Cited by 250Mitochondrial Function and PathologyDNA Repair MechanismsMetabolism and Genetic Disorders

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Twinkle helicase is essential for mtDNA maintenance and regulates mtDNA copy number

Tyynismaa, Henna, Sembongi, Hiroshi, Bokori-Brown, Monika, Granycome, Caroline, Ashley, Neil, Poulton, Joanna, Jalanko, Anu, Spelbrink, Johannes N., Holt, Ian J., Suomalainen, Anu·2004·Human Molecular Genetics

DOI 10.1093/hmg/ddh342

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Abstract

Mechanisms of mitochondrial DNA (mtDNA) maintenance have recently gained wide interest owing to their role in inherited diseases as well as in aging. Twinkle is a new mitochondrial 5'-3' DNA helicase, defects of which we have previously shown to underlie a mitochondrial disease, progressive external ophthalmoplegia with multiple mtDNA deletions. Mouse Twinkle is highly similar to the human counterpart, suggesting conserved function. Here, we have characterized the mouse Twinkle gene and expression profile and report that the expression patterns are not conserved between human and mouse, but are synchronized with the adjacent gene MrpL43, suggesting a shared promoter. To elucidate the in vivo role of Twinkle in mtDNA maintenance, we generated two transgenic mouse lines overexpressing wild-type Twinkle. We could demonstrate for the first time that increased expression of Twinkle in muscle and heart increases mtDNA copy number up to 3-fold higher than controls, more than any other factor reported to date. Additionally, we utilized cultured human cells and observed that reduced expression of Twinkle by RNA interference mediated a rapid drop in mtDNA copy number, further supporting the in vivo results. These data demonstrate that Twinkle helicase is essential for mtDNA maintenance, and that it may be a key regulator of mtDNA copy number in mammals.

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Self-citation
Elevation of Pollen Mitochondrial DNA Copy Number by WHIRLY2: Altered Respiration and Pollen Tube Growth in Arabidopsis
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Authors: Tyynismaa, H., Sembongi, H., Bokori-Brown, M., Granycome, C., Ashley, N., Poulton, J., Jalanko, A., Spelbrink, J. N., Holt, I. J., & Suomalainen, A.
Affiliations: University of Helsinki (FI)
MRC Mitochondrial Biology Unit (GB)
John Radcliffe Hospital (GB)
Institute for Molecular Medicine Finland (FI)
Corresponding author: Tyynismaa, Henna
ORCID: Tyynismaa, Henna
Ashley, Neil
Poulton, Joanna
Spelbrink, Johannes N.
Holt, Ian J.
Suomalainen, Anu
Venue: Human Molecular Genetics
Publisher: Oxford University Press (OUP)
Published: 2004-10-27
Volume: 13
Issue: 24
Pages: 3219-3227
ISSN: 0964-6906 (ISSN-L)
1460-2083
DOI: 10.1093/hmg/ddh342
OpenAlex: W2154067341
Cited by: 250
References: 36
Citations by year: 2026: 9 · 2025: 14 · 2024: 13 · 2023: 5 · 2022: 13 · 2021: 9 · 2020: 11 · 2019: 6 · 2018: 13 · 2017: 10 · 2016: 12 · 2015: 15 · 2014: 10 · 2013: 14 · 2012: 10
FWCI: 4.03
Type: journal article
Language: en
Open access: closed
Locations: Human Molecular Genetics (publishedVersion)
PubMed (publishedVersion)
UCL Discovery (University College London) (submittedVersion)
HighWire Press Open Archive (submittedVersion)
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 helicase, mitochondrial DNA maintenance, mitochondrial DNA copy number, mitochondrial disease, chronic progressive external ophthalmoplegia, mitochondrial DNA deletions, transgenic overexpression, RNA interference, muscle, heart, mouse model
MeSH terms: Animals, DNA Helicases, DNA, Mitochondrial, Humans, Mitochondria, Gene Dosage, DNA Primase, Gene Expression Profiling, Mitochondrial Proteins, RNA Interference, Mice

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Twinkle helicase is essential for mtDNA maintenance and regulates mtDNA copy number

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