRNAs and 22 tRNAs. Defects of this genome are now recognized as important causes of disease and may take the form of point mutations or rearrangements. There is no effective treatment for patients with mtDNA mutations. In the majority of patients with mtDNA defects, both mutant and wild-type molecules are present in the same cell-a phenomenon known as intracellular heteroplasmy. In addition, in the presence of heteroplasmy there is a threshold whereby a certain level of mutant mtDNA is necessary before the disease becomes biochemically and clinically apparent. Based on the presence of heteroplasmy and the recessive nature of these mutations, we believe it will be possible to treat patients by selectively inhibiting the replication of the mutant mtDNA, thereby allowing propagation of only the wild-type molecule. To confirm the validity of such an approach we synthesised peptide nucleic acids (PNAs) complementary to human mtDNA templates containing a deletion breakpoint or single base mutation, both mutations well documented to cause disease. Using an in vitro replication run-off assay under physiological conditions, the antigenomic PNAs specifically inhibited replication of mutant but not wild-type mtDNA templates. Furthermore, we have shown uptake of these PNAs into cultured human myoblasts. We believe that we have therefore established the potential value of antigenomic PNA therapy for patients with heteroplasmic mtDNA disorders.
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“Antigenomic therapy, which involves using sequence-specific nucleic acid derivatives that selectively target and inhibit the replication of mutated mtDNA thus allowing the wild-type genome to propagate, showed promising initial results in vitro with peptide nucleic acids (PNAs) [234].”
From Mitochondrial DNA mutations and human disease (2010) · cites this paper as [234]
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“Antigenomic therapy, which involves using sequence-specific nucleic acid derivatives that selectively target and inhibit the replication of mutated mtDNA thus allowing the wild-type genome to propagate, showed promising initial results in vitro with peptide nucleic acids (PNAs) [234].”
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“There are also some reports of direct PNA uptake in rat embryo fibroblasts (109) and human myoblasts (75), although at extremely high exposure concentrations (;20 mM).”
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“The selective elimination of mutated mtDNA allows a cell to repopulate with wild-type mtDNA molecules by a yet uncharacterized mechanism of mtDNA copy number maintenance (Carling et al , 2011), alleviating the defective mitochondrial function that underlies mtDNA diseases (Taylor et al , 1997).”
An Introduction to Peptide Nucleic Acid
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“Furthermore PNAs are efficient inhibitors of DNA polymerase [replication] (57); and finally, but not least interestingly, PNA triplex invasion loops function as quite efficient promoters for transcription (58) and thereby open the (theoretical) possibilities of generating specific gene-activating drugs with the PNA fu…”
Yamada, Y., & Harashima, H. (2008) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2008.04.016 · Cited by 260
“proposed selective inhibition of mutant mtDNA replication, which would allow propagation of only wild-type DNA, as treatment for mitochondrial disease [182].”
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“Patients with mtDNA diseases often have both wild-type and mutant mtDNA molecules and selectively blocking the replication of the mutant mtDNA to allow repopulation of the cell with wild-type DNA has also been suggested as a potential treatment strategy (Taylor et al., 1997).”
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Tanaka, M., Borgeld, H. W., Zhang, J., Muramatsu, S., Gong, J., Yoneda, M., Maruyama, W., Naoi, M., Ibi, T., Sahashi, K., et al. (2002) · Journal of Biomedical Science · doi:10.1159/000064726 · Cited by 232
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“As cells have a tendency to maintain a fixed number of mtDNA molecules (6), one treatment option is the selective elimination of mutated mtDNA, thus allowing the cell to re-populate itself with wt mtDNA, thereby correcting the defective phenotype (7).”
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“For example, blocking the replication of mutated mtDNA by peptide nucleic acid might result in repopulated cells with unaffected wild-type DNA [258].”
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“Mitochondrial disorders of the heteroplasmic type and the associated disease could be remedied by selectively blocking the replication of mutant DNA molecules to allow repopulation of the wild-type mtDNA (567).”
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“A method for the selective targeting of mutated mtDNA has been designed, with the aim of inhibiting replication (3,4).”
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Chinnery, P. F., Taylor, R. W., Diekert, K., Lill, R., Turnbull, D. M., & Lightowlers, R. N. (1999) · Gene Therapy · doi:10.1038/sj.gt.3301061 · Cited by 178
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“Similarly, in myoblasts the ratio of the 173 bp restriction fragment (MERRF) to the uncut 200 bp PCR product (wild-type) was unchanged after incubation with ph–PNA for up to 21 days (Fig.”
BackgroundMethodInfluentialInhibition of translation and bacterial growth by peptide nucleic acid targeted to ribosomal RNA
Good, L., & Nielsen, P. E. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.5.2073 · Cited by 166
Sequence-specific modification of mitochondrial DNA using a chimeric zinc finger methylase
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Mohanty, A., Tiwari-Pandey, R., & Pandey, N. R. (2019) · Journal of Cell Communication and Signaling · doi:10.1007/s12079-019-00507-9 · Cited by 164
Mitochondrial Disorders: Clinical and Genetic Features
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Chinnery, P. F., & Turnbull, D. (1999) · The Lancet · doi:10.1016/s0140-6736(99)90244-1 · Cited by 143
The potential of mitochondrial genome engineering
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Reversal of a mitochondrial DNA defect in human skeletal muscle
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Approaches to the treatment of mitochondrial diseases
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Mitochondria as a centrally positioned hub in the innate immune response
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“Some success was obtained in decreasing the ratio of A8344G MERRF mutants in vitro (Taylor et al. 123 1997), but there were problems with the delivery of peptide nucleic acids to human mitochondria (Chinnery et al. 1999).”
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“Nevertheless, several experimental strategies have been developed [133,134,141–145], of which two will be discussed below.”
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Weissig, V., & Torchilin, V. P. (2001) · Advanced Drug Delivery Reviews · doi:10.1016/s0169-409x(01)00131-4 · Cited by 113
Clinical mitochondrial genetics
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Emerging concepts in the therapy of mitochondrial disease
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“001 E D P R O O F device [117,118].”
MethodMitochondrial DNA mutations in the pathogenesis of human disease
Chinnery, P. F., & Turnbull, D. M. (2000) · Molecular Medicine Today · doi:10.1016/s1357-4310(00)01805-0 · Cited by 75
Progress in Developing PNA as a Gene-Targeted Drug
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“In vitro assays have shown that duplex-forming PNAs targeted to mutant sequences can selectively inhibit the replication of defective mitochondrial genomes without inhibiting the replication of normal mitochondrial DNA (Taylor et al., 1997).”
Antisense PNA effects in Escherichia coli are limited by the outer-membrane LPS layer
Good, L., Sandberg, R., Larsson, O. S., Nielsen, P. E., & Wahlestedt, C. (2000) · Microbiology · doi:10.1099/00221287-146-10-2665 · Cited by 105
“Also, in vitro assays for telomerase activity and mitochondrial genome replication show that PNAs are often effective in applications where other (modified) oligonucleotides perform poorly (Norton et al., 1996; Taylor et al., 1997).”
BackgroundPeptide nucleic acids as therapeutic agents
Nielsen, P. E. (1999) · Current Opinion in Structural Biology · doi:10.1016/s0959-440x(99)80047-5 · Cited by 105
Clinical features, investigation, and management of patients with defects of mitochondrial DNA
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Mitochondrial DNA disease—molecular insights and potential routes to a cure
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“These include: (i) inhibiting the replication of mutant mtDNA by selective hybridization with nucleic acid derivatives (such as peptide nucleic acids, PNAs) [82, 83]; (ii) importation of yeast tRNA to replace mutated human tRNA [84]; (iii) importation of wild-type polypeptides (either allotopically or xenotopically ex…”
Villa, R., Folini, M., Lualdi, S., Veronese, S. M., Daidone, M. G., & Zaffaroni, N. (2000) · FEBS Letters · doi:10.1016/s0014-5793(00)01540-4 · Cited by 95
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“On the other hand, oligo DNA (linear DNA), as a therapeutic agent for muted mtDNA, was investigated, in order to repair mutated mtDNA and inhibit the replication of mutated mtDNA [34,35].”
BackgroundMitochondrial Heterogeneity in the Brain at the Cellular Level
Sonnewald, U., Hertz, L., & Schousboe, A. (1998) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1097/00004647-199803000-00001 · Cited by 92
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Chiral introduction of positive charges to PNA for double-duplex invasion to versatile sequences
Ishizuka, T., Yoshida, J., Yamamoto, Y., Sumaoka, J., Tedeschi, T., Corradini, R., Sforza, S., & Komiyama, M. (2008) · Nucleic Acids Research · doi:10.1093/nar/gkm1154 · Cited by 85
Fate of microinjected sperm components in the mouse oocyte and embryo
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Treating neurodegeneration by modifying mitochondria: potential solutions to a “complex” problem
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“Sophisticated in vitro approaches for repairing mtDNA defects and using mitochondria to house transgenes as part of an overall gene therapy strategy have tremendous translational potential (63, 76, 173).”
Mitochondrial medicine: entering the era of treatment
Koene, S., & Smeitink, J. A. M. (2009) · Journal of Internal Medicine · doi:10.1111/j.1365-2796.2008.02058.x · Cited by 82
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“To obtain single-stranded templates, we used the method described in (11).”
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Mitochondrial DNA disease: new options for prevention
Craven, L., Elson, J. L., Irving, L., Tuppen, H. A. L., Lister, L., Greggains, G. D., Byerley, S., Murdoch, A. P., Herbert, M., & Turnbull, D. M. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddr373 · Cited by 78
Mitochondrial DNA m.3243A > G heteroplasmy affects multiple aging phenotypes and risk of mortality
Tranah, G. J., Katzman, S. M., Lauterjung, K., Yaffe, K. S., Manini, T. M., Kritchevsky, S. B., Newman, A. B., Harris, T. B., & Cummings, S. R. (2018) · Scientific Reports · doi:10.1038/s41598-018-30255-6 · Cited by 78
Therapeutic Manipulation of mtDNA Heteroplasmy: A Shifting Perspective
Jackson, C. B., Turnbull, D. M., Minczuk, M. A., & Gammage, P. A. (2020) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2020.02.006 · Cited by 81
“Experimental Origins of Direct Heteroplasmy Manipulation The first reported heteroplasmy shifting approaches made use of peptide nucleic acid (PNA) oligomers [16,23].”
BackgroundResultDevelopment of lipophilic cations as therapies for disorders due to mitochondrial dysfunction
Murphy, M. P. (2001) · Expert Opinion on Biological Therapy · doi:10.1517/14712598.1.5.753 · Cited by 76
“For diseases due to nuclear mutations, replacement or complementation of the mutated gene is being investigated [132,133] but faces the same challenges of delivery, expression and safety as other gene therapies [29].”
BackgroundSomatic Mitochondrial DNA Mutations in Human Cancers
Yu, M. (2012) · Advances in clinical chemistry · doi:10.1016/b978-0-12-394384-2.00004-8 · Cited by 73
Peptide nucleic acids: versatile tools for gene therapy strategies
Dean, D. (2000) · Advanced Drug Delivery Reviews · doi:10.1016/s0169-409x(00)00087-9 · Cited by 61
“By contrast, several groups have found that certain cells are amenable to PNA entry, suggesting specific transport mechanisms for the molecules [19,20,24,27,31,38,40].”
BackgroundMethodPNA oligomers as tools for specific modulation of gene expression
Pooga, M., Land, T., Bartfai, T., & Langel, Ü. (2001) · Biomolecular Engineering · doi:10.1016/s1389-0344(01)00075-2 · Cited by 74
Mitochondrial Abnormalities in Alzheimer’s Disease
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“Although protein nucleic acids (PNAs) were reported years ago to have the ability to strategically influence mtDNA replication under in vitro conditions (Taylor et al., 1997), this approach has had problems under more physiologic conditions.”
BackgroundSelection of RNA aptamers imported into yeast and human mitochondria
Kolesnikova, O., Kazakova, H., Comte, C., Steinberg, S. V., Kamenski, P. A., Martin, R. P., Tarassov, I., & Entelis, N. (2010) · RNA · doi:10.1261/rna.1914110 · Cited by 67
“’’ Antigenomic rescue of deleterious mtDNA mutations was proposed (but not yet realized), consisting in selective inhibition of the mutant mtDNA replication, thereby allowing propagation of only wild-type molecules (Taylor et al. 1997).”
BackgroundTreatment of Mitochondrial Disease
Taylor, R. W., Chinnery, P. F., Clark, K. M., Lightowlers, R. N., & Turnbull, D. M. (1997) · Journal of Bioenergetics and Biomembranes · doi:10.1023/a:1022646215643 · Cited by 65
Towards Mitochondrial Gene Therapy: DQAsomes as a Strategy
Weissig, V., & Torchilin, V. P. (2001) · Journal of drug targeting · doi:10.3109/10611860108995628 · Cited by 65
Larsson, N. ‐., & Oldfors, A. (2001) · Acta Physiologica Scandinavica · doi:10.1046/j.1365-201x.2001.00842.x · Cited by 65
Two distinct structural elements of 5S rRNA are needed for its import into human mitochondria.
Smirnov, A., Tarassov, I., Mager-Heckel, A., Letzelter, M., Martin, R., Krasheninnikov, I., & Entelis, N. (2008) · RNA: A publication of the RNA Society · doi:10.1261/rna.952208 · Cited by 67
“Such an approach was previously assayed with artificial PNA (peptide nucleic acids) oligonucleotides and proved to be efficient in vitro, but not in vivo (Taylor et al. 1997; Muratovska et al. 2001).”
MethodTargeting large molecules to mitochondria
Muratovska, A., Lightowlers, R. N., Taylor, R. W., Wilce, M. C. J., & Murphy, M. P. (2001) · Advanced Drug Delivery Reviews · doi:10.1016/s0169-409x(01)00134-x · Cited by 63
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Engineered mitochondria in diseases: mechanisms, strategies, and applications
Li, M., Wu, L., Si, H., Wu, Y., Liu, Y., Zeng, Y., & Shen, B. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-02081-y · Cited by 71
“106 These small molecules with nucleobases linked to an achiral peptide backbone exhibit higher af fi nity than equivalent oligodeoxynucleotides when binding to single-stranded complementary DNA.”
Mitochondrial Encephalomyopathies: Therapeutic Approach
DiMauro, S., Mancuso, M., & Naini, A. (2004) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1293.023 · Cited by 61
Peptide nucleic acid (PNA) binding-mediated gene regulation
Wang, G., & Xu, X. (2004) · Cell Research · doi:10.1038/sj.cr.7290209 · Cited by 59
Antisense Inhibition of δ-Opioid Receptor Gene Function In Vivo by Peptide Nucleic Acids
Fraser, G. L., Holmgren, J., Clarke, P. B. S., & Wahlestedt, C. (2000) · Molecular Pharmacology · doi:10.1016/s0026-895x(24)26472-5 · Cited by 58
Site‐directed inhibition of DNA replication by triple helix formation
Diviacco, S., Rapozzi, V., Xodo, L. E., Hélène, C., Quadrifoglio, F., & Giovannangeli, C. (2001) · The FASEB Journal · doi:10.1096/fj.01-0440com · Cited by 57
“However, duplex-forming PNAs (DNA:PNA complex) have been described to arrest in vitro single-stranded DNA replication ( 26 ).”
BackgroundSieber, F., Duchêne, A., & Maréchal‐Drouard, L. (2011) · International review of cytology · doi:10.1016/b978-0-12-386043-9.00004-9 · Cited by 54
Tonin, Y., Heckel, A., Vysokikh, M. Y., Dovydenko, I. S., Meschaninova, M. I., Rötig, A., Münnich, A., Venyaminova, A. G., Tarassov, I., & Entelis, N. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.528968 · Cited by 55
“This strategy has first been tested in vitro using peptide nucleic acids with high affinity to mutant mtDNA (12).”
BackgroundDiagnosis and management of MELAS
Thambisetty, M., & Newman, N. J. (2004) · Expert Review of Molecular Diagnostics · doi:10.1586/14737159.4.5.631 · Cited by 50
Tripathi, S. (2005) · Nucleic Acids Research · doi:10.1093/nar/gki743 · Cited by 51
“A number of methods for their intracellular delivery have been developed which include microinjection (43), electroporation (44), co-transfection with DNA (45,46) and conjugation with transporter peptides (23,24).”
Mitochondrial DNA nucleoids determine mitochondrial genetics and dysfunction
Gilkerson, R. (2009) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2009.03.016 · Cited by 49
“…which preferntially recognize mutant mtDNAs, have been developed which an inhibit replication of the A8344G pathogenic mtDNA mutaion in vitro (Taylor et al., 1997), as well as bind preferentially o the sequence-repeat breakpoint of the “common deletion” of tDNA (McGregor et al., 2003);…”
BackgroundMinczuk, M. A., Kolasinska-Zwierz, P., Murphy, M. P., & Papworth, M. A. (2010) · Nature Protocols · doi:10.1038/nprot.2009.245 · Cited by 49
“The selective elimination of mutated mtDNA from this population results in repopulation of a cell with wild-type mtDNA molecules and alleviation of the defective mitochondrial function that underlies mtDNA disease”
BackgroundAntisense properties of peptide nucleic acids
Soomets, U. (1999) · Frontiers in bioscience · doi:10.2741/soomets · Cited by 48
“In addition, the selective inhibition of mitochondrial DNA replication (18) and reverse transcription of the HIV-1 gag gene (17) by PNAs have been demonstrated.”
BackgroundRai, P. K., Craven, L., Hoogewijs, K., Russell, O. M., & Lightowlers, R. N. (2018) · Essays in Biochemistry · doi:10.1042/ebc20170113 · Cited by 52
Géromel, V., Cao, A., Briane, D., Vassy, J., Rötig, A., Rustin, P., Coudert, R., Rigaut, J. P., Münnich, A., & Taillandier, E. (2001) · Antisense and Nucleic Acid Drug Development · doi:10.1089/108729001300338708 · Cited by 47
“The use of peptide nucleic acid (PNA) has been reported to selectively inhibit mtDNA replication both in vitro and in cultured myoblasts (Seibel et al., 1999; Taylor et al., 1997).”
PNAs: synthetische Polyamidnucleinsäuren mit außergewöhnlichen Bindungseigenschaften
Uhlmann, E., Peyman, A., Breipohl, G., & Will, D. W. (1998) · Angewandte Chemie · doi:10.1002/(sici)1521-3757(19981016)110:20 · Cited by 41
Current advances in gene therapy of mitochondrial diseases
Soldatov, V. O., Kubekina, M. V., Skorkina, M. Y., Белых, А. Е., Egorova, T. V., Корокин, М. В., Pokrovskiy, M. V., Deykin, A. V., & Angelova, P. R. (2022) · Journal of Translational Medicine · doi:10.1186/s12967-022-03685-0 · Cited by 45
“Antireplicative machines The first approach to shift heteroplasmy was the application of peptide nucleic acid (PNA) oligomers interrupting replication of mutant mtDNA [160].”
BackgroundEmerging therapeutic approaches to mitochondrial diseases
Wenz, T., Williams, S. L., Bacman, S. R., & Moraes, C. T. (2010) · Developmental Disabilities Research Reviews · doi:10.1002/ddrr.109 · Cited by 42
Pathogenesis and Treatment of Mitochondrial Disorders
DiMauro, S., & Hirano, M. (2009) · Advances in experimental medicine and biology · doi:10.1007/978-90-481-2813-6_10 · Cited by 39
Gene therapy by mitochondrial transfer
Kagawa, Y., Inoki, Y., & Endo, H. (2001) · Advanced Drug Delivery Reviews · doi:10.1016/s0169-409x(01)00129-6 · Cited by 39
Mitochondrial medicine: to a new era of gene therapy for mitochondrial DNA mutations
Cwerman‐Thibault, H., Sahel, J., & Corral‐Debrinski, M. (2010) · Journal of Inherited Metabolic Disease · doi:10.1007/s10545-010-9131-5 · Cited by 36
“…sections of DNA or RNA into mitochondria either to replace mutant tRNA (Kolesnikova et al. 2004) or to selectively inhibit mutant mtDNA replication (Taylor et al. 1997) (Taylor et al. , 2000); (2) manipulation of the mitochondrial genetic content by importing specific restriction endonucleases…”
BackgroundHow Can We Treat Mitochondrial Encephalomyopathies? Approaches to Therapy
Horváth, R., Gorman, G. S., & Chinnery, P. F. (2008) · Neurotherapeutics · doi:10.1016/j.nurt.2008.07.002 · Cited by 36
Respiratory chain defects: what do we know for sure about their consequences in vivo?
Brière, J.-J., Chrétien, D., Bénit, P., & Rustin, P. (2004) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2004.07.002 · Cited by 38
“After a burst of hope triggered by reports on the successful use of peptide nucleic acids to change mitochondrial heteroplasmy in cell models [4], further attempts have shown the major limitation of such an approach [5].”
Background
Metadata
- Authors
- Taylor, R. W., Chinnery, P. F., Turnbull, D. M., & Lightowlers, R. N.
- Affiliations
- Newcastle University (GB)
- Corresponding author
- Turnbull, Douglass M.
- Venue
- Nature Genetics
- Published
- 1997-02
- Volume
- 15
- Issue
- 2
- Pages
- 212-215
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W1964789697
- Cited by
- 249
- References
- 31
- Citations by year
- 2025: 5 · 2024: 2 · 2023: 3 · 2022: 4 · 2021: 4 · 2020: 2 · 2019: 3 · 2018: 9 · 2017: 2 · 2016: 6 · 2015: 8 · 2014: 6 · 2013: 2 · 2012: 10
- FWCI
- 5.65
- 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 › Molecular Biology › DNA and Nucleic Acid Chemistry
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- mitochondrial DNA, mitochondrial DNA replication, peptide nucleic acid, heteroplasmy, myoblasts, mitochondrial disease, deletion breakpoints, single-base mutations
- MeSH terms
- Cell Line, Depression, Chemical, DNA Replication, DNA, Mitochondrial, DNA, Single-Stranded, Humans, Mitochondria, Muscle, Oligodeoxyribonucleotides, Peptides, Templates, Genetic, Drug Design, MERRF Syndrome
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