Mitochondrial transcription factors B1 and B2 activate transcription of human mtDNA
Abstract
Characterization of the basic transcription machinery of mammalian mitochondrial DNA (mtDNA) is of fundamental biological interest and may also lead to therapeutic interventions for human diseases associated with mitochondrial dysfunction. 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) and mitochondrial transcription factor A. 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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Tfam is ubiquitously expressed and absolutely required for mtDNA transcription.
“Tfam is ubiquitously expressed and absolutely required for mtDNA transcription (8,13).”
From Increased mitochondrial mass in mitochondrial myopathy mice (2002) · cites this paper as [13]
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“The increase of de novo transcription correlated with increased levels of TFB2M protein, which activates transcription (Falkenberg et al., 2002; Metodiev et al., 2009), from week 5 and decreased levels of MTERF3 protein, which represses mtDNA transcription (Park et al.”
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“Recently, it was shown that additional transcription factors may influence the transcription of human mitochondrial DNA in vitro (11), namely mitochondrial transcription factors B1 (TFB1M) and B2 (TFB2M).”
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“In vitro mitochondrial DNA (mtDNA) transcription is produced from both the light-strand (LSP) and the heavy-strand (HSP) promoters (13,14) and promoter-specific initiation of transcription is induced under the presence of TFAM (14,15).”
BackgroundMethodMTERF3 Is a Negative Regulator of Mammalian mtDNA Transcription
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“Both TFB1M and TFB2M form stable heterodimers with POLRMT, but TFB2M is at least an order of magnitude more active than TFB1M in promoting in vitro transcription initiation (Falkenberg et al., 2002).”
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“The presence of two proteins that interact with mammalian POLRMT may allow fl exible regulation of mtDNA gene expression in response to the complex physiological demands of mammalian metabolism [103].”
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“In in vitro transcription assays, normal levels of transcripts from LSP and HSP1 require TFAM 5, 6 .”
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Germline selection shapes human mitochondrial DNA diversity
Wei, W., Tuna, S., Keogh, M. J., Smith, K. R., Aitman, T. J., Beales, P. L., Bennett, D., Gale, D. P., Bitner-Glindzicz, M. A. K., Black, G. C. M., et al. (2019) · Science · doi:10.1126/science.aau6520 · Cited by 237 · see citing works
“31, Fisher’s exact test), which are required for mtDNA transcription and mtDNA replication (29).”
BackgroundFacucho-Oliveira, J., & John, J. C. S. (2009) · Stem Cell Reviews and Reports · doi:10.1007/s12015-009-9058-0 · Cited by 235 · see citing works
“Initiation of mtDNA replication begins with the transcription of an RNA primer from LSP [47], which necessitates the recruitment of TFAM, TFB1M or TFB2M and mtRNApol to transcribe the replication primer.”
BackgroundInfluentialJohn, J. C. S., Ramalho‐Santos, J., Gray, H. L., Petrosko, P., Rawe, V. Y., Navara, C. S., Simerly, C. R., & Schatten, G. P. (2005) · Cloning and Stem Cells · doi:10.1089/clo.2005.7.141 · Cited by 231 · see citing works
“Those cells at the on-set and tubular mitochondria (Sathananthan et al., 2002) and, in mouse ESCs, also harvested to TFAM other factors factor B1 ( (Falkenberg possess both al., 2003).”
Mitochondrial transcription and its regulation in mammalian cells
Asin-Cayuela, J., & Gustafsson, C. M. (2007) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2007.01.003 · Cited by 223 · see citing works
Self-citationMitochondrial RNA Polymerase Is Needed for Activation of the Origin of Light-Strand DNA Replication
Fusté, J. M., Wanrooij, S., Jemt, E., Granycome, C., Cluett, T. J., Shi, Y., Atanassova, N., Holt, I. J., Gustafsson, C. M., & Falkenberg, M. (2010) · Molecular Cell · doi:10.1016/j.molcel.2009.12.021 · Cited by 223 · see citing works
“Interestingly, only POLRMT is required for origin-specific primer synthesis, and the transcription factor B2 (TFB2M) found essential at mitochondrial promoters is not needed for activation of OriL (Falkenberg et al., 2002).”
BackgroundMethodSelf-citationMaking Proteins in the Powerhouse
Hällberg, B. M., & Larsson, N. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.07.001 · Cited by 212 · see citing works
Self-citationZhang, X., Agborbesong, E., & Li, X. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222011253 · Cited by 217 · see citing works
“The transcription of human mtDNA in vitro requires the single-subunit mitochondrial RNA polymerase (POLRMT) and human mitochondrial transcription factor B2, h-mtTFB2 [75,76].”
MethodHuman Mitochondrial Transcription Revisited
Litonin, D., Sologub, M., Shi, Y., Savkina, M. V., Anikin, M., Falkenberg, M., Gustafsson, C. M., & Temiakov, D. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.c110.128918 · Cited by 212 · see citing works
Self-citationMitochondrial DNA Transcription and Its Regulation: An Evolutionary Perspective
Barshad, G., Marom, S., Cohen, T., & Mishmar, D. (2018) · Trends in Genetics · doi:10.1016/j.tig.2018.05.009 · Cited by 207 · see citing works
Structure of human mitochondrial RNA polymerase
Ringel, R., Sologub, M., Morozov, Y. I., Litonin, D., Cramer, P., & Temiakov, D. (2011) · Nature · doi:10.1038/nature10435 · Cited by 235 · see citing works
The pathophysiology of mitochondrial disease as modeled in the mousePreprint
Wallace, D. C., & Fan, W. (2009) · Genes & Development · doi:10.1101/gad.1784909 · Cited by 201 · see citing works
“Mammalian POLRMT is homologous to the RNA polymerase found in T3/T7 family of bacteriophage (Falkenberg et al. 2002).”
BackgroundInfluentialMolecular control of mitochondrial function in preimplantation mouse embryos
Thundathil, J. C., Filion, F., & Smith, L. C. (2005) · Molecular Reproduction and Development · doi:10.1002/mrd.20260 · Cited by 200 · see citing works
Human mitochondrial transcription factor A induces a U-turn structure in the light strand promoter
Rubio‐Cosials, A., Sydow, J. F., Jiménez‐Menéndez, N., Fernández-Millán, P., Montoya, J., Jacobs, H. T., Coll, M., Bernadó, P., & Solà, M. (2011) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.2160 · Cited by 198 · see citing works
“To determine the binding sites of TFAM to DNA, footprinting studies were conducted with the protein in the presence or absence of the mtRNA polymerase ( MTRPOL ), which forms a complex with transcription factor B2 ( TFB2M”
MethodMiller, V. J., Villamena, F. A., & Volek, J. S. (2018) · Journal of Nutrition and Metabolism · doi:10.1155/2018/5157645 · Cited by 200 · see citing works
Metabolic reprogramming in osteoclasts
Park‐Min, K. (2019) · Seminars in Immunopathology · doi:10.1007/s00281-019-00757-0 · Cited by 196 · see citing works
Mitochondrial Disease—Its Impact, Etiology, and Pathology
McFarland, R., Taylor, R. W., & Turnbull, D. M. (2007) · Current topics in developmental biology/Current Topics in Developmental Biology · doi:10.1016/s0070-2153(06)77005-3 · Cited by 192 · see citing works
Martin, M., Cho, J., Cesare, A. J., Griffith, J. D., & Attardi, G. M. (2005) · Cell · doi:10.1016/j.cell.2005.09.040 · Cited by 192 · see citing works
Regulation of Mammalian Mitochondrial Gene Expression: Recent Advances
Pearce, S. F., Rebelo‐Guiomar, P., D’Souza, A. R., Powell, C. A., Haute, L. V., & Minczuk, M. A. (2017) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2017.02.003 · Cited by 191 · see citing works
“In addition, mitochondrial transcription factor A (TFAM), mitochondrial transcription factor B2 (TFB2M), and mitochondrial transcription elongation factor (TEFM) are required for efficient transcription in vivo [88,89].”
BackgroundBlanch, M., Mosquera, J. L., Ansoleaga, B., Ferrer, I., & Barrachina, M. (2016) · The American Journal of Pathology · doi:10.1016/j.ajpath.2015.10.004 · Cited by 192 · see citing works
“Moreover, mtDNA is devoid of intronic regions, and the only noncoding sequence is known as the control region or D-loop, which regulates mitochondrial transcription and replication.11 Interestingly, reduced content and activity of complex I and IV subunits of the respiratory chain, such as ND4 in AD brains12e15 and ND…”
BackgroundMammalian transcription factor A is a core component of the mitochondrial transcription machinery
Shi, Y.-H., Dierckx, A., Wanrooij, P. H., Wanrooij, S., Larsson, N., Wilhelmsson, L., Falkenberg, M., & Gustafsson, C. (2012) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.1119738109 · Cited by 189 · see citing works
“POLRMT (amino acids 42–1230, N-terminal 10× His-tag), TFAM (amino acids 43–246, N-terminal 6× His-tag), and TFB2M (amino acids 1–396, C-terminal 6× His-tag) were expressed from recombinant baculoviruses in insect cells and purified as described previously (15).”
BackgroundMethodResultSelf-citationHuman mitochondrial transcription factor B1 methylates ribosomal RNA at a conserved stem-loop
Seidel-Rogol, B. L., McCulloch, V., & Shadel, G. S. (2002) · Nature Genetics · doi:10.1038/ng1064 · Cited by 188 · see citing works
Human mitochondrial RNA polymerase primes lagging-strand DNA synthesis in vitro
Wanrooij, S., Fusté, J. M., Farge, G., Shi, Y., Gustafsson, C. M., & Falkenberg, M. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0805399105 · Cited by 185 · see citing works
“We demonstrated that POLRMT can efficiently synthesize long stretches of RNA on a dsDNA template (23) and we were therefore surprised to see preferential synthesis of short transcripts on an ssDNA template.”
BackgroundSelf-citationWanrooij, P. H., Uhler, J. P., Simonsson, T., Falkenberg, M., & Gustafsson, C. M. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1006026107 · Cited by 184 · see citing works
“We used an in vitro transcription system with purified POLRMT, TFAM, and TFB2M to examine the potential role of G-quadruplexes in premature termination of LSP transcripts (23).”
BackgroundMethodInfluentialSelf-citationThe mitochondrial RNA polymerase contributes critically to promoter specificity in mammalian cells
Gaspari, M., Falkenberg, M., Larsson, N., & Gustafsson, C. M. (2004) · The EMBO Journal · doi:10.1038/sj.emboj.7600465 · Cited by 178 · see citing works
“The recombinant proteins were expressed in Spodoptera frugiperda (Sf9) cells and whole-cell protein extracts were generated as described (Falkenberg et al, 2002).”
BackgroundMethodResultInfluentialSelf-citationGoffart, S., VONKLEISTRETZOW, J., & Wiesner, R. H. (2004) · Cardiovascular Research · doi:10.1016/j.cardiores.2004.06.030 · Cited by 176 · see citing works
“…of nuclear encoded proteins, and a minimal mtDNA transcription machinery was only recently assembled from recombinant purified proteins in vitro [28], consisting of mtRNA polymerase, and two transcription factors termed TFAM and TFBM (transcription factor A and B, mitochondrial, respectively,…”
BackgroundWanrooij, P. H., Uhler, J. P., Shi, Y., Westerlund, F., Falkenberg, M., & Gustafsson, C. M. (2012) · Nucleic Acids Research · doi:10.1093/nar/gks802 · Cited by 172 · see citing works
“For mitochondrial transcription in vitro, recombinant human POLRMT, TFAM and TFB2M were expressed and purified from insect cells as described previously (4).”
MethodInfluentialSelf-citationFredriksson, K., Tjäder, I., Keller, P., Petrovič, N., Ahlman, B. H. J., Scheele, C. C., Wernerman, J., Timmons, J. A., & Rooyackers, O. (2008) · PLoS ONE · doi:10.1371/journal.pone.0003686 · Cited by 168 · see citing works
“To further examine factors which directly regulate mtDNA encoded genes, we determined TFAM, TFB1M and TFB2M expression.”
BackgroundInfluentialHeme oxygenase-1 regulates mitochondrial quality control in the heart
Hull, T. D., Boddu, R., Guo, L., Tisher, C. C., Traylor, A., Patel, B., Joseph, R., Prabhu, S. D., Suliman, H. B., Piantadosi, C. A., et al. (2016) · JCI Insight · doi:10.1172/jci.insight.85817 · Cited by 171 · see citing works
Pohjoismäki, J., Wanrooij, S., Hyvärinen, A. K., Goffart, S., Holt, I. J., Spelbrink, J. N., & Jacobs, H. T. (2006) · Nucleic Acids Research · doi:10.1093/nar/gkl703 · Cited by 168 · see citing works
“However, high levels of TFAM added exogenously in vitro (9,28,29), as well as prolonged over expression in HEKcultured cells (27), bring about a paradoxical decrease in transcription.”
BackgroundLjubicic, V., Joseph, A.-M., Saleem, A., Uguccioni, G., Collu-Marchese, M., Lai, R. Y. J., Nguyen, L. M.-D., & Hood, D. A. (2010) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2009.07.031 · Cited by 167 · see citing works
Mitochondrial biogenesis in the axons of vertebrate peripheral neurons
Amiri, M., & Hollenbeck, P. J. (2008) · Developmental Neurobiology · doi:10.1002/dneu.20668 · Cited by 161 · see citing works
“Finally, components of the mitochondrial replication apparatus have been identified outside the perinuclear region in nonneuronal cells (Larsson et al., 1994; Tiranti et al., 1997; Spelbrink et al., 2000, 2001; Falkenberg et al., 2002; Magnusson et al., 2003) and neuron-like cell lines (Magnusson et al.”
Protein Components of Mitochondrial DNA Nucleoids in Higher Eukaryotes*
Bogenhagen, D., Wang, Y., Shen, E. L., & Kobayashi, R. (2003) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m300035-mcp200 · Cited by 159 · see citing works
Chinnery, P. F. (2003) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp.74.9.1188 · Cited by 160 · see citing works
Kühn, K., Richter, U., Meyer, E. H., Delannoy, É., de Longevialle, A. F., O’Toole, N., Börner, T., Millar, A. H., Small, I., & Whelan, J. (2009) · The Plant Cell · doi:10.1105/tpc.109.068536 · Cited by 157 · see citing works
“A similar enzyme functions as the core RNA polymerase in human mitochondria (Tiranti et al., 1997; Falkenberg et al., 2002).”
BackgroundImpact of Aging and Exercise on Mitochondrial Quality Control in Skeletal Muscle
Kim, Y., Triolo, M., & Hood, D. A. (2017) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2017/3165396 · Cited by 158 · see citing works
“Mitochondrial gene transcription is initiated by the nuclear-encodedmitochondrialRNApolymerase (POLRMT) [79], with the aid of mitochondrial transcription factors B1 and B2 (TFB1/2) and Tfam [80, 81].”
BackgroundActivation of cardiac Cdk9 represses PGC‐1 and confers a predisposition to heart failure
Sano, M., Wang, S. C., Shirai, M., Scaglia, F., Xie, M., Sakai, S., Tanaka, T., Kulkarni, P. A., Barger, P. M., Youker, K. A., et al. (2004) · The EMBO Journal · doi:10.1038/sj.emboj.7600351 · Cited by 156 · see citing works
“…mitochondrial gene transcription and replication, transcription is driven only at high levels of TFAM, with replication active across a wider range (Falkenberg et al, 2002): this dosage effect potentially explains the downregulation of genes for mitochondrial function without a concomitant…”
BackgroundRoles for the Human ATP-dependent Lon Protease in Mitochondrial DNA Maintenance
Lü, B., Yadav, S. S., Shah, P. G., Liu, T., Tian, B., Pukszta, S., Villaluna, N., Kutějová, E., Newlon, C. S., Santos, J. H., et al. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m611540200 · Cited by 148 · see citing works
Bohnsack, M. T., & Sloan, K. E. (2017) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-017-2598-6 · Cited by 145 · see citing works
“Notably, these proteins were initially characterised as mitochondrial transcription factors [37]; however, in vivo analyses revealed that TFB1M is primarily responsible for modification of 12S rRNA, while TFB2M mainly functions as a transcription factor (reviewed in [38]).”
BackgroundKühl, I., Miranda, M., Posse, V., Milenkovic, D., Mourier, A., Siira, S. J., Bonekamp, N. A., Neumann, U., Filipovska, A., Polosa, P. L., et al. (2016) · Science Advances · doi:10.1126/sciadv.1600963 · Cited by 146 · see citing works
“According to in vitro studies, initiation of mitochondrial transcription requires three proteins, namely, POLRMT, the mitochondrial transcription factor B2 (TFB2M), and the mitochondrial transcription factor A (TFAM) (9, 10, 12).”
BackgroundResultSelf-citationSchmidt, J. K., Carrillo, J. A., Namous, H., Daniels, A., Salih, S. M., Song, J., & Khatib, H. (2017) · BMC Genomics · doi:10.1186/s12864-017-3673-y · Cited by 148 · see citing works
“The transcription factor B2, mitochondrial (TFB2M) gene is a mitochondrial transcription factor [46], where overexpression in rat cardiac myocytes resulted in increased mRNA levels of mitochondrial enzymes and increased mitochondrial DNA copy [46, 47].”
BackgroundResveratrol protects against peripheral deficits in a mouse model of Huntington's disease
Ho, D. J., Calingasan, N. Y., Wille, E. J., Dumont, M., & Beal, M. F. (2010) · Experimental Neurology · doi:10.1016/j.expneurol.2010.05.006 · Cited by 147 · see citing works
Maniura‐Weber, K. (2004) · Nucleic Acids Research · doi:10.1093/nar/gkh921 · Cited by 145 · see citing works
“In contrast, the TFBM proteins bind directly to POLRMT with high affinity, and at a 1:1 stoichiometry a maximal transcription rate is obtained (2).”
InfluentialAharoni-Simon, M., Hahn-Obercyger, M., Pen, S., Madar, Z., & Tirosh, O. (2011) · Laboratory Investigation · doi:10.1038/labinvest.2011.55 · Cited by 143 · see citing works
“Nevertheless, although both human TFB1M and TFB2M interact directly with mitochondrial RNA polymerase to induce mtDNA replication and transcription, TFB2M is more active than TFB1M.(24)”
BackgroundMcCulloch, V., & Shadel, G. S. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.16.5816-5824.2003 · Cited by 142 · see citing works
“As was the case for full-length hmtTFA (1-204), a protein missing the C-terminal 5 amino acids (1-199) was still capable of interacting with h-mtTFA (Fig.”
BackgroundInfluentialConserved Sequence Box II Directs Transcription Termination and Primer Formation in Mitochondria*
Pham, X. H., Farge, G., Shi, Y.-H., Gaspari, M., Gustafsson, C., & Falkenberg, M. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m602429200 · Cited by 142 · see citing works
Self-citationARID5B regulates metabolic programming in human adaptive NK cells
Cichocki, F. M., Wu, C., Zhang, B., Felices, M., Tesi, B., Tuininga, K., Dougherty, P., Taras, E., Hinderlie, P., Blazar, B. R., et al. (2018) · The Journal of Experimental Medicine · doi:10.1084/jem.20172168 · Cited by 131 · see citing works
TFB2 is a transient component of the catalytic site of the human mitochondrial RNA polymerase
Sologub, M., Litonin, D., Anikin, M., Mustaev, A., & Temiakov, D. (2009) · Cell · doi:10.1016/j.cell.2009.10.031 · Cited by 145 · see citing works
Gender dimorphism in rat liver mitochondrial oxidative metabolism and biogenesis
Justo, R., Boada, J., Frontera, M., Oliver, J., Bermúdez, J., & Gianotti, M. (2005) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00035.2005 · Cited by 133 · see citing works
“3 and 4) as a mitochondrial differentiation marker (10).”
- Authors
- Falkenberg, M., Gaspari, M., Rantanen, A., Trifunovic, A., Larsson, N.-G., & Gustafsson, C. M.
- Affiliations
- Karolinska Institutet (SE)
- Corresponding author
- Larsson, Nils-Göran
- Gustafsson, Claes M.
- Venue
- Nature Genetics
- Published
- 2002-06-17
- Volume
- 31
- Issue
- 3
- Pages
- 289-294
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W2081360068
- Cited by
- 598
- References
- 30
- Citations by year
- 2026: 5 · 2025: 14 · 2024: 14 · 2023: 14 · 2022: 15 · 2021: 18 · 2020: 19 · 2019: 24 · 2018: 23 · 2017: 31 · 2016: 17 · 2015: 26 · 2014: 22 · 2013: 30 · 2012: 30
- FWCI
- 10.08
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Keywords
- mitochondrial transcription factors, TFB1M, TFB2M, mitochondrial transcription, mitochondrial RNA polymerase, transcriptional regulation, mitochondrial dysfunction
- MeSH terms
- Amino Acid Sequence, Animals, DNA-Binding Proteins, DNA, Mitochondrial, Humans, Leukocytes, Methyltransferases, Molecular Sequence Data, Promoter Regions, Genetic, Recombinant Proteins, DNA-Directed RNA Polymerases, Transcription Factors, Transcription, Genetic, Sequence Homology, Amino Acid, Mitochondrial Proteins, Mice, In Vitro Techniques
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