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Mitochondrial transcription factors B1 and B2 activate transcription of human mtDNA

Nature Genetics volume 31, pages 289294 (2002) | Download Citation

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Abstract

Characterization of the basic transcription machinery of mammalian mitochondrial DNA (mtDNA)1,2 is of fundamental biological interest and may also lead to therapeutic interventions for human diseases associated with mitochondrial dysfunction3,4,5,6. Here we report that mitochondrial transcription factors B1 (TFB1M) and B2 (TFB2M) are necessary for basal transcription of mammalian mitochondrial DNA (mtDNA). Human TFB1M and TFB2M are expressed ubiquitously and can each support promoter-specific mtDNA transcription in a pure recombinant in vitro system containing mitochondrial RNA polymerase (POLRMT)7 and mitochondrial transcription factor A8,9. Both TFB1M and TFB2M interact directly with POLRMT, but TFB2M is at least one order of magnitude more active in promoting transcription than TFB1M. Both factors are highly homologous to bacterial rRNA dimethyltransferases, which suggests that an RNA-modifying enzyme has been recruited during evolution to function as a mitochondrial transcription factor. The presence of two proteins that interact with mammalian POLRMT may allow flexible regulation of mtDNA gene expression in response to the complex physiological demands of mammalian metabolism.

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Acknowledgements

We thank R. Wibom and E. Holme for the kind gift of mitochondrial extracts. M.F. is supported by a postdoctoral fellowship from the Karolinska Institutet. N.G.L. is supported by grants from the Swedish Research Council, Funds of Karolinska Institutet, Torsten and Ragnar Söderbergs stiftelse, Human Frontiers Science Program, the Swedish Heart and Lung Foundation and the Swedish Foundation for Strategic Research (Functional Genomics and INGVAR). C.M.G. is supported by grants from the Swedish Cancer Society, the Swedish Research Council, Human Frontiers Science Program, the Swedish Foundation for Strategic Research (INGVAR), the Swedish Society for Medical Research, the Ake Wiberg Foundation, and the Magn. Bergwall Foundation.

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Affiliations

  1. Department of Medical Nutrition, Karolinska Institutet, Novum, Huddinge Hospital, S-141 86 Huddinge, Sweden.

    • Maria Falkenberg
    • , Martina Gaspari
    • , Anja Rantanen
    • , Aleksandra Trifunovic
    • , Nils-Göran Larsson
    •  & Claes M. Gustafsson
  2. Department of Biosciences, Karolinska Institutet, Novum, Huddinge Hospital, S-141 86 Huddinge, Sweden.

    • Maria Falkenberg
    • , Martina Gaspari
    • , Anja Rantanen
    • , Aleksandra Trifunovic
    •  & Nils-Göran Larsson

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Competing interests

Two of the authors (N.-G.L. and C.G.) own stock in a startup biotech company, MitoTech AB, that holds patent rights to medical applications of TFB1M and TFB2M.

Corresponding authors

Correspondence to Nils-Göran Larsson or Claes M. Gustafsson.

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DOI

https://doi.org/10.1038/ng909

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