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

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 +1 more·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
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
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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