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.
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?
Antigenomic therapy with PNAs showed promising initial results in vitro.
“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]
Cites
DNA sequencing with chain-terminating inhibitors
Sanger, F., Nicklen, S., & Coulson, A. R. (1977) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.74.12.5463 · Cited by 68,572 · see citing works
Sequence and organization of the human mitochondrial genome
Anderson, S., Bankier, A. T., Barrell, B. G., de Bruijn, M. H. L., Coulson, A. R., Drouin, J., Eperon, I. C., Nierlich, D. P., Roe, B. A., Sanger, F., et al. (1981) · Nature · doi:10.1038/290457a0 · Cited by 9,640 · see citing works
Sequence-Selective Recognition of DNA by Strand Displacement with a Thymine-Substituted Polyamide
Nielsen, P. E., Egholm, M., Berg, R. H., & Buchardt, O. (1991) · Science · doi:10.1126/science.1962210 · Cited by 3,332 · see citing works
PNA hybridizes to complementary oligonucleotides obeying the Watson–Crick hydrogen-bonding rules
Egholm, M., Buchardt, O., Christensen, L., Behrens, C., Freier, S. M., Driver, D. A., Berg, R. H., Kim, S. K., Norden, B., & Nielsen, P. E. (1993) · Nature · doi:10.1038/365566a0 · Cited by 2,079 · see citing works
Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies
Holt, I. J., Harding, A. E., & MORGAN-HUGHES, J. A. (1988) · Nature · doi:10.1038/331717a0 · Cited by 1,845 · see citing works
Shoffner, J. M., Lott, M. T., Lezza, A. M. S., Seibel, P., Ballinger, S. W., & Wallace, D. C. (1990) · Cell · doi:10.1016/0092-8674(90)90059-n · Cited by 1,468 · see citing works
Diseases of the mitochondrial DNA
Wallace, D. C. (1992) · Annual Review of Biochemistry · doi:10.1146/annurev.bi.61.070192.005523 · Cited by 1,319 · see citing works
Mitochondrial Genetics: A Paradigm for Aging and Degenerative Diseases?
Wallace, D. C. (1992) · Science · doi:10.1126/science.1533953 · Cited by 1,256 · see citing works
Mitochondrial DNA Deletions in Progressive External Ophthalmoplegia and Kearns-Sayre Syndrome
Moraes, C. T., DiMauro, S., Zeviani, M., Lombès, A., Shanske, S., Miranda, A. F., Nakase, H., Bonilla, E., Werneck, L. C., Servidei, S., et al. (1989) · New England Journal of Medicine · doi:10.1056/nejm198905183202001 · Cited by 1,029 · see citing works
Peptide nucleic acids (PNA). Oligonucleotide analogs with an achiral peptide backbone
Egholm, M., Buchardt, O., Nielsen, P. E., & Berg, R. H. (1992) · Journal of the American Chemical Society · doi:10.1021/ja00031a062 · Cited by 739 · see citing works
Stability of peptide nucleic acids in human serum and cellular extracts
Demidov, V. V., Potaman, V. N., Frank-Kamenetskii, M. D., Egholm, M., Buchard, O., Sönnichsen, S. H., & Nlelsen, P. E. (1994) · Biochemical Pharmacology · doi:10.1016/0006-2952(94)90171-6 · Cited by 738 · see citing works
A Direct Repeat Is a Hotspot for Large-Scale Deletion of Human Mitochondrial DNA
Schon, E. A., Rizzuto, R., Moraes, C. T., Nakase, H., Zeviani, M., & DiMauro, S. (1989) · Science · doi:10.1126/science.2711184 · Cited by 569 · see citing works
Chomyn, A., Martinuzzi, A., Yoneda, M., Daga, A., Hurko, O., Johns, D. R., Lai, S. T., Nonaka, I., Angelini, C. I., & Attardi, G. M. (1992) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.89.10.4221 · Cited by 491 · see citing works
King, M. P., Koga, Y., Davidson, M., & Schon, E. A. (1992) · Molecular and Cellular Biology · doi:10.1128/mcb.12.2.480 · Cited by 458 · see citing works
Johns, D. R. (1995) · New England Journal of Medicine · doi:10.1056/nejm199509073331007 · Cited by 440 · see citing works
Lohman, T. M., & Overman, L. B. (1985) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)83663-3 · Cited by 367 · see citing works
Transcription and Replication of Animal Mitochondrial DNAs
Clayton, D. A. (1992) · International review of cytology · doi:10.1016/s0074-7696(08)62067-7 · Cited by 360 · see citing works
Single base pair mutation analysis by PNA directed PCR clamping
Ørum, H., Nielsen, P. E., Egholm, M., Berg, R. H., Buchardt, O., & Stanley, C. (1993) · Nucleic Acids Research · doi:10.1093/nar/21.23.5332 · Cited by 334 · see citing works
Boulet, L., Karpati, G., & Shoubridge, E. A. (1992) · Europe PMC (PubMed Central) · Cited by 331 · see citing works
Silvestri, G., Ciafaloni, E., Santorelli, F. M., Shanske, S., Servidei, S., Graf, W. D., Sumi, M., & DiMauro, S. (1993) · Neurology · doi:10.1212/wnl.43.6.1200 · Cited by 201 · see citing works
DNA-protein conjugates can enter mitochondria via the protein import pathway
Vestweber, D., & Schatz, G. (1989) · Nature · doi:10.1038/338170a0 · Cited by 199 · see citing works
Nuclear gadgets in mitochondrial DNA replication and transcription
Clayton, D. A. (1991) · Trends in Biochemical Sciences · doi:10.1016/0968-0004(91)90043-u · Cited by 187 · see citing works
Transfection of mitochondria: strategy towards a gene therapy of mitochondrial DNA diseases
Seibel, P., Trappe, J., Villani, G., Klopstock, T., Papa, S., & Reichmann, H. (1995) · Nucleic Acids Research · doi:10.1093/nar/23.1.10 · Cited by 153 · see citing works
Curth, U., Urbanke, C., Greipel, J., Gerberding, H., Tiranti, V., & Zeviani, M. (1994) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1994.tb18756.x · Cited by 99 · see citing works
Isolation and characterization of a DNA primase from human mitochondria.
Wong, T. W., & Clayton, D. A. (1985) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)39063-4 · Cited by 75 · see citing works
Structural and functional studies of the rat mitochondrial single strand DNA binding protein P16
Hoke, G. D., Pavco, P. A., Ledwith, B. J., & Tuyle, G. C. V. (1990) · Archives of Biochemistry and Biophysics · doi:10.1016/0003-9861(90)90094-f · Cited by 53 · see citing works
Gene Therapy for Mitochondrial DNA Defects - is it possible?
Chrzanowska‐Lightowlers, Z. M., Lightowlers, R., & Turnbull, D. (1995) · PubMed · doi:10.25405/ncl.34087875 · Cited by 50 · see citing works
Stimulation of Drosophila Mitochondrial DNA Polymerase by Single-stranded DNA-binding Protein
Williams, A. J., & Kaguni, L. S. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.2.860 · Cited by 43 · see citing works
Stimulation of DNA polymerase gamma by a mitochondrial single-strand DNA binding protein.
Genuario, R. R., & Wong, T. W. (1993) · PubMed · Cited by 20 · see citing works
About the "Asian"-specific 9-bp deletion of mtDNA....
Torroni, A., Petrozzi, M., Santolamazza, P., Sellitto, D., Cruciani, F., & Scozzari, R. (1995) · Europe PMC (PubMed Central) · Cited by 19 · see citing works
Reply to Newton Freire‐Maia on inbreeding among medical geneticists II
Stoll, C. G., Alembik, Y., Dott, B., & Feingold, J. (1995) · American Journal of Medical Genetics · doi:10.1002/ajmg.1320570334 · Cited by 7 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Mitochondrial DNA mutations in human disease
Taylor, R. W., & Turnbull, D. M. (2005) · Nature Reviews Genetics · doi:10.1038/nrg1606 · Cited by 1,866 · see citing works
“The selective inhibition of mutated mtDNA replication by antigenomic agents has been applied to manipulate mtDNA heteroplasm”
Mitochondrial Energetics and Therapeutics
Wallace, D. C., Fan, W., & Procaccio, V. (2010) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev.pathol.4.110807.092314 · Cited by 727 · see citing works
“However, in vivo efficacy of this approach has yet to be established (104, 105).”
Mitochondrial DNA mutations and human disease
Tuppen, H. A. L., Blakely, E. L., Turnbull, D. M., & Taylor, R. W. (2010) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2009.09.005 · Cited by 676 · see citing works
“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].”
BackgroundMammalian mitochondrial genetics: heredity, heteroplasmy and disease
Lightowlers, R. N., Chinnery, P. F., Turnbull, D. M., & Howell, N. (1997) · Trends in Genetics · doi:10.1016/s0168-9525(97)01266-3 · Cited by 471 · see citing works
Mitochondrial Diseases: Hope for the Future
Russell, O. M., Gorman, G. S., Lightowlers, R. N., & Turnbull, D. M. (2020) · Cell · doi:10.1016/j.cell.2020.02.051 · Cited by 460 · see citing works
Specific elimination of mutant mitochondrial genomes in patient-derived cells by mitoTALENs
Bacman, S. R., Williams, S. L., Pinto, M., Peralta, S., & Moraes, C. T. (2013) · Nature Medicine · doi:10.1038/nm.3261 · Cited by 432 · see citing works
Drug delivery to mitochondria: the key to mitochondrial medicine
Murphy, M. P., & Smith, R. A. J. (2000) · Advanced Drug Delivery Reviews · doi:10.1016/s0169-409x(99)00069-1 · Cited by 426 · see citing works
Peptide nucleic acid (PNA): its medical and biotechnical applications and promise for the future
Ray, A., & Nordén, B. (2000) · The FASEB Journal · doi:10.1096/fasebj.14.9.1041 · Cited by 417 · see citing works
“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).”
BackgroundBactericidal antisense effects of peptide–PNA conjugates
Good, L., Awasthi, S. K., Dryselius, R., Larsson, O. S., & Nielsen, P. E. (2001) · Nature Biotechnology · doi:10.1038/86753 · Cited by 391 · see citing works
Selective targeting of bioactive compounds to mitochondria
Murphy, M. P. (1997) · Trends in Biotechnology · doi:10.1016/s0167-7799(97)01068-8 · Cited by 366 · see citing works
Targeting Mitochondria with Organelle‐Specific Compounds: Strategies and Applications
Yousif, L. F., Stewart, K. M., & Kelley, S. O. (2009) · ChemBioChem · doi:10.1002/cbic.200900185 · Cited by 330 · see citing works
Greaves, L. C., Reeve, A. K., Taylor, R. W., & Turnbull, D. M. (2011) · The Journal of Pathology · doi:10.1002/path.3028 · Cited by 301 · see citing works
Gammage, P. A., Rorbach, J., Vincent, A. I., Rebar, E. J., & Minczuk, M. A. (2014) · EMBO Molecular Medicine · doi:10.1002/emmm.201303672 · Cited by 301 · see citing works
“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
Nielsen, P. E., & Egholm, M. (1999) · Current Issues in Molecular Biology · doi:10.21775/cimb.001.089 · Cited by 275 · see citing works
“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 258 · see citing works
“proposed selective inhibition of mutant mtDNA replication, which would allow propagation of only wild-type DNA, as treatment for mitochondrial disease [182].”
BackgroundAntisense inhibition of gene expression in bacteria by PNA targeted to mRNA
Good, L., & Nielsen, P. E. (1998) · Nature Biotechnology · doi:10.1038/nbt0498-355 · Cited by 257 · see citing works
Progressive myoclonic epilepsies: a review of genetic and therapeutic aspects
Shahwan, A., Farrell, M. A., & Delanty, N. (2005) · The Lancet Neurology · doi:10.1016/s1474-4422(05)70043-0 · Cited by 243 · see citing works
Mitochondrial Medicine: Pharmacological targeting of mitochondria in disease
Armstrong, J. S. (2007) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0707288 · Cited by 235 · see citing works
“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).”
BackgroundGene Therapy for Mitochondrial Disease by Delivering Restriction Endonuclease SmaI into Mitochondria
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 · see citing works
“To inhibit the replication of mutant mtDNA, Taylor et al. [ 22 ] utilized peptide nucleic acids complementary to mutant mtDNA.”
Mitochondrial diseases: from molecular mechanisms to therapeutic advances
Wen, H., Deng, H., Li, B., Chen, J., Zhu, J., Zhang, X., Yoshida, S., & Zhou, Y. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-02044-3 · Cited by 250 · 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
“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).”
Backgroundvan Gisbergen, M. W., Voets, A. M., Starmans, M. H. W., de Coo, I. F. M., Yadak, R., Hoffmann, R. F., Boutros, P. C., Smeets, H. J. M., Dubois, L. J., & Lambin, P. (2015) · Mutation Research/Reviews in Mutation Research · doi:10.1016/j.mrrev.2015.01.001 · Cited by 199 · see citing works
“For example, blocking the replication of mutated mtDNA by peptide nucleic acid might result in repopulated cells with unaffected wild-type DNA [258].”
Epidemiology and treatment of mitochondrial disorders
Chinnery, P. F., & Turnbull, D. M. (2001) · American Journal of Medical Genetics · doi:10.1002/ajmg.1426 · Cited by 202 · see citing works
Wallace, D. C. (2005) · Gene · doi:10.1016/j.gene.2005.05.001 · Cited by 199 · see citing works
Potential Therapeutic Benefits of Strategies Directed to Mitochondria
Camara, A. K. S., Lesnefsky, E. J., & Stowe, D. F. (2009) · Antioxidants and Redox Signaling · doi:10.1089/ars.2009.2788 · Cited by 195 · see citing works
“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).”
BackgroundMismatch repair activity in mammalian mitochondria
Mason, P. A. (2003) · Nucleic Acids Research · doi:10.1093/nar/gkg167 · Cited by 185 · see citing works
“A method for the selective targeting of mutated mtDNA has been designed, with the aim of inhibiting replication (3,4).”
MethodPeptide nucleic acid delivery to human mitochondria
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 · see citing works
Bayona‐Bafaluy, M. P., Blits, B., Battersby, B. J., Shoubridge, E. A., & Moraes, C. T. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0502896102 · Cited by 169 · see citing works
Muratovska, A. (2001) · Nucleic Acids Research · doi:10.1093/nar/29.9.1852 · Cited by 167 · see citing works
“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 168 · see citing works
Sequence-specific modification of mitochondrial DNA using a chimeric zinc finger methylase
Minczuk, M., Papworth, M. A., Kolasinska, P., Murphy, M. P., & Klug, A. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0609502103 · Cited by 166 · see citing works
Chinnery, P. F. (2003) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp.74.9.1188 · Cited by 160 · see citing works
Mohanty, A., Tiwari-Pandey, R., & Pandey, N. R. (2019) · Journal of Cell Communication and Signaling · doi:10.1007/s12079-019-00507-9 · Cited by 157 · see citing works
Mitochondrial Disorders: Clinical and Genetic Features
Simon, D. K., & Johns, D. R. (1999) · Annual Review of Medicine · doi:10.1146/annurev.med.50.1.111 · Cited by 150 · see citing works
Chinnery, P. F., & Turnbull, D. (1999) · The Lancet · doi:10.1016/s0140-6736(99)90244-1 · Cited by 143 · see citing works
The potential of mitochondrial genome engineering
Silva-Pinheiro, P., & Minczuk, M. A. (2021) · Nature Reviews Genetics · doi:10.1038/s41576-021-00432-x · Cited by 139 · see citing works
Reversal of a mitochondrial DNA defect in human skeletal muscle
Clark, K. M., Bindoff, L. A., Lightowlers, R. N., Andrews, R. M., Griffiths, P. G., Johnson, M. A., Brierley, E. J., & Turnbull, D. M. (1997) · Nature Genetics · doi:10.1038/ng0797-222 · Cited by 141 · see citing works
Approaches to the treatment of mitochondrial diseases
DiMauro, S., Hirano, M., & Schon, E. A. (2006) · Muscle & Nerve · doi:10.1002/mus.20598 · Cited by 138 · see citing works
Mitochondria as a centrally positioned hub in the innate immune response
Sandhir, R., Halder, A., & Sunkaria, A. (2017) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2016.10.020 · Cited by 135 · see citing works
The neurology of mitochondrial DNA disease
McFarland, R., Taylor, R. W., & Turnbull, D. M. (2002) · The Lancet Neurology · doi:10.1016/s1474-4422(02)00159-x · Cited by 134 · see citing works
Mitochondrial Diseases: Therapeutic Approaches
DiMauro, S., & Mancuso, M. (2007) · Bioscience Reports · doi:10.1007/s10540-007-9041-4 · Cited by 121 · see citing works
“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).”
BackgroundKucharczyk, R., Zick, M., Bietenhader, M., Rak, M., Couplan, E., Blondel, M., Duvezin‐Caubet, S., & di Rago, J. (2008) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2008.06.012 · Cited by 121 · see citing works
“Nevertheless, several experimental strategies have been developed [133,134,141–145], of which two will be discussed below.”
BackgroundCationic bolasomes with delocalized charge centers as mitochondria-specific DNA delivery systems
Weissig, V., & Torchilin, V. P. (2001) · Advanced Drug Delivery Reviews · doi:10.1016/s0169-409x(01)00131-4 · Cited by 113 · see citing works
Clinical mitochondrial genetics
Chinnery, P. F., Howell, N., Andrews, R. M., & Turnbull, D. M. (1999) · Journal of Medical Genetics · doi:10.1136/jmg.36.6.425 · Cited by 110 · see citing works
Emerging concepts in the therapy of mitochondrial disease
Viscomi, C. F., Bottani, E., & Zeviani, M. (2015) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2015.03.001 · Cited by 107 · see citing works
“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 105 · see citing works
Progress in Developing PNA as a Gene-Targeted Drug
Good, L., & Nielsen, P. E. (1997) · Antisense and Nucleic Acid Drug Development · doi:10.1089/oli.1.1997.7.431 · Cited by 107 · see citing works
“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 · see citing works
“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 104 · see citing works
Clinical features, investigation, and management of patients with defects of mitochondrial DNA
Chinnery, P. F., & Turnbull, D. M. (1997) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp.63.5.559 · Cited by 103 · see citing works
Mitochondrial DNA disease—molecular insights and potential routes to a cure
Russell, O. M., & Turnbull, D. M. (2014) · Experimental Cell Research · doi:10.1016/j.yexcr.2014.03.012 · Cited by 96 · see citing works
Bacman, S. R., Williams, S. L., Hernandez, D., & Moraes, C. T. (2007) · Gene Therapy · doi:10.1038/sj.gt.3302981 · Cited by 93 · see citing works
DiMauro, S., & Rustin, P. (2008) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2008.10.015 · Cited by 94 · see citing works
“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 94 · see citing works
Yamada, Y., & Harashima, H. (2011) · Biomaterials · doi:10.1016/j.biomaterials.2011.10.082 · Cited by 92 · see citing works
“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 · see citing works
Zeviani, M., Tiranti, V., & Piantadosi, C. (1998) · Medicine · doi:10.1097/00005792-199801000-00006 · Cited by 87 · see citing works
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 84 · see citing works
Fate of microinjected sperm components in the mouse oocyte and embryo
Cummins, J. M., Wakayama, T., & Yanagimachi, R. (1997) · Zygote · doi:10.1017/s0967199400003889 · Cited by 82 · see citing works
Treating neurodegeneration by modifying mitochondria: potential solutions to a “complex” problem
Swerdlow, R. H. (2007) · Antioxidants & Redox Signaling · doi:10.1089/ars.2007.1676 · Cited by 81 · see citing works
“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 80 · see citing works
Comte, C., Tonin, Y., Heckel-Mager, A.-M., Boucheham, A., Smirnov, A., Auré, K., Lombès, A., Martin, R., Entelis, N., & Tarassov, I. (2012) · Nucleic Acids Research · doi:10.1093/nar/gks965 · Cited by 71 · see citing works
“To obtain single-stranded templates, we used the method described in (11).”
BackgroundMethodInfluentialMitochondrial medicine – recent advances
Graff, C., Clayton, D. A., & Larsson, N. (1999) · Journal of Internal Medicine · doi:10.1046/j.1365-2796.1999.00514.x · Cited by 79 · see citing works
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 · see citing works
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 · see citing works
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 77 · see citing works
“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 · see citing works
“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 · see citing works
Peptide nucleic acids: versatile tools for gene therapy strategies
Dean, D. A. (2000) · Advanced Drug Delivery Reviews · doi:10.1016/s0169-409x(00)00087-9 · Cited by 73 · see citing works
“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 72 · see citing works
Mitochondrial Abnormalities in Alzheimer’s Disease
Silva, D. F., Selfridge, J. E., Lu, J., E, L., Cardoso, S. M., & Swerdlow, R. H. (2012) · Advances in Pharmacology · doi:10.1016/b978-0-12-394816-8.00003-9 · Cited by 86 · see citing works
“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 · see citing works
“’’ 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 64 · see citing works
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 · see citing works
Larsson, N. ‐., & Oldfors, A. (2001) · Acta Physiologica Scandinavica · doi:10.1046/j.1365-201x.2001.00842.x · Cited by 65 · see citing works
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 · see citing works
“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 62 · see citing works
Naviaux, R. K. (2000) · European Journal of Pediatrics · doi:10.1007/pl00014407 · Cited by 62 · see citing works
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 64 · see citing works
“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 · see citing works
Peptide nucleic acid (PNA) binding-mediated gene regulation
Wang, G., & Xu, X. (2004) · Cell Research · doi:10.1038/sj.cr.7290209 · Cited by 59 · see citing works
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 · see citing works
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 · see citing works
“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 · see citing works
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 52 · see citing works
“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 51 · see citing works
Tripathi, S. (2005) · Nucleic Acids Research · doi:10.1093/nar/gki743 · Cited by 51 · see citing works
“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 · see citing works
“…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 · see citing works
“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 · see citing works
“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 47 · see citing works
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 · see citing works
“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).”
Effiziente Sialyltransferase-Inhibitoren auf der Basis von Übergangszustandsanaloga des Sialyldonors
Müller, B. H., Schaub, C., & Schmidt, R. R. (1998) · Angewandte Chemie · doi:10.1002/(sici)1521-3757(19981016)110:20 · Cited by 25 · see citing works
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 41 · see citing works
“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 40 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
“…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 · see citing works
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 36 · see citing works
“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
- 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
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
