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Structural basis of mitochondrial transcription
Open accessAbstract
The mitochondrial genome is transcribed by a single-subunit DNA-dependent RNA polymerase (mtRNAP) and its auxiliary factors. Structural studies have elucidated how mtRNAP cooperates with its dedicated transcription factors to direct RNA synthesis: initiation factors TFAM and TFB2M assist in promoter-DNA binding and opening by mtRNAP while the elongation factor TEFM increases polymerase processivity to the levels required for synthesis of long polycistronic mtRNA transcripts. Here, we review the emerging body of structural and functional studies of human mitochondrial transcription, provide a molecular movie that can be used for teaching purposes and discuss the open questions to guide future directions of investigation.
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“TFAM is essential for mtDNA genome maintenance and initiates mitochondrial transcription by recruiting mitochondrial RNA polymerase (POLRMT) and mitochondrial transcription factor B (TFBM) to specific promoter regions on mtDNA (Hillen et al, 2017; Hillen et al, 2018).”
From The mitochondrial long non-coding RNA lncMtloop regulates mitochondrial transcription and suppresses Alzheimer’s disease (2024) · cites this paper as Hillen et al, 2018
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Oxazinomycin arrests RNA polymerase at the polythymidine sequences
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“Recombinant TEFM protein strongly promotes mitochondrial RNA polymerase (POLRMT) processivity as it stimulates the formation of longer transcripts in vitro (12).”
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“For example, since mitochondrial DNA is normally transcribed as a single polycistron (e.g., Hillen et al. 2018), structural signals ought to be present to cleave single transcripts, which are normally found between protein-coding genes as tRNA genes or short noncoding regions with stem-and-loop…”
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“[13] In addition, TEFM also enhances the transcriptional capacity of POLRMT by reducing the frequency and shortening the duration of long-lived pauses.”
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“…executed by a three-component transcription initiation complex, comprised of a single-subunit DNA-directed RNA polymerase mitochondrial (POLRMT), and its auxiliary factors TFAM and mitochondrial transcription factor B2 (TFB2M) (Ramachandran et al., 2017; Morozov et al., 2015; Hillen et al., 2018).”
Cellular and viral RNA polymerases: evolutionary insights into eukaryotic origins
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“Mitochondria have a series of special machinery in DNA replication and transcription, different from nuclear DNA replication and transcription (Hillen et al. 2018).”
BackgroundPOLRMT overexpression increases mtDNA transcription without affecting steady-state mRNA levels
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“…as atomic structures of transcription protein complexes (Wanrooij et al, 2008; Schwinghammer et al, 2013; Morozov et al, 2015; Posse et al, 2015; Hillen et al, 2018; Herbine et al, 2025) and several conditional knockout mouse models (Larsson et al, 1998; Kühl et al, 2016; Matic et al, 2018;…”
Xu, L., Zhang, T., Zhu, B., Tao, H., Liu, Y., Liu, X., Zhang, Y., & Meng, X. (2024) · Journal of Pharmaceutical Analysis · doi:10.1016/j.jpha.2024.101146 · Cited by 4
“Mitochondrial transcription factor A (TFAM), synthesized from nuclear DNA, is essential for transcribing 13 key enzymes encoded by the mitochondrial genome, vital for ETC assembly [69].”
Tissue specificity of energy metabolism in mitochondria
Moreno‐Loshuertos, R., & Fernández‐Silva, P. (2020) · Elsevier eBooks · doi:10.1016/b978-0-12-819621-2.00001-2 · Cited by 4
Mitochondrial Gene Expression of Three Different Dragonflies Under the Stress of Chlorpyrifos
Chen, Y., Yang, Z., Guo, Z., Zhan, L., Storey, K. B., Yu, D., & Zhang, J. (2025) · Insects · doi:10.3390/insects16010085 · Cited by 3
“…have been sequenced (providing important sequence information), data have also been gathered on other aspects of mitochondrial genes, including replication strategies [19,20], transcriptional and translational architectures [21,22], mutational information [23–25], and arrangements [26–30].”
He, X., Zhang, H., Wang, Y., Yan, H., Chen, Q., Su, M., Shi, Q., Zeng, X., Sheng, W., Wang, Y., et al. (2025) · Science China Life Sciences · doi:10.1007/s11427-025-3041-4 · Cited by 3
“Furthermore, Tfam and Tfb2m , two key transcription factors governing mitochondrial transcription (Hillen et al., 2018), were markedly upregulated in Aged-Defective oocytes (Figure 2F and G), suggesting that the elevation of mtRNA expression was likely driven by enhanced transcriptional activity of…”
TFAM in mtDNA Homeostasis: Open Questions
ALEXEYEV, M. F. (2023) · DNA · doi:10.3390/dna3030011 · Cited by 3
Structure-function relationships in mitochondrial transcriptional condensatesPreprint
Feric, M., Sarfallah, A., Dar, F., Temiakov, D., Pappu, R. V., & Misteli, T. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.12.30.474545 · Cited by 3
Self-citationXu, C., Wu, Y., Yang, S., Zhao, X., Zhang, H., Yan, Y., Zhao, J., Wei, W., Meng, Q., Wang, Y., et al. (2025) · Cellular Signalling · doi:10.1016/j.cellsig.2025.111765 · Cited by 2
Epigenetic Threads of Neurodegeneration: TFAM’s Intricate Role in Mitochondrial Transcription
M, A. B. H., Prabhakaran, P., Logesh, R., Beeraka, N. M., Mathew, B., & Ravanappa, P. K. B. (2025) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/0118715273334342250108043032 · Cited by 2
The Central FacilitaTOR: Coordinating Transcription and Translation in Eukaryotes
Adams-Brown, S. E., & Reid, K. Z. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26072845 · Cited by 2
“TFAM, the mammalian ortholog of Hmo1, is mainly characterized as a component of the mitochondrial transcription initiation complex, which has its own polymerase, mtRNAP or POLRMT [208,209].”
High-Throughput Measurement of Mitochondrial RNA Turnover in Human Cultured Cells
Kotrys, A. V., Borowski, L. S., & Szczęsny, R. J. (2020) · Methods in molecular biology · doi:10.1007/978-1-0716-0834-0_11 · Cited by 2
McElhenney, S. J., & Yu, J. (2025) · Journal of Chemical Theory and Computation · doi:10.1021/acs.jctc.4c01568 · Cited by 2
“1,9,10,15 34 In T7 RNAP, both the PPi release and translocation have been studied via the all-atom MD and MSM construction.”
Mitochondrial DNA homeostasis: A novel therapeutic target for neurodegenerative diseases
Fu, T., Chen, X., Zhang, S., Fu, Y., Huang, L., & Xiong, W. (2025) · Neural Regeneration Research · doi:10.4103/nrr.nrr-d-25-00495 · Cited by 1
Nuclear genetic disorders of mitochondrial DNA gene expression
Glasgow, R. I. C., Lim, A. Z., Nicholls, T. J. J., McFarland, R., Taylor, R. W., & Oláhová, M. (2020) · Elsevier eBooks · doi:10.1016/b978-0-12-819656-4.00015-2 · Cited by 1
C6orf203 controls OXPHOS function through modulation of mitochondrial protein biosynthesisPreprint
Palacios-Zambrano, S., Vázquez-Fonseca, L., González-Paramos, C., Mamblona, L., Sánchez‐Caballero, L., Nijtmans, L. G. J., Garesse, R., & Fernández‐Moreno, M. Á. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/704403 · Cited by 1
“described the involvement of C6orf203 in mitochondrial transcription under induced mtDNA depletion and its interaction with mitochondrial RNA polymerase and with TFAM [28], proteins well known to be involved in the synthesis of mtRNAs [48].”
BackgroundThe PPR domain of mitochondrial RNA polymerase is a ribonuclease required for mtDNA replicationPreprint
Liu, Y., Chen, Z., Wang, Z., Delaney, K., Tang, J., Pirooznia, M., Lee, D., Li, Y., & Xu, H. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.03.12.435139 · Cited by 1
“However, it is not clear how POLRMT, which transcribes both strands of mtDNA to long polycistronic transcripts (Hillen et al., 2018), can switch from continuous transcription to primer”
BackgroundYazicioglu, Y. F., Marin, E., Sandhu, C., Galiani, S., Raza, I. G. A., Ali, M. A., Kronsteiner, B., Compeer, E. B., Attar, M., Dunachie, S. J., et al. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.07.19.500689 · Cited by 1
The mtDNA-derived lncMtDloop promotes mitochondrial homeostasis maintenance and implications in ADPreprint
Xiong, W., Xu, K., Sun, J. K., Liu, S., Zhao, B., Shi, J., Herrup, K., Chow, H., Lü, L., & Li, J. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.10.30.564670 · Cited by 1
Cellular metabolic state controls mitochondrial RNA kineticsPreprint
Reardon, S. D., Bautista, C., Cole, S., Cicero, J., & Mishanina, T. V. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.05.13.653903 · Cited by 2
Transcription-dependent phase coexistence of mitochondrial nucleoids and RNA granulesPreprint
Parikh, N., Penna, S. C., Neal, E., & Feric, M. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2025.12.19.694874 · Cited by 1
“For example, mitochondria contain a single mitochondrial RNA polymerase (POLRMT) that transcribes both rRNA and mRNA as long, polycistronic transcripts 30–32 .”
Hanitsch, E. (2020) · eDiss (Georg-August-Universität Göttingen) · doi:10.53846/goediss-8315
Mitochondrien: wie die Gene im Kraftwerk der Zelle aktiviert werden
Bhatta, A., & Hillen, H. S. (2022) · BIOspektrum · doi:10.1007/s12268-022-1711-z
“ren ein molekulares Bild des Transkriptionszyklus in menschlichen Mitochondrien [8].”
BackgroundInfluentialSelf-citationAge-related decrease in mitochondrial lncMtDloop expression potentiates Alzheimer's pathogenesisPreprint
Xiong, W., Xu, K., Sun, J. K., Liu, S., Zhang, Y., Zhang, Z., Liao, F., Zheng, Y., Shi, J., Herrup, K., et al. (2022) · Research Square · doi:10.21203/rs.3.rs-1363630/v1
Yeast mtDNA transcription initiation in single nucleotide addition stepsPreprint
Goovaerts, Q., Shen, J., Wijngaert, B. D., Basu, U., Patel, S. S., & Das, K. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.09.27.509796
Post-transcriptional regulation of genes and mitochondrial disorder
Sabharwal, A., & Kar, B. (2022) · Elsevier eBooks · doi:10.1016/b978-0-323-91305-8.00008-9
Translation Termination in Human Mitochondria: The Role of mtRF1 and mtRF1a
Nadler, F. (2022) · eDiss (Georg-August-Universität Göttingen) · doi:10.53846/goediss-9612
Increased mitochondrial transcription initiation does not promote oxidative phosphorylationPreprint
Miranda, M., Mesaros, A., Kuznetsova, I., Purrio, M., Pérard, L., Filipovska, A., Mourier, A., Larsson, N., & Kühl, I. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.01.11.575236
“Although the basic machinery of mtDNA transcription has been thoroughly studied in vitro (Hillen et al., 2018), little is known about its regulation in vivo .”
BackgroundStructural and biochemical studies on chromatin-protein complexes in transcription initiation
Garrido, J. A. (2024) · eDiss (Georg-August-Universität Göttingen) · doi:10.53846/goediss-10412
mtTF1: A Novel Factor Involved in Mitochondrial Gene Expression in Trypanosoma bruceiPreprint
Berger, B. M., Manjunatha, H., Gerber, M., & Ochsenreiter, T. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.05.22.655275
“In human mitochondria, for instance, transcription involves four transcription factors (Gustafsson et al., 2016; Hillen et al., 2018).”
Metadata
- Authors
- Hillen, H. S., Temiakov, D., & Cramer, P.
- Affiliations
- Max Planck Institute for Biophysical Chemistry (DE)
- Thomas Jefferson University (US)
- Corresponding author
- Hillen, Hauke S.
- Cramer, Patrick
- Venue
- Nature Structural & Molecular Biology
- Published
- 2018-09
- Volume
- 25
- Issue
- 9
- Pages
- 754-765
- ISSN
- 1545-9985 (ISSN-L)
- 1545-9993
- PMC
- PMC6583890
- OpenAlex
- W2890710316
- Cited by
- 111
- References
- 130
- Citations by year
- 2026: 6 · 2025: 22 · 2024: 15 · 2023: 11 · 2022: 19 · 2021: 14 · 2020: 15 · 2019: 8 · 2018: 1
- FWCI
- 0.93
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Structural & Molecular Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- The Medicine Forum (submittedVersion)
- Max Planck Digital Library (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Funders
- Boehringer Ingelheim Fonds
- Deutsche Forschungsgemeinschaft
- National Institutes of Health
- National Institute of General Medical Sciences (R01GM104231, R01GM118941)
- 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 › Structural Biology › Enzyme Structure and Function
- Keywords
- mitochondrial transcription, mitochondrial RNA polymerase, TFAM, TFB2M, transcription factors, promoter binding, polymerase processivity, human mitochondria
- MeSH terms
- Humans, Mitochondria, Protein Conformation, Terminator Regions, Genetic, Transcription, Genetic, Evolution, Molecular, Mitochondrial Proteins, Transcriptional Elongation Factors
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