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Human Molecular Genetics Advance Access originally published online on October 27, 2004
Human Molecular Genetics 2004 13(24):3219-3227; doi:10.1093/hmg/ddh342
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Human Molecular Genetics, Vol. 13, No. 24 © Oxford University Press 2004; all rights reserved

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

Henna Tyynismaa1, Hiroshi Sembongi2, Monika Bokori-Brown2, Caroline Granycome2, Neil Ashley3, Joanna Poulton3, Anu Jalanko4, Johannes N. Spelbrink5, Ian J. Holt2 and Anu Suomalainen1,6,*

1Department of Neurology and Programme of Neurosciences, University of Helsinki, 00290 Helsinki, Finland, 2Dunn Human Nutrition Unit, Wellcome Trust/MRC Building, Hills Road, Cambridge CB2 2XY, UK, 3Nuffield Department of Obstetrics and Gynaecology, John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK, 4Department of Molecular Medicine, National Public Health Institute, 00290 Helsinki, Finland, 5Institute of Medical Technology and Tampere University Hospital, 33014 Tampere, Finland and 6Department of Clinical Chemistry, Helsinki University Central Hospital, 00290 Helsinki, Finland

Received September 1, 2004; Accepted October 19, 2004

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.

* To whom correspondence should be addressed at: Biomedicum-Helsinki, r. c522B, University of Helsinki, Haartmaninkatu 8, 00290 Helsinki, Finland. Tel: +358 947171965/+358 405936386; Fax: +358 947171964; Email: anu.wartiovaara{at}helsinki.fi


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