The DOI matches its Crossref record; 52 of the 52 references it cites were found in a registry or an index.
TWINKLE is an essential mitochondrial helicase required for synthesis of nascent D-loop strands and complete mtDNA replication
Open accessAbstract
Replication of the mammalian mitochondrial DNA (mtDNA) is dependent on the minimal replisome, consisting of the heterotrimeric mtDNA polymerase (POLG), the hexameric DNA helicase TWINKLE and the tetrameric single-stranded DNA-binding protein (mtSSB). TWINKLE has been shown to unwind DNA during the replication process and many disease-causing mutations have been mapped to its gene. Patients carrying Twinkle mutations develop multiple deletions of mtDNA, deficient respiratory chain function and neuromuscular symptoms. Despite its importance in human disease, it has been unclear whether TWINKLE is the only replicative DNA helicase in mammalian mitochondria. Furthermore, a substantial portion of mtDNA replication events is prematurely terminated at the end of mitochondrial control region (D-loop) and it is unknown whether TWINKLE also has a role in this abortive replication. Here, we present a conditional mouse knockout for Twinkle and demonstrate that TWINKLE is essential for mouse embryonic development and thus is the only replicative DNA helicase in mammalian mitochondria. Conditional knockout of Twinkle results in severe and rapid mtDNA depletion in heart and skeletal muscle. No replication intermediates or deleted mtDNA molecules are observed after Twinkle knockout, suggesting that TWINKLE once loaded is very processive. We also demonstrate that TWINKLE is essential for nascent H-strand synthesis in the D-loop, thus showing that there is no separate DNA helicase responsible for replication of this region. Our data thus suggest that the relative levels of abortive D-loop synthesis versus complete mtDNA replication are regulated and may provide a mechanism to control progression to complete mtDNA replication.
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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 [156]
In the citing paper
“It is involved in D-loop formation and localizes to the nucleoid (Jemt et al., 2015; Milenkovic et al., 2013; Spelbrink et al., 2001).”
From Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases (2017) · cites this paper as Milenkovic et al., 2013
In the citing paper
“A homozygous Twinkle knock-out mouse is embryonic lethal at E8.5”
From Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases (2017) · cites this paper as Milenkovic et al., 2013
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Metadata
- Authors
- Milenkovic, D., Matic, S., Kuhl, I., Ruzzenente, B., Freyer, C., Jemt, E., Park, C. B., Falkenberg, M., & Larsson, N.-G.
- Affiliations
- Max Planck Institute for Biology of Ageing (DE)
- Karolinska Institutet (SE)
- University of Gothenburg (SE)
- Corresponding author
- Larsson, N.-G.
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2013-02-07
- Volume
- 22
- Issue
- 10
- Pages
- 1983-1993
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- PMC
- PMC3633371
- OpenAlex
- W2167764669
- Cited by
- 173
- References
- 52
- Citations by year
- 2026: 11 · 2025: 18 · 2024: 11 · 2023: 1 · 2022: 19 · 2021: 10 · 2020: 13 · 2019: 17 · 2018: 15 · 2017: 12 · 2016: 19 · 2015: 11 · 2014: 9 · 2013: 7
- FWCI
- 6.86
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc
- Locations
- Human Molecular Genetics (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- AJOU Open Repository (Ajou University) (submittedVersion, cc-by-nc)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Funders
- Swedish Cancer Foundation
- Vetenskapsrådet
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Keywords
- Twinkle, mitochondrial DNA replication, DNA helicase, D-loop, mtDNA depletion, conditional knockout, mouse embryo development, DNA polymerase gamma, mitochondrial DNA control region, mitochondrial disease
- MeSH terms
- Animals, DNA Replication, DNA Helicases, DNA, Mitochondrial, Humans, Mutation, Neuromuscular Diseases, Mice, Knockout, Mitochondrial Proteins, Genetic Diseases, Inborn, Mice
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