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Gene Review

TFAM  -  transcription factor A, mitochondrial

Homo sapiens

Synonyms: MTTF1, MTTFA, Mitochondrial transcription factor 1, MtTF1, TCF-6, ...
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Disease relevance of TFAM

  • The mRNA levels for nuclear respiratory factor 1 and 2 (NRF-1 and -2), the proteins that are known to interact with specific regulatory elements on human TFAM promoter, were 5- and 3-fold higher, respectively, in the hepatoma relative to the host liver [1].
  • TFAM resolves D-loops in vitro if added in similar stoichiometries. mtSSB inhibits the resolution of mtDNA by TFAM but enhances resolution by RecG, a junction-specific helicase from Escherichia coli [2].
  • METHODS AND RESULTS: We have now addressed this question by creating transgenic (Tg) mice that overexpress human TFAM gene and examined whether TFAM could protect the heart from mtDNA deficiencies and attenuate left ventricular (LV) remodeling and failure after myocardial infarction (MI) created by ligating the left coronary artery [3].
  • The mRNA expression of both mtTFA and NRF-1 was upregulated at nephrosis phase, but mtTFA was downregulated at FSGS phase [4].
  • Low levels of mitochondrial transcription factor A (mtTFA) were found in muscle fibers with mitochondrial DNA (mtDNA) depletion in a child with fatal mitochondrial myopathy and also in a human cell line lacking mtDNA [5].

High impact information on TFAM


Chemical compound and disease context of TFAM


Biological context of TFAM

  • The upregulation of TFAM and NRF-1, in aged skeletal muscle, appears involved in the pathway leading to the age-related increase of mitochondrial DNA content [11].
  • We discuss an architectural role for TFAM in the maintenance of mtDNA in addition to its role in transcription activation [12].
  • The amount of TFAM decreased maximally to about 15% of the normal level at day 3 after RNA interference and then recovered gradually [12].
  • TFAM, the gene encoding TFAM maps to chromosome 10q21.1, a region that showed linkage to late-onset AD in several study samples [13].
  • Expression of mitochondrial proteins from the nuclear and mitochondrial genomes is coordinated and involves the nuclear-encoded transcription factors NRF-1 and TFAM [14].

Anatomical context of TFAM

  • When TFAM-DeltaC was expressed at levels comparable to those of endogenous TFAM in HeLa cells, mtDNA increased twofold, suggesting that TFAM-DeltaC is as competent in maintaining mtDNA as endogenous TFAM under these conditions [12].
  • In conclusion, we show that transcription of mtDNA is submaximal in cultured cells and that a subtle increase of TFAM within the matrix is sufficient to stimulate mitochondrial transcription [15].
  • TFAM-null mouse embryos lack mitochondria and fail to develop a heart [16].
  • We conclude that the rate of transcription is submaximal in freshly isolated rat liver mitochondria and that increasing intra-mitochondrial TFAM levels is sufficient for stimulation [17].
  • We now report molecular characterization of human mtTFA (h-mtTFA) expression in somatic tissues and male germ cells [18].

Associations of TFAM with chemical compounds

  • Stimulation of transcription was more evident when TFAM was transiently overexpressed in cells pre-treated with ethidium bromide (EBr) having lowered mtDNA, TFAM and mitochondrial transcript levels [15].
  • Binding of mtTFA to cisplatin-modified DNA was significantly enhanced by p53, whereas binding to oxidized DNA was inhibited [19].
  • Renal expression of TFAM and TOM20 was not altered by neonatal enalapril treatment [20].
  • When human mitochondria are solubilized with non-ionic detergent Nonidet-P40 and then separated into soluble and particulate fractions, most TFAM is recovered from the particulate fraction together with mtDNA, suggesting that human mtDNA forms a nucleoid structure [21].
  • TFAM overexpression could be partially phenocopied by treatment of cells with dideoxycytidine, suggesting that its effects are partially attributable to a decreased rate of fork progression [22].

Regulatory relationships of TFAM

  • Pretreatment with a JAK2 inhibitor AG490 (10 nM) and a MEK inhibitor PD98059 (10 microM) suppressed rhGH-induced rise in mtTF1 mRNA levels of VSMC to the control levels [23].

Other interactions of TFAM

  • Furthermore, mtDNA polymerase POLG and various other as yet unidentified proteins copurify with mtDNA nucleoids using a biochemical isolation procedure, as does TFAM [24].
  • Despite increased levels of TFAM and POLG mRNA and protein at the four-cell stage, no increase in mtDNA copy number was observed in early preimplantation development [25].
  • Possible association of mitochondrial transcription factor A (TFAM) genotype with sporadic Alzheimer disease [13].
  • During an attempt to search for proteins associated with the TFAM-containing complex by a proteomic method, we found one protein that has not been considered to be mitochondrial: PDIP38 [26].
  • The affinity-purified factors from HeLa cells specifically bind to the mtTFA NRF-1 and NRF-2 sites through guanine nucleotide contacts that are characteristic for each site [27].

Analytical, diagnostic and therapeutic context of TFAM


  1. Mitochondrial transcription factor A and its downstream targets are up-regulated in a rat hepatoma. Dong, X., Ghoshal, K., Majumder, S., Yadav, S.P., Jacob, S.T. J. Biol. Chem. (2002) [Pubmed]
  2. Regulation of mitochondrial D-loops by transcription factor A and single-stranded DNA-binding protein. Takamatsu, C., Umeda, S., Ohsato, T., Ohno, T., Abe, Y., Fukuoh, A., Shinagawa, H., Hamasaki, N., Kang, D. EMBO Rep. (2002) [Pubmed]
  3. Overexpression of mitochondrial transcription factor a ameliorates mitochondrial deficiencies and cardiac failure after myocardial infarction. Ikeuchi, M., Matsusaka, H., Kang, D., Matsushima, S., Ide, T., Kubota, T., Fujiwara, T., Hamasaki, N., Takeshita, A., Sunagawa, K., Tsutsui, H. Circulation (2005) [Pubmed]
  4. Mitochondrial dysfunction in focal segmental glomerulosclerosis of puromycin aminonucleoside nephrosis. Hagiwara, M., Yamagata, K., Capaldi, R.A., Koyama, A. Kidney Int. (2006) [Pubmed]
  5. Low levels of mitochondrial transcription factor A in mitochondrial DNA depletion. Larsson, N.G., Oldfors, A., Holme, E., Clayton, D.A. Biochem. Biophys. Res. Commun. (1994) [Pubmed]
  6. Similarity of human mitochondrial transcription factor 1 to high mobility group proteins. Parisi, M.A., Clayton, D.A. Science (1991) [Pubmed]
  7. Flexible recognition of rapidly evolving promoter sequences by mitochondrial transcription factor 1. Fisher, R.P., Parisi, M.A., Clayton, D.A. Genes Dev. (1989) [Pubmed]
  8. Increased expression of mitochondrial-encoded genes in skeletal muscle of humans with diabetes mellitus. Antonetti, D.A., Reynet, C., Kahn, C.R. J. Clin. Invest. (1995) [Pubmed]
  9. The mitochondrial RNA polymerase contributes critically to promoter specificity in mammalian cells. Gaspari, M., Falkenberg, M., Larsson, N.G., Gustafsson, C.M. EMBO J. (2004) [Pubmed]
  10. Regulation of mitochondrial transcription factor A expression by high glucose. Choi, Y.S., Lee, K.U., Pak, Y.K. Ann. N. Y. Acad. Sci. (2004) [Pubmed]
  11. Increased expression of mitochondrial transcription factor A and nuclear respiratory factor-1 in skeletal muscle from aged human subjects. Lezza, A.M., Pesce, V., Cormio, A., Fracasso, F., Vecchiet, J., Felzani, G., Cantatore, P., Gadaleta, M.N. FEBS Lett. (2001) [Pubmed]
  12. Architectural role of mitochondrial transcription factor A in maintenance of human mitochondrial DNA. Kanki, T., Ohgaki, K., Gaspari, M., Gustafsson, C.M., Fukuoh, A., Sasaki, N., Hamasaki, N., Kang, D. Mol. Cell. Biol. (2004) [Pubmed]
  13. Possible association of mitochondrial transcription factor A (TFAM) genotype with sporadic Alzheimer disease. Günther, C., von Hadeln, K., Müller-Thomsen, T., Alberici, A., Binetti, G., Hock, C., Nitsch, R.M., Stoppe, G., Reiss, J., Gal, A., Finckh, U. Neurosci. Lett. (2004) [Pubmed]
  14. Plasticity of skeletal muscle mitochondria: structure and function. Hoppeler, H., Fluck, M. Medicine and science in sports and exercise. (2003) [Pubmed]
  15. Transient overexpression of mitochondrial transcription factor A (TFAM) is sufficient to stimulate mitochondrial DNA transcription, but not sufficient to increase mtDNA copy number in cultured cells. Maniura-Weber, K., Goffart, S., Garstka, H.L., Montoya, J., Wiesner, R.J. Nucleic Acids Res. (2004) [Pubmed]
  16. Review: Mitochondrial medicine--cardiomyopathy caused by defective oxidative phosphorylation. Fosslien, E. Ann. Clin. Lab. Sci. (2003) [Pubmed]
  17. Import of mitochondrial transcription factor A (TFAM) into rat liver mitochondria stimulates transcription of mitochondrial DNA. Garstka, H.L., Schmitt, W.E., Schultz, J., Sogl, B., Silakowski, B., Pérez-Martos, A., Montoya, J., Wiesner, R.J. Nucleic Acids Res. (2003) [Pubmed]
  18. Down-regulation of mitochondrial transcription factor A during spermatogenesis in humans. Larsson, N.G., Oldfors, A., Garman, J.D., Barsh, G.S., Clayton, D.A. Hum. Mol. Genet. (1997) [Pubmed]
  19. P53 physically interacts with mitochondrial transcription factor A and differentially regulates binding to damaged DNA. Yoshida, Y., Izumi, H., Torigoe, T., Ishiguchi, H., Itoh, H., Kang, D., Kohno, K. Cancer Res. (2003) [Pubmed]
  20. Tubular mitochondrial alterations in neonatal rats subjected to RAS inhibition. Lasaitiene, D., Chen, Y., Mildaziene, V., Nauciene, Z., Sundelin, B., Johansson, B.R., Yano, M., Friberg, P. Am. J. Physiol. Renal Physiol. (2006) [Pubmed]
  21. Mitochondrial nucleoid and transcription factor A. Kanki, T., Nakayama, H., Sasaki, N., Takio, K., Alam, T.I., Hamasaki, N., Kang, D. Ann. N. Y. Acad. Sci. (2004) [Pubmed]
  22. Alterations to the expression level of mitochondrial transcription factor A, TFAM, modify the mode of mitochondrial DNA replication in cultured human cells. Pohjoism??ki, J.L., Wanrooij, S., Hyv??rinen, A.K., Goffart, S., Holt, I.J., Spelbrink, J.N., Jacobs, H.T. Nucleic Acids Res. (2006) [Pubmed]
  23. Up-regulation of mitochondrial transcription factor 1 mRNA levels by GH in VSMC. Yoshioka, S., Okimura, Y., Takahashi, Y., Iida, K., Kaji, H., Matsuo, M., Chihara, K. Life Sci. (2004) [Pubmed]
  24. Composition and dynamics of human mitochondrial nucleoids. Garrido, N., Griparic, L., Jokitalo, E., Wartiovaara, J., van der Bliek, A.M., Spelbrink, J.N. Mol. Biol. Cell (2003) [Pubmed]
  25. Regulated mitochondrial DNA replication during oocyte maturation is essential for successful porcine embryonic development. Spikings, E.C., Alderson, J., John, J.C. Biol. Reprod. (2007) [Pubmed]
  26. PDIP38 Associates with Proteins Constituting the Mitochondrial DNA Nucleoid. Cheng, X., Kanki, T., Fukuoh, A., Ohgaki, K., Takeya, R., Aoki, Y., Hamasaki, N., Kang, D. J. Biochem. (2005) [Pubmed]
  27. Activation of the human mitochondrial transcription factor A gene by nuclear respiratory factors: a potential regulatory link between nuclear and mitochondrial gene expression in organelle biogenesis. Virbasius, J.V., Scarpulla, R.C. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  28. History of the Tfam gene in primates. D'Errico, I., Dinardo, M.M., Capozzi, O., De Virgilio, C., Gadaleta, G. Gene (2005) [Pubmed]
  29. Familial mitochondrial DNA depletion in liver: haplotype analysis of candidate genes. Spelbrink, J.N., Van Galen, M.J., Zwart, R., Bakker, H.D., Rovio, A., Jacobs, H.T., Van den Bogert, C. Hum. Genet. (1998) [Pubmed]
  30. Purification and characterization of human mitochondrial transcription factor 1. Fisher, R.P., Clayton, D.A. Mol. Cell. Biol. (1988) [Pubmed]
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