Cited by 342Mitochondrial Function and PathologyMetabolism and Genetic DisordersDNA Repair Mechanisms

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Mutant mitochondrial helicase Twinkle causes multiple mtDNA deletions and a late-onset mitochondrial disease in mice

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Tyynismaa, Henna, Mjosund, Katja Peltola, Wanrooij, Sjoerd, Lappalainen, Ilse, Ylikallio, Emil, Jalanko, Anu, Spelbrink, Johannes N., Paetau, Anders, Suomalainen, Anu·2005·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.0505551102PMC PMC1308896

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Abstract

Defects of mitochondrial DNA (mtDNA) maintenance have recently been associated with inherited neurodegenerative and muscle diseases and the aging process. Twinkle is a nuclear-encoded mtDNA helicase, dominant mutations of which cause adult-onset progressive external ophthalmoplegia (PEO) with multiple mtDNA deletions. We have generated transgenic mice expressing mouse Twinkle with PEO patient mutations. Multiple mtDNA deletions accumulate in the tissues of these mice, resulting in progressive respiratory dysfunction and chronic late-onset mitochondrial disease starting at 1 year of age. The muscles of the mice faithfully replicate all of the key histological, genetic, and biochemical features of PEO patients. Furthermore, the mice have progressive deficiency of cytochrome c oxidase in distinct neuronal populations. These "deletor" mice do not, however, show premature aging, indicating that subtle accumulation of mtDNA deletions and progressive respiratory chain dysfunction are not sufficient to accelerate aging. This model is a valuable tool for therapy development and testing for adult-onset mitochondrial disorders.

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Authors: Tyynismaa, H., Mjosund, K. P., Wanrooij, S., Lappalainen, I., Ylikallio, E., Jalanko, A., Spelbrink, J. N., Paetau, A., & Suomalainen, A.
Affiliations: University of Helsinki (FI)
Department of Neurology and Programme of Neurosciences, University of Helsinki, 00290, Helsinki, Finland; Institute of Medical Technology and Tampere University Hospital, 33014, Tampere, Finland; Department of Molecular Medicine, National Public Health Institute, 00290, Helsinki, Finland; and Department of Pathology, Helsinki University Central Hospital and Haartman Institute, University of Helsinki, 00290, Helsinki, Finland
ORCID: Tyynismaa, Henna
Wanrooij, Sjoerd
Ylikallio, Emil
Spelbrink, Johannes N.
Suomalainen, Anu
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 2005-11-21
Volume: 102
Issue: 49
Pages: 17687-17692
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.0505551102
PMC: PMC1308896
OpenAlex: W2144944663
Cited by: 342
References: 31
Citations by year: 2026: 19 · 2025: 16 · 2024: 17 · 2023: 11 · 2022: 20 · 2021: 9 · 2020: 20 · 2019: 15 · 2018: 19 · 2017: 13 · 2016: 23 · 2015: 20 · 2014: 20 · 2013: 19 · 2012: 18
FWCI: 3.89
Type: journal article
Language: en
Open access: green
europepmc.org
Locations: Proceedings of the National Academy of Sciences (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
STM:n Hallinnonalan avoin julkaisuarkisto (Julkari) (submittedVersion)
Funders: Tays
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
Keywords: Twinkle helicase, mitochondrial DNA deletions, chronic progressive external ophthalmoplegia, transgenic mouse model, cytochrome c oxidase deficiency, respiratory chain deficiency, aging, neurodegenerative diseases, myopathy, mtDNA maintenance
MeSH terms: Aging, Animals, Brain, DNA Helicases, DNA, Mitochondrial, Mice, Transgenic, Muscles, Mutation, Neurons, Phenotype, Mitochondrial Myopathies, Sequence Deletion, Mice

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Mutant mitochondrial helicase Twinkle causes multiple mtDNA deletions and a late-onset mitochondrial disease in mice

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