Letter | Published:

Mitochondrial transcription factors B1 and B2 activate transcription of human mtDNA

Nature Genetics 31, 289–294 (2002) | Download Citation

Subjects

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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

Rent or Buy

All prices are NET prices.

References

  1. 1.

    Transcription of the mammalian mitochondrial genome. Annu. Rev. Biochem. 53, 573–594 (1984).

  2. 2.

    Replication and transcription of vertebrate mitochondrial DNA. Annu. Rev. Cell Biol. 7, 453–478 (1991).

  3. 3.

    & Molecular genetic aspects of human mitochondrial disorders. Annu. Rev. Genet. 29, 151–178 (1995).

  4. 4.

    , & The genetics and pathology of oxidative phosphorylation. Nature Rev. Genet. 2, 342–352 (2001).

  5. 5.

    & Revolution in mitochondrial medicine. FEBS Lett. 455, 199–202 (1999).

  6. 6.

    Mitochondrial diseases in man and mouse. Science 283, 1482–1488 (1999).

  7. 7.

    et al. Identification of the gene encoding the human mitochondrial RNA polymerase (h-mtRPOL) by cyberscreening of the expressed sequence tags database. Hum. Mol. Genet. 6, 615–625 (1997).

  8. 8.

    & A transcription factor required for promoter recognition by human mitochondrial RNA polymerase. Accurate initiation at the heavy- and light-strand promoters dissected and reconstituted in vitro. J. Biol. Chem. 260, 11330–11338 (1985).

  9. 9.

    & Similarity of human mitochondrial transcription factor 1 to high mobility group proteins. Science 252, 965–969 (1991).

  10. 10.

    , & Yeast mitochondrial RNA polymerase is homologous to those encoded by bacteriophages T3 and T7. Cell 51, 89–99 (1987).

  11. 11.

    , , & Specificity factor of yeast mitochondrial RNA polymerase. Purification and interaction with core RNA polymerase. J. Biol. Chem. 262, 12785–12791 (1987).

  12. 12.

    , & A human mitochondrial transcriptional activator can functionally replace a yeast mitochondrial HMG-box protein both in vivo and in vitro. Mol. Cell. Biol. 13, 1951–1961 (1993).

  13. 13.

    & Purification and characterization of human mitochondrial transcription factor 1. Mol. Cell. Biol. 8, 3496–3509 (1988).

  14. 14.

    et al. Sequence and organization of the human mitochondrial genome. Nature 290, 457–465 (1981).

  15. 15.

    , , , & Sequence and organization of mouse mitochondrial DNA. Cell 26, 167–180 (1981).

  16. 16.

    , & Distinctive features of the 5′-terminal sequences of the human mitochondrial mRNAs. Nature 290, 465–470 (1981).

  17. 17.

    , & tRNA punctuation model of RNA processing in human mitochondria. Nature 290, 470–474 (1981).

  18. 18.

    et al. Mitochondrial transcription factor A is necessary for mtDNA maintenance and embryogenesis in mice. Nature Genet. 18, 231–236 (1998).

  19. 19.

    , & Addition of a 29 residue carboxyl-terminal tail converts a simple HMG box-containing protein into a transcriptional activator. J. Mol. Biol. 249, 11–28 (1995).

  20. 20.

    & Distinct roles for two purified factors in transcription of Xenopus mitochondrial DNA. Mol. Cell. Biol. 15, 7032–7042 (1995).

  21. 21.

    Interaction of mtTFB and mtRNA polymerase at core promoters for transcription of Xenopus laevis mtDNA. J. Biol. Chem. 271, 12036–12041 (1996).

  22. 22.

    & Import of transcription factor MTF1 into the yeast mitochondria takes place through an unusual pathway. J. Biol. Chem. 270, 11970–11976 (1995).

  23. 23.

    et al. Visualization of mitochondrial protein import in cultured mammalian cells with green fluorescent protein and effects of overexpression of the human import receptor Tom20. J. Biol. Chem. 272, 8459–8465 (1997).

  24. 24.

    , , , & A single mouse gene encodes the mitochondrial transcription factor A and a testis-specific nuclear HMG-box protein. Nat. Genet. 13, 296–302 (1996).

  25. 25.

    , , , & Down-regulation of mitochondrial transcription factor A during spermatogenesis in humans. Hum. Mol. Genet. 6, 185–191 (1997).

  26. 26.

    et al. Crystal structure of the transcription factor sc-mtTFB offers insights into mitochondrial transcription. Protein Sci. 10, 1980–1988 (2001).

  27. 27.

    , & A human mitochondrial transcription factor is related to RNA adenine methyltransferases and binds S-adenosylmethionine. Mol. Cell. Biol. 22, 1116–1125 (2002).

  28. 28.

    , , & Crystal structure and deletion analysis show that the accessory subunit of mammalian DNA polymerase γ, Pol γ B, functions as a homodimer. Mol. Cell 7, 43–54 (2001).

  29. 29.

    , & Mitochondrial DNA transcription initiation and termination using mitochondrial lysates from cultured human cells. Methods Enzymol. 264, 129–139 (1996).

  30. 30.

    et al. Yeast global transcriptional regulators Sin4 and Rgr1 are components of mediator complex/RNA polymerase II holoenzyme. Proc. Natl Acad. Sci. USA 92, 10864–10868 (1995).

Download references

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.

Author information

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

Authors

  1. Search for Maria Falkenberg in:

  2. Search for Martina Gaspari in:

  3. Search for Anja Rantanen in:

  4. Search for Aleksandra Trifunovic in:

  5. Search for Nils-Göran Larsson in:

  6. Search for Claes M. Gustafsson in:

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.

To obtain permission to re-use content from this article visit RightsLink.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/ng909

Further reading