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Mutant mitochondrial helicase Twinkle causes multiple mtDNA deletions and a late-onset mitochondrial disease in mice
Open accessAbstract
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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“Mouse models have further been used to study comparable phenotypes due to mutations in nuclear-encoded proteins involved in mitochondrial biogenesis, such as TFAM [152], PolG [153], Twinkle [154,155,156], and SURF-1 [157].”
From The Mitochondrial Genome in Aging and Disease and the Future of Mitochondrial Therapeutics (2022) · cites this paper as [154]
In the citing paper
“The Twinkle duplication mouse, herein referred to as the deletor mouse, presents with mitochondrial myopathy around 12 months of age (Tyynismaa et al., 2005).”
From Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases (2017) · cites this paper as Tyynismaa et al., 2005
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“Alternative and more successful approaches to developing mouse models of mitochondrial disease involve manipulating the nuclear genes that regulate mtDNA maintenance and replication, such as TFAM [176 – 182], POLG ( ‘ Mutator ’ model) [183], and PEO1 (Twinkle; ‘ Deletor ’ model) [184].”
Background
Metadata
- 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
- 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
- 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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