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

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. +2 more·2004·Human Molecular Genetics

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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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
Venue
Human Molecular Genetics
Published
2004-10-27
Volume
13
Issue
24
Pages
3219-3227
ISSN
  • 0964-6906 (ISSN-L)
  • 1460-2083
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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