Affinage

TFAM

Transcription factor A, mitochondrial · UniProt Q00059

Length
246 aa
Mass
29.1 kDa
Annotated
2026-04-28
100 papers in source corpus 39 papers cited in narrative 39 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TFAM is a dual-function HMG-box protein that serves as both the principal architectural packager of the mitochondrial genome and an essential activator of mitochondrial transcription. Structurally, TFAM bends promoter DNA into a U-turn via two HMG-box domains that wedge into the minor groove, and it cooperates with TFB2M and POLRMT to melt the promoter and initiate transcription; at higher stoichiometries, TFAM coats the entire mtDNA through non-sequence-specific binding, cross-strand bridging, and dimerization to compact it into single-copy nucleoids, with the TFAM-to-mtDNA ratio determining whether expression is activated or repressed (PMID:22037171, PMID:24435062, PMID:20410300, PMID:26305956, PMID:34462320). TFAM activity is fine-tuned by phosphorylation (cAMP-dependent kinase, ERK1/2 at S177) and acetylation (GCN5L1 at K76; SIRT3 at K5/K7/K8), which reduce DNA binding and compaction through distinct kinetic mechanisms; DNA-free phosphorylated or acetylated TFAM is selectively degraded by the Lon protease, coupling post-translational modification to mtDNA copy-number homeostasis (PMID:23201127, PMID:24768991, PMID:29897602, PMID:36474281, PMID:38547618). Beyond its canonical mitochondrial roles, TFAM functions as an autophagy receptor for cytoplasmic mtDNA via a LIR motif that binds LC3, limiting cGAS–STING inflammatory signaling triggered by escaped mtDNA, and when released extracellularly acts as a DAMP recognized through the receptor AGER (PMID:38783142, PMID:36858460, PMID:29872558).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 2001 Medium

    An in vivo correlation between TFAM protein abundance and mtDNA copy number was established across mammalian spermatogenesis, raising the question of whether TFAM directly maintains mtDNA levels.

    Evidence Immunoblotting and mtDNA quantification across spermatogenic stages in rat, mouse, and human

    PMID:11668394

    Open questions at the time
    • Correlative; no genetic manipulation to test causality
    • Mechanism of TFAM downregulation during spermatogenesis unknown
  2. 2003 High

    The physical association of TFAM with mtDNA in vivo was demonstrated, establishing that TFAM is an abundant nucleoid component rather than merely a transient transcription factor.

    Evidence Co-immunoprecipitation from human placental mitochondria with DNase I release validation

    PMID:12626705

    Open questions at the time
    • Stoichiometry was estimated but not precisely determined
    • Whether TFAM binding is uniform or site-specific was unknown
  3. 2010 High

    Reconstitution of minimal mitochondrial transcription demonstrated that TFAM and TFB2M (but not TFB1M) are the essential co-activators of POLRMT, defining the core transcription initiation machinery.

    Evidence Fully reconstituted in vitro transcription with systematic factor omission

    PMID:20410300

    Open questions at the time
    • How TFAM mechanistically contributes beyond recruitment was not resolved
    • Structural basis of promoter recognition was still unknown
  4. 2011 High

    The crystal structure of TFAM on LSP revealed that TFAM bends promoter DNA into a U-turn through two HMG-box insertions, providing the first atomic-resolution mechanism for how TFAM remodels DNA for transcription.

    Evidence X-ray crystallography of human TFAM–LSP complex with functional mutagenesis

    PMID:22037171

    Open questions at the time
    • Structure on HSP1 and non-specific DNA was not yet available
    • Role of DNA bending in compaction versus transcription was unresolved
  5. 2012 High

    Discovery that cAMP-dependent kinase phosphorylates TFAM within HMG1, impairing DNA binding and rendering TFAM susceptible to Lon protease degradation, established the first post-translational mechanism coupling signaling to mtDNA copy-number control.

    Evidence Mass spectrometry phosphomapping, in vitro kinase and Lon degradation assays, siRNA knockdown

    PMID:23201127

    Open questions at the time
    • In vivo kinase identity in mitochondria was debated
    • Whether acetylation similarly regulated Lon degradation was unknown
  6. 2013 High

    ChIP-seq revealed that TFAM uniformly coats the entire mitochondrial genome without preferred non-promoter binding sites, confirming its role as a general mtDNA packaging factor.

    Evidence Genome-wide ChIP-seq in human cells

    PMID:23991223

    Open questions at the time
    • Resolution limited by nucleoid compaction
    • Whether coating density varies with physiological state was untested
  7. 2014 High

    Crystal structures of TFAM on HSP1 and non-specific DNA showed that TFAM imposes a U-turn regardless of sequence but binds the two promoters in opposite orientations; dimerization was shown to be required for DNA compaction but dispensable for transcription activation, separating the two functions structurally.

    Evidence X-ray crystallography, in vitro transcription, dimerization mutagenesis

    PMID:24435062

    Open questions at the time
    • How dimerization leads to higher-order compaction at the nucleoid scale was not resolved
    • In vivo validation of dimerization mutants was lacking
  8. 2014 High

    ERK1/2 was identified as a second kinase phosphorylating TFAM at S177, linking mitochondrial toxin (MPP+) signaling to reduced TFAM–DNA binding and transcriptional suppression.

    Evidence Mass spectrometry, phosphomimetic mutagenesis, TFAM-DNA binding and transcription assays

    PMID:24768991

    Open questions at the time
    • How ERK1/2 accesses mitochondrial TFAM was not fully established
    • Interplay between PKA and ERK phosphorylation sites was not studied
  9. 2015 High

    Super-resolution and electron microscopy established that each nucleoid contains a single mtDNA copy, and TFAM cross-strand binding and aggregation initiate nucleoid compaction, defining the fundamental unit of mtDNA organization.

    Evidence STED microscopy, cryo-ET, rotary shadowing EM, in vitro reconstitution

    PMID:26305956

    Open questions at the time
    • Full 3D architecture of the nucleoid in situ was not achieved
    • Contribution of other nucleoid proteins to compaction was not addressed
  10. 2016 High

    Fluorescence-based promoter melting assays revealed that TFAM has post-recruitment roles in open complex formation, working with TFB2M to melt LSP DNA and enable productive RNA synthesis beyond 2-mer abortive transcripts.

    Evidence 2-aminopurine fluorescence, equilibrium binding, and abortive RNA synthesis assays

    PMID:27903899

    Open questions at the time
    • Structural intermediates of the open complex were not visualized
    • Whether TFAM participates in promoter escape was unknown
  11. 2018 High

    Single-molecule studies demonstrated that acetylation and phosphorylation of TFAM reduce DNA compaction through kinetically distinct mechanisms—acetylation lowering the on-rate and phosphorylation increasing the off-rate—explaining how different modifications yield different functional outcomes.

    Evidence Single-molecule fluorescence, bulk binding, PTM-mimic mutagenesis

    PMID:29897602

    Open questions at the time
    • Physiological acetylation sites responsible were not mapped in this study
    • Combined effects of multiple simultaneous PTMs were not tested
  12. 2018 High

    Tissue-specific conditional knockout of TFAM in kidney tubules caused fibrosis, and Notch2 was shown to directly repress Tfam transcription, establishing TFAM as a downstream effector whose loss mediates Notch-driven metabolic reprogramming.

    Evidence ChIP for Notch2 on Tfam promoter, conditional Tfam knockout mice, adenoviral Tfam rescue

    PMID:30226866

    Open questions at the time
    • Whether other developmental pathways similarly regulate Tfam transcription was untested
    • Mechanism linking TFAM loss to profibrotic gene programs was incompletely defined
  13. 2021 High

    In vivo TFAM overexpression in mice demonstrated that the TFAM-to-mtDNA ratio—not absolute TFAM level—determines transcriptional output, with excess TFAM silencing mtDNA expression in skeletal muscle, resolving a long-standing paradox about TFAM's dual activator/repressor behavior.

    Evidence Transgenic TFAM-overexpressing mice with tissue-specific OXPHOS and transcription analysis

    PMID:34462320

    Open questions at the time
    • How cells sense and regulate the ratio was not determined
    • Whether the ratio model applies to all tissues equally was not fully tested
  14. 2022 High

    GCN5L1 was identified as the acetyltransferase that acetylates TFAM at K76, inhibiting its binding to the TOM70 import receptor and thereby reducing mitochondrial TFAM import, revealing a new layer of TFAM regulation at the protein import step.

    Evidence Acetylome proteomics, proximity ligation assay, co-IP, GCN5L1 knockdown with mtDNA readout

    PMID:36474281

    Open questions at the time
    • Whether K76 acetylation also affects DNA binding inside mitochondria was not tested
    • In vivo GCN5L1–TFAM epistasis was limited to kidney injury context
  15. 2022 High

    A crystal structure of TFAM on non-specific DNA revealed a GN10G guanine-specific recognition motif that bridges two DNA substrates, explaining how TFAM achieves both sequence-specific promoter recognition and genome-wide non-specific packaging.

    Evidence X-ray crystallography, site-directed mutagenesis, in vitro transcription and binding assays

    PMID:34928349

    Open questions at the time
    • Contribution of GN10G to nucleoid architecture in vivo was not tested
    • Whether GN10G frequency in mtDNA influences regional compaction is unknown
  16. 2022 Medium

    Chimeric TFAM variants demonstrated that TFAM's contributions to mtDNA replication and respiratory chain biogenesis are genetically separable, with DNA-contacting residues primarily driving replication.

    Evidence GeneSwap chimeric protein engineering with mtDNA copy number and respiration assays

    PMID:36497015

    Open questions at the time
    • Structural basis for the separation of function was not determined
    • Only tested in cell culture, not in vivo
  17. 2023 High

    TFAM was shown to form covalent DNA-protein crosslinks at abasic sites via a lyase-like activity, with Lys residues cleaving AP-DNA to generate a reactive aldehyde trapped by Cys residues, establishing TFAM as a participant in mtDNA damage responses.

    Evidence In vitro DPC formation assay, mass spectrometry of crosslinked species, Lys/Cys mutagenesis, cellular DPC assay

    PMID:36583367

    Open questions at the time
    • Biological consequence of TFAM-DPC accumulation for mtDNA maintenance is unknown
    • Whether DPCs are resolved by specific repair pathways was not addressed
  18. 2023 Medium

    SIRT3 was identified as the deacetylase acting on TFAM at K5, K7, and K8, placing TFAM acetylation under mitochondrial sirtuin control and linking SIRT3 decline to TFAM hyper-acetylation and mitochondrial dysfunction.

    Evidence IP-MS identifying acetylation sites, SIRT3 knockdown/inhibitor, mitochondrial function assays

    PMID:38547618

    Open questions at the time
    • Direct in vitro deacetylation assay with purified SIRT3 on specific TFAM peptides was not shown
    • Interplay between GCN5L1 acetylation at K76 and SIRT3 deacetylation at N-terminal lysines was not studied
  19. 2023 High

    TFAM loss in dendritic cells was shown to trigger cytosolic mtDNA release and cGAS–STING activation, enhancing antigen presentation and anti-tumor immunity, establishing TFAM as a gatekeeper preventing innate immune activation by mitochondrial DNA.

    Evidence Conditional Tfam knockout in DCs, STING pharmacological inhibition, tumor models, antigen presentation assays

    PMID:36858460

    Open questions at the time
    • Whether the effect is specific to dendritic cells or general to all antigen-presenting cells was not established
    • Direct visualization of mtDNA escape from mitochondria was limited
  20. 2024 High

    TFAM was discovered to function as an autophagy receptor for cytoplasmic mtDNA through a LIR motif that binds LC3, defining a nucleoid-phagy pathway that clears escaped mtDNA and suppresses cGAS–STING signaling independently of TFAM's intramitochondrial roles.

    Evidence LIR motif mutagenesis, co-IP with LC3, live-cell autolysosome imaging, inflammatory pathway readout

    PMID:38783142

    Open questions at the time
    • Whether nucleoid-phagy operates in all cell types is unknown
    • Regulation of TFAM's LIR motif accessibility was not addressed
    • How cytoplasmic TFAM is distinguished from mitochondrial TFAM for this function is unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • Outstanding questions include: (1) the full 3D structure of the TFAM-organized nucleoid in situ; (2) how the combined landscape of phosphorylation, acetylation, and DPC formation is integrated to control TFAM's partition between transcription activation, genome packaging, and degradation; and (3) the structural and regulatory basis for TFAM's cytoplasmic autophagy receptor function versus its mitochondrial roles.
  • No in situ structure of the complete nucleoid exists
  • Combinatorial PTM effects on TFAM have not been reconstituted
  • Mechanism governing TFAM cytoplasmic pool availability for nucleoid-phagy is undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 5 GO:0005198 structural molecule activity 3 GO:0140110 transcription regulator activity 2 GO:0038024 cargo receptor activity 1
Localization
GO:0005739 mitochondrion 5 GO:0005694 chromosome 3
Pathway
R-HSA-168256 Immune System 3 R-HSA-1852241 Organelle biogenesis and maintenance 3 R-HSA-9612973 Autophagy 1
Partners
AGERGCN5L1LONP1MAP1LC3BPOLRMTSIRT3TFB2MTOMM70
Complex memberships
mitochondrial nucleoidmitochondrial transcription initiation complex (TFAM–TFB2M–POLRMT)

Evidence

Reading pass · 39 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 Human mtDNA is packaged with TFAM: TFAM and mtDNA co-immunoprecipitate using anti-TFAM antibodies from human placental mitochondria, TFAM is released by DNase I digestion, and TFAM is abundant enough to coat the entire mtDNA molecule, demonstrating tight physical association of TFAM with mtDNA in vivo. Co-immunoprecipitation, subcellular fractionation, DNase I digestion assay Nucleic Acids Research High 12626705
2011 X-ray crystal structure of human TFAM bound to mitochondrial LSP promoter DNA reveals that TFAM forces DNA to undergo a U-turn, with each HMG-box domain wedging into the DNA minor groove to generate two kinks on one face, and a positively charged α-helix on the opposite face serving as a bending platform. X-ray crystallography with functional mutagenesis Nature Structural & Molecular Biology High 22037171
2014 Crystal structures of TFAM bound to HSP1 and non-specific DNA show TFAM imposes a U-turn in both contexts but binds HSP1 in the opposite orientation from LSP, explaining promoter-specific transcriptional requirements. TFAM dimerizes when DNA-bound; dimerization is dispensable for DNA bending and transcriptional activation but important for DNA compaction and looping. X-ray crystallography, in vitro transcription assay, dimerization mutagenesis Nature Communications High 24435062
2015 Superresolution and electron microscopy showed that the mitochondrial nucleoid contains a single copy of mtDNA, and rotary-shadowing EM revealed that nucleoid formation in vitro is initiated by TFAM aggregation and cross-strand binding, establishing the fundamental organizational unit of the nucleoid. Superresolution microscopy (STED), electron cryo-tomography, rotary shadowing EM, biochemistry Proceedings of the National Academy of Sciences of the United States of America High 26305956
2010 Reconstituted in vitro transcription demonstrates that only TFAM and TFB2M (not TFB1M) are required to drive transcription from LSP and HSP1, acting synergistically to increase transcription 100–200-fold over RNA polymerase alone, with maximal activity when TFAM is equimolar to the DNA template. Reconstituted in vitro transcription with recombinant proteins Journal of Biological Chemistry High 20410300
2016 2-aminopurine fluorescence mapping of promoter melting shows TFAM has post-recruitment roles in LSP promoter melting and stabilization of the open complex; POLRMT requires both TFB2M and TFAM to efficiently melt the promoter, and TFAM is necessary for synthesis of abortive RNAs longer than 2-mer. 2-aminopurine fluorescence assay, equilibrium binding assay, abortive RNA synthesis assay Nucleic Acids Research High 27903899
2012 TFAM is phosphorylated within HMG box 1 (HMG1) by cAMP-dependent protein kinase inside mitochondria; HMG1 phosphorylation impairs TFAM DNA binding and transcriptional activation. Only DNA-free TFAM is degraded by the Lon protease; in cells with normal mtDNA levels, phosphorylated TFAM is selectively degraded by Lon. Mass spectrometry phosphorylation mapping, in vitro kinase assay, in vitro transcription, Lon protease degradation assay, siRNA knockdown Molecular Cell High 23201127
2014 ERK1/2 directly phosphorylates TFAM at serine 177; phosphomimetic mutation at S177 recapitulates the effect of MPP+ in decreasing TFAM binding to the LSP and suppressing mitochondrial transcription, and mutant TFAM fails to rescue respiratory function. Mass spectrometry phosphosite identification, site-directed mutagenesis, TFAM-DNA binding assay, mitochondrial transcription assay Mitochondrion High 24768991
2018 TFAM is lysine-acetylated within HMG box 1; acetyl-lysine and phosphoserine mimics both reduce TFAM DNA compaction capacity but through distinct kinetic mechanisms: the acetyl-lysine mimic shows a lower on-rate, whereas the phosphoserine mimic shows both decreased on-rate and increased off-rate with faster diffusion of TFAM along DNA. Single-molecule fluorescence assay, bulk binding assay, site-directed mutagenesis with PTM mimics Nucleic Acids Research High 29897602
2021 The TFAM-to-mtDNA ratio (not absolute TFAM level) determines mtDNA expression; very high TFAM levels in mouse skeletal muscle repress mtDNA transcription, while in liver elevated LONP1 protease and mtRNA polymerase counteract TFAM-mediated silencing, establishing TFAM as a general repressor of mtDNA expression. Transgenic mouse overexpression, tissue-specific analysis, OXPHOS functional assays Life Science Alliance High 34462320
2013 ChIP-seq in human cells demonstrates that TFAM uniformly coats the entire mitochondrial genome without preferred binding sites (beyond promoter regions) and shows no robust binding to the nuclear genome, establishing genome-wide non-specific mtDNA packaging by TFAM. ChIP-seq PLoS One High 23991223
2009 PDX1 directly regulates TFAM as a transcriptional target in beta cells; adenoviral overexpression of TFAM in PDX1-dominant-negative islets rescues mtDNA copy number, respiratory chain activity, ATP synthesis, and glucose-stimulated insulin secretion. Transcript profiling, promoter binding assay, adenoviral overexpression, respiratory chain activity assay, insulin secretion assay Cell Metabolism High 19656489
2024 TFAM acts as an autophagy receptor (nucleoid-phagy) for cytoplasmic mtDNA via a LIR (LC3-interacting region) motif that enables direct binding to LC3 on autolysosomes; mutating the LIR motif increases cytoplasmic mtDNA accumulation and activates inflammatory signaling without affecting TFAM's mitochondrial functions. LIR motif mutagenesis, co-immunoprecipitation with LC3, live-cell autolysosome imaging, inflammatory pathway readout Nature Cell Biology High 38783142
2022 TFAM deficiency blocks the TCA cycle and increases intracellular malonyl-CoA, leading to malonylation of the actin nucleator mDia2, which promotes mDia2 nuclear translocation and polymerization of nuclear actin, thereby altering chromatin accessibility and upregulating metastasis-associated gene programs in liver cancer. Metabolomics, malonylation proteomics, nuclear actin imaging, chromatin accessibility assay, in vivo metastasis model EMBO Journal High 35451091
2010 TFAM and TFB2M localize to the nucleus in rat neonatal cardiomyocytes and directly bind the Serca2 gene promoter (at −122 to −114 nt and −122 to −117 nt regions respectively) as shown by ChIP and fluorescence correlation spectroscopy; mutation of these sites decreases Serca2 transcription. Chromatin immunoprecipitation (ChIP), fluorescence correlation spectroscopy, promoter mutation/reporter assay, immunostaining Cardiovascular Research Medium 21113058
2014 Nuclear TFAM suppresses its own gene expression by interacting with NRF-1 and acting as an NRF-1 repressor; TFAM co-immunoprecipitates with NRF-1, and mitochondria targeting sequence-deficient TFAM represses the Tfam promoter to the same degree, indicating this autoregulatory role is nuclear and independent of mitochondrial function. Immunostaining, subcellular fractionation, GFP fusion localization, co-immunoprecipitation, luciferase promoter assay Biochemical and Biophysical Research Communications Medium 24875355
2015 H2S (via the CSE/H2S system) maintains TFAM expression and mtDNA copy number by S-sulfhydrating the transcriptional repressor IRF-1, enhancing its binding to the Dnmt3a promoter and reducing Dnmt3a expression, thereby preventing TFAM promoter methylation. S-sulfhydration assay, ChIP, bisulfite sequencing/methylation assay, siRNA knockdown, qPCR Antioxidants & Redox Signaling Medium 25758951
2018 In kidney fibrosis, Notch2 signaling (activated by Jagged1) directly represses Tfam transcription as identified by chromatin immunoprecipitation; re-expression of Tfam in tubule cells prevents Notch-induced metabolic and profibrotic reprogramming, and tubule-specific Tfam deletion itself causes fibrosis. Chromatin immunoprecipitation (ChIP), genome-wide expression profiling, conditional knockout mice, adenoviral re-expression PLoS Biology High 30226866
2021 mtROS promotes Lon protease-mediated TFAM degradation and suppresses TFAM transcription, reducing mtDNA copy number; silencing TFAM abolishes the rescue of mitochondrial function and cytokine release by the mtROS inhibitor Mito-Tempo, placing TFAM downstream of mtROS in kidney injury. Lon protease functional assay, TFAM knockdown (siRNA), mitochondrial respiration assay, cytokine measurement, Mito-Tempo pharmacological inhibition Theranostics Medium 33408785
2020 In sepsis, ATF4 represses TFAM by binding to and inhibiting the transcriptional activity of NRF1 (a key TFAM activator) at its promoter; hepatocyte-specific TFAM overexpression rescues alcohol-induced mitochondrial dysfunction and liver damage in mice. ATF4 knockout mice, TFAM overexpression mice, promoter binding assay (ChIP/luciferase), mitochondrial biogenesis/respiration assays Gut High 33177163
2022 GCN5L1 acetyltransferase acetylates TFAM at lysine 76 (K76), which inhibits TFAM binding to the mitochondrial import receptor TOM70, thereby reducing TFAM import into mitochondria and mitochondrial biogenesis in acute kidney injury. Acetylated proteomics, proximity ligation assay, co-immunoprecipitation, GCN5L1 knockdown, mtDNA copy number assay Journal of Translational Medicine High 36474281
2023 SIRT3 deacetylates TFAM at K5, K7, and K8 residues as demonstrated by immunoprecipitation and mass spectrometry; decreased SIRT3 leads to hyper-acetylated TFAM, impaired mitochondrial function, and vascular dementia pathology. Co-immunoprecipitation, mass spectrometry, SIRT3 inhibitor/knockdown, mitochondrial function assays Phytomedicine Medium 38547618
2014 Extracellular TFAM acts as a DAMP recognized by human microglia: recombinant human TFAM induces secretion of IL-1β, IL-6, and IL-8 from THP-1 monocytic cells and, with IFN-γ, elicits cytotoxic secretions from microglia and monocytes through a mechanism partially dependent on JNK activation. Recombinant protein treatment of primary human microglia and THP-1 cells, cytokine ELISA, neurotoxicity assay, specific kinase inhibitors Molecular and Cellular Neurosciences Medium 24769106
2018 Release of TFAM from apoptotic cancer cells acts as a mitochondrial DAMP that contributes to immunogenic cell death via the receptor AGER; neutralizing antibodies to TFAM or AGER abolish the immunogenic effect of spautin-1-treated cancer cells in vivo. Neutralizing antibody blockade, in vivo tumor inoculation, in vitro apoptosis assay Oncoimmunology Medium 29872558
2022 Crystal structure of TFAM bound to non-sequence-specific DNA containing a GN10G motif reveals that TFAM bridges two DNA substrates via two guanine-specific interactions; mutagenesis and biochemical assays show the GN10G consensus is essential for transcription initiation and contributes to general DNA binding. X-ray crystallography, site-directed mutagenesis, in vitro transcription assay, DNA binding assay Nucleic Acids Research High 34928349
2023 TFAM forms DNA-protein cross-links (DPCs) with abasic (AP) sites in mtDNA: TFAM cleaves AP-DNA, generating a 3'-phospho-α,β-unsaturated aldehyde (3'pUA) that reacts with Cys residues of TFAM to form stable DPCs, with Lys residues critical for initial AP-DNA cleavage; glutathione competes with TFAM-DPC formation. In vitro DPC formation assay, mass spectrometry, mutagenesis of Lys/Cys residues, cellular DPC assay with glutathione modulation Nucleic Acids Research High 36583367
2001 During mammalian spermatogenesis, mitochondrial TFAM protein levels are progressively downregulated coincident with downregulation of mtDNA copy number, establishing a direct in vivo correlation between mitochondrial TFAM abundance and mtDNA copy number control during differentiation. Immunoblotting with subcellular fractionation, mtDNA quantification across spermatogenic stages in rat, mouse, and human Mammalian Genome Medium 11668394
2022 TFAM-deficient alveolar macrophages (AMs) show diminished proliferation/self-renewal gene programs and increased inflammatory gene expression; conditional TFAM knockout in mice reduces AM numbers and impairs AM maturation without affecting AM precursor generation or initial differentiation, establishing TFAM-mediated mitochondrial metabolism as specifically required for AM compartment maintenance. Conditional knockout mice, transcriptional profiling, flow cytometry, in vivo influenza infection model Journal of Immunology High 35165165
2023 TFAM deficiency in dendritic cells causes mitochondrial dysfunction and cytosolic mtDNA leakage that activates the cGAS-STING pathway, enhancing antigen presentation and reversing immunosuppressive tumor microenvironment; STING inhibitors abrogate this effect, placing TFAM upstream of cGAS-STING in DC immune activation. Conditional knockout mice, primary BMDC functional assays, STING inhibitor, tumor models, antigen presentation assay Journal for Immunotherapy of Cancer High 36858460
2018 KLF16 transcription factor directly suppresses glioma cell proliferation by binding a site near the TFAM transcription start site and repressing TFAM expression, as validated by luciferase assay and chromatin immunoprecipitation. Luciferase reporter assay, chromatin immunoprecipitation (ChIP), KLF16 overexpression/siRNA, in vivo xenograft Artificial Cells, Nanomedicine, and Biotechnology Medium 29374989
2007 The transcription factor hStaf/ZNF143 is required for normal human TFAM gene expression: two conserved hStaf/ZNF143 binding sites in the TFAM promoter are identified by promoter binding assays and ChIP, and mutation of these sites reduces TFAM promoter activity. Promoter binding assay, transient transfection with mutant reporter constructs, chromatin immunoprecipitation (ChIP) Gene Medium 17707600
2022 Genetic analysis using chimeric TFAM variants (GeneSwap approach) shows that TFAM's contributions to mtDNA replication and respiratory chain biogenesis are genetically separable: variant Ch13 has low mtDNA copy number but robust respiration, while Ch22 has the converse; residues making DNA contacts are primarily responsible for mtDNA replication. Chimeric protein engineering (GeneSwap), mtDNA copy number assay, respiratory function assay, mutagenesis Cells Medium 36497015
2023 GCN5L1 loss reduces TFAM acetylation, which is linked to decreased mtDNA levels and impaired mitochondrial bioenergetics under hemodynamic stress in the heart; GCN5L1 cardiomyocyte-specific knockout mice show exacerbated heart failure after transaortic constriction. Cardiomyocyte-specific GCN5L1 knockout mice, TAC model, TFAM acetylation assay, mtDNA quantification, bioenergetics assay iScience Medium 37305705
2020 TFAM knockdown in gastric cancer cells activates mtDNA depletion-dependent calcium-mediated retrograde signaling through the CFAP65-PCK1 axis; knockdown of CFAP65 or PCK1 rescues cell morphology and proliferation changes caused by TFAM depletion, and mtDNA depletion by ddC is sufficient to induce CFAP65 and PCK1 upregulation. TFAM siRNA knockdown, mtDNA depletion by ddC, gene-specific knockdown rescue, transcriptomic analysis Scientific Reports Medium 29259235
2023 SIRT3 deacetylates TFAM, and sepsis-induced AKI is associated with melatonin promoting SIRT3-mediated TFAM deacetylation to promote mitophagy. In vivo sepsis model, SIRT3 activity assay, mitophagy assay (mKeima), TFAM acetylation measurement Autophagy Low 37651673
2018 RNA-binding protein HuR binds and stabilizes TFAM mRNA in irradiated cancer cells; radiation-activated ATM/p38 signaling promotes nuclear-to-cytosol translocation of HuR, enhancing its binding to TFAM mRNA without affecting TFAM transcription or mRNA intrinsic stability. RNA immunoprecipitation (RIP), HuR knockdown, subcellular fractionation of HuR, ATM/p38 inhibitors, mRNA stability assay Cancer Science Medium 29856906
2011 ERAL1 (an ERA-like G-protein) and p32 are identified as TFAM-associated proteins within the mitochondrial nucleoid involved in RNA metabolism: ERAL1 binds mitochondrial 12S rRNA and is an important constituent of the mitochondrial small ribosomal subunit. Co-immunoprecipitation/pulldown to identify TFAM interactors, rRNA binding assay Biochimica et Biophysica Acta Low 21920408
2018 TFAM loss in intestinal epithelium (Shh-Cre conditional knockout) impairs villus elongation and enterocyte maturation during fetal development, and in adult intestinal epithelium reduces stem cell renewal and organoid formation while preserving transit-amplifying zone proliferation. Conditional knockout mice (Shh-Cre and inducible adult deletion), molecular profiling, intestinal organoid formation assay Developmental Biology High 29684311
2021 Conditional Tfam ablation in adult mouse cardiomyocytes reveals functional resilience: mtDNA content, mitochondrial function, and cardiac function are preserved despite decreased transcript abundance during the acute phase, whereas long-term inactivation downregulates the core mtDNA transcription/replication machinery and causes cardiomyopathy. Conditional knockout mice, mtDNA quantification, mitochondrial function assays, cardiac function assays over time American Journal of Physiology - Cell Physiology High 33760663

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2021 Mitochondrial ROS promote mitochondrial dysfunction and inflammation in ischemic acute kidney injury by disrupting TFAM-mediated mtDNA maintenance. Theranostics 618 33408785
2006 Mitochondrial transcription factor A (TFAM): roles in maintenance of mtDNA and cellular functions. Mitochondrion 367 17280879
2003 Human mitochondrial DNA is packaged with TFAM. Nucleic acids research 303 12626705
2015 Cross-strand binding of TFAM to a single mtDNA molecule forms the mitochondrial nucleoid. Proceedings of the National Academy of Sciences of the United States of America 283 26305956
2012 Phosphorylation of human TFAM in mitochondria impairs DNA binding and promotes degradation by the AAA+ Lon protease. Molecular cell 265 23201127
2018 The mitochondrial transcription factor TFAM in neurodegeneration: emerging evidence and mechanisms. FEBS letters 244 29364506
2015 Regulation of mitochondrial biogenesis through TFAM-mitochondrial DNA interactions: Useful insights from aging and calorie restriction studies. Mitochondrion 239 26437364
2011 The mitochondrial transcription and packaging factor Tfam imposes a U-turn on mitochondrial DNA. Nature structural & molecular biology 235 22037171
2014 Distinct structural features of TFAM drive mitochondrial DNA packaging versus transcriptional activation. Nature communications 201 24435062
2010 Human mitochondrial transcription revisited: only TFAM and TFB2M are required for transcription of the mitochondrial genes in vitro. The Journal of biological chemistry 162 20410300
2023 Melatonin attenuates sepsis-induced acute kidney injury by promoting mitophagy through SIRT3-mediated TFAM deacetylation. Autophagy 127 37651673
2015 Overexpression of TFAM or twinkle increases mtDNA copy number and facilitates cardioprotection associated with limited mitochondrial oxidative stress. PloS one 123 25822152
2020 ATF4 activation promotes hepatic mitochondrial dysfunction by repressing NRF1-TFAM signalling in alcoholic steatohepatitis. Gut 120 33177163
2017 The Role of Exercise and TFAM in Preventing Skeletal Muscle Atrophy. Journal of cellular physiology 119 27966783
2024 TFAM is an autophagy receptor that limits inflammation by binding to cytoplasmic mitochondrial DNA. Nature cell biology 109 38783142
2019 Role of mitochondria in diabetic peripheral neuropathy: Influencing the NAD+-dependent SIRT1-PGC-1α-TFAM pathway. International review of neurobiology 106 31208524
2009 PDX1 deficiency causes mitochondrial dysfunction and defective insulin secretion through TFAM suppression. Cell metabolism 103 19656489
2016 Mutations in TFAM, encoding mitochondrial transcription factor A, cause neonatal liver failure associated with mtDNA depletion. Molecular genetics and metabolism 95 27448789
2016 Mitochondrial pathways to cardiac recovery: TFAM. Heart failure reviews 86 27166683
2023 Astragaloside IV attenuates podocyte apoptosis through ameliorating mitochondrial dysfunction by up-regulated Nrf2-ARE/TFAM signaling in diabetic kidney disease. Free radical biology & medicine 85 37030337
2009 Overexpression of Tfam protects mitochondria against beta-amyloid-induced oxidative damage in SH-SY5Y cells. The FEBS journal 78 19496804
2019 TFAM Enhances Fat Oxidation and Attenuates High-Fat Diet-Induced Insulin Resistance in Skeletal Muscle. Diabetes 74 31088855
2018 Acetylation and phosphorylation of human TFAM regulate TFAM-DNA interactions via contrasting mechanisms. Nucleic acids research 73 29897602
2017 MiR-199a-3p enhances breast cancer cell sensitivity to cisplatin by downregulating TFAM (TFAM). Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 72 28126676
2011 Overexpression of TFAM, NRF-1 and myr-AKT protects the MPP(+)-induced mitochondrial dysfunctions in neuronal cells. Biochimica et biophysica acta 71 21856379
2016 Human mitochondrial transcription factors TFAM and TFB2M work synergistically in promoter melting during transcription initiation. Nucleic acids research 69 27903899
2015 Hydrogen Sulfide Maintains Mitochondrial DNA Replication via Demethylation of TFAM. Antioxidants & redox signaling 68 25758951
2016 Downregulation of TFAM inhibits the tumorigenesis of non-small cell lung cancer by activating ROS-mediated JNK/p38MAPK signaling and reducing cellular bioenergetics. Oncotarget 66 26820294
2021 High levels of TFAM repress mammalian mitochondrial DNA transcription in vivo. Life science alliance 65 34462320
2017 TP73-AS1 promotes breast cancer cell proliferation through miR-200a-mediated TFAM inhibition. Journal of cellular biochemistry 64 28639399
2018 Jagged1/Notch2 controls kidney fibrosis via Tfam-mediated metabolic reprogramming. PLoS biology 63 30226866
2014 ERK-mediated phosphorylation of TFAM downregulates mitochondrial transcription: implications for Parkinson's disease. Mitochondrion 63 24768991
2014 Mitochondrial transcription factor A (Tfam) is a pro-inflammatory extracellular signaling molecule recognized by brain microglia. Molecular and cellular neurosciences 62 24769106
2001 Downregulation of Tfam and mtDNA copy number during mammalian spermatogenesis. Mammalian genome : official journal of the International Mammalian Genome Society 58 11668394
2022 TFAM loss induces nuclear actin assembly upon mDia2 malonylation to promote liver cancer metastasis. The EMBO journal 57 35451091
2013 Genome-wide analysis reveals coating of the mitochondrial genome by TFAM. PloS one 57 23991223
2022 TFAM downregulation promotes autophagy and ESCC survival through mtDNA stress-mediated STING pathway. Oncogene 55 35750756
2023 TFAM deficiency in dendritic cells leads to mitochondrial dysfunction and enhanced antitumor immunity through cGAS-STING pathway. Journal for immunotherapy of cancer 52 36858460
2023 Placental Mesenchymal Stem Cells Alleviate Podocyte Injury in Diabetic Kidney Disease by Modulating Mitophagy via the SIRT1-PGC-1alpha-TFAM Pathway. International journal of molecular sciences 50 36902127
2018 Mitochondrial transcription factor A (TFAM) shapes metabolic and invasion gene signatures in melanoma. Scientific reports 48 30242167
2010 Mitochondrial transcription factors TFAM and TFB2M regulate Serca2 gene transcription. Cardiovascular research 45 21113058
2022 mito-TEMPO Attenuates Oxidative Stress and Mitochondrial Dysfunction in Noise-Induced Hearing Loss via Maintaining TFAM-mtDNA Interaction and Mitochondrial Biogenesis. Frontiers in cellular neuroscience 42 35210991
2020 Tfam Knockdown Results in Reduction of mtDNA Copy Number, OXPHOS Deficiency and Abnormalities in Zebrafish Embryos. Frontiers in cell and developmental biology 40 32596237
2020 Mitochondrial dysfunction in sepsis is associated with diminished intramitochondrial TFAM despite its increased cellular expression. Scientific reports 40 33273525
2017 Role of microRNA-130b in placental PGC-1α/TFAM mitochondrial biogenesis pathway. Biochemical and biophysical research communications 39 28433632
2019 Limited predictive value of TFAM in mitochondrial biogenesis. Mitochondrion 37 31419493
2017 Transcriptomic analysis of mitochondrial TFAM depletion changing cell morphology and proliferation. Scientific reports 36 29259235
2015 Dietary isoflavone daidzein promotes Tfam expression that increases mitochondrial biogenesis in C2C12 muscle cells. The Journal of nutritional biochemistry 36 26166229
2008 Expression of mitochondrial transcription factor A (TFAM) during porcine gametogenesis and preimplantation embryo development. Journal of cellular physiology 36 18636550
2020 The interaction between C/EBPβ and TFAM promotes acute kidney injury via regulating NLRP3 inflammasome-mediated pyroptosis. Molecular immunology 35 32971400
2018 TFAM is a novel mediator of immunogenic cancer cell death. Oncoimmunology 35 29872558
2018 Resistin destroys mitochondrial biogenesis by inhibiting the PGC-1α/ NRF1/TFAM signaling pathway. Biochemical and biophysical research communications 35 30172371
2016 HIF-1 regulates insect lifespan extension by inhibiting c-Myc-TFAM signaling and mitochondrial biogenesis. Biochimica et biophysica acta 35 27469241
2020 TFAM depletion overcomes hepatocellular carcinoma resistance to doxorubicin and sorafenib through AMPK activation and mitochondrial dysfunction. Gene 34 32461017
2015 The regulation of mitochondrial transcription factor A (Tfam) expression during skeletal muscle cell differentiation. Bioscience reports 34 26182383
2010 Mitochondrial transcription factor A (TFAM) polymorphisms and risk of late-onset Alzheimer's disease in Han Chinese. Brain research 34 20977898
2018 KLF16 suppresses human glioma cell proliferation and tumourigenicity by targeting TFAM. Artificial cells, nanomedicine, and biotechnology 32 29374989
2014 Upregulation of TFAM and mitochondria copy number in human lymphoblastoid cells. Mitochondrion 32 24462998
2021 The HIF-1/SNHG1/miR-199a-3p/TFAM axis explains tumor angiogenesis and metastasis under hypoxic conditions in breast cancer. BioFactors (Oxford, England) 31 34003544
2022 TFAM-Dependent Mitochondrial Metabolism Is Required for Alveolar Macrophage Maintenance and Homeostasis. Journal of immunology (Baltimore, Md. : 1950) 30 35165165
2021 Integrated Genomics Identifies miR-181/TFAM Pathway as a Critical Driver of Drug Resistance in Melanoma. International journal of molecular sciences 30 33670365
2023 The Protective Mechanism of TFAM on Mitochondrial DNA and its Role in Neurodegenerative Diseases. Molecular neurobiology 29 38087167
2018 HuR stabilizes TFAM mRNA in an ATM/p38-dependent manner in ionizing irradiated cancer cells. Cancer science 29 29856906
2020 Platelet factor 4 enhances CD4+ T effector memory cell responses via Akt-PGC1α-TFAM signaling-mediated mitochondrial biogenesis. Journal of thrombosis and haemostasis : JTH 28 32671959
2017 Mitochondrial transcription factor A (TFAM) is upregulated in glioma. Molecular medicine reports 27 28440425
2017 Hypoxia-induced suppression of c-Myc by HIF-2α in human pulmonary endothelial cells attenuates TFAM expression. Cellular signalling 27 28709643
2020 The neuroprotective effect of NeuroAid on morphine-induced amnesia with respect to the expression of TFAM, PGC-1α, ΔfosB and CART genes in the hippocampus of male Wistar rats. Gene 26 32198124
2015 Chromosome 21-derived hsa-miR-155-5p regulates mitochondrial biogenesis by targeting Mitochondrial Transcription Factor A (TFAM). Biochimica et biophysica acta 26 25869329
2008 Mitochondrial transcription factor A (TFAM) gene variation and risk of late-onset Alzheimer's disease. Journal of Alzheimer's disease : JAD 26 18430995
2024 Gastrodin alleviates mitochondrial dysfunction by regulating SIRT3-mediated TFAM acetylation in vascular dementia. Phytomedicine : international journal of phytotherapy and phytopharmacology 25 38547618
2023 35 Years of TFAM Research: Old Protein, New Puzzles. Biology 25 37372108
2018 TFAM is required for maturation of the fetal and adult intestinal epithelium. Developmental biology 25 29684311
2022 Photobiomodulation promotes repair following spinal cord injury by restoring neuronal mitochondrial bioenergetics via AMPK/PGC-1α/TFAM pathway. Frontiers in pharmacology 24 36172183
2022 Zhen Wu decoction represses renal fibrosis by invigorating tubular NRF2 and TFAM to fuel mitochondrial bioenergetics. Phytomedicine : international journal of phytotherapy and phytopharmacology 24 36257219
2014 Negative transcriptional regulation of mitochondrial transcription factor A (TFAM) by nuclear TFAM. Biochemical and biophysical research communications 24 24875355
2007 Mitochondrial transcription factor A (TFAM) gene variation in Parkinson's disease. Neuroscience letters 24 18248889
2024 Baicalin and N-acetylcysteine regulate choline metabolism via TFAM to attenuate cadmium-induced liver fibrosis. Phytomedicine : international journal of phytotherapy and phytopharmacology 23 38241915
2023 DNA-protein cross-links between abasic DNA damage and mitochondrial transcription factor A (TFAM). Nucleic acids research 23 36583367
2011 The role of TFAM-associated proteins in mitochondrial RNA metabolism. Biochimica et biophysica acta 23 21920408
2018 TGF-β and BMP signals regulate insect diapause through Smad1-POU-TFAM pathway. Biochimica et biophysica acta. Molecular cell research 21 29902488
2017 Polymorphisms in the TFAM and PGC1-α genes and their association with polycystic ovary syndrome among South Indian women. Gene 21 29030253
2022 GCN5L1-mediated TFAM acetylation at K76 participates in mitochondrial biogenesis in acute kidney injury. Journal of translational medicine 19 36474281
2021 Mitochondrial functional resilience after TFAM ablation in the adult heart. American journal of physiology. Cell physiology 19 33760663
2024 Potential effect of acupuncture on mitochondrial biogenesis, energy metabolism and oxidation stress in MCAO rat via PGC-1α/NRF1/TFAM pathway. Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association 18 38346661
2023 Mitochondrial DNA release mediated by TFAM deficiency promotes copper-induced mitochondrial innate immune response via cGAS-STING signalling in chicken hepatocytes. The Science of the total environment 18 37742962
2019 Down-regulation of TFAM increases the sensitivity of tumour cells to radiation via p53/TIGAR signalling pathway. Journal of cellular and molecular medicine 18 31062473
2019 Differences in Liver TFAM Binding to mtDNA and mtDNA Damage between Aged and Extremely Aged Rats. International journal of molecular sciences 18 31137890
2007 Transcription factor hStaf/ZNF143 is required for expression of the human TFAM gene. Gene 18 17707600
2024 Polysaccharides from Polygonatum kingianum Collett & Hemsl ameliorated fatigue by regulating NRF2/HO-1/NQO1 and AMPK/PGC-1α/TFAM signaling pathways, and gut microbiota. International journal of biological macromolecules 17 38593898
2022 A minimal motif for sequence recognition by mitochondrial transcription factor A (TFAM). Nucleic acids research 17 34928349
2020 Loss of mitochondrial ClpP, Lonp1, and Tfam triggers transcriptional induction of Rnf213, a susceptibility factor for moyamoya disease. Neurogenetics 17 32342250
2022 Agrimol B inhibits colon carcinoma progression by blocking mitochondrial function through the PGC-1α/NRF1/TFAM signaling pathway. Frontiers in oncology 16 36591497
2017 Mitochondrial transcription factor A (TFAM) rs1937 and AP endonuclease 1 (APE1) rs1130409 alleles are associated with reduced cognitive performance. Neuroscience letters 16 28242328
2017 Mechanisms of TFAM-mediated cardiomyocyte protection. Canadian journal of physiology and pharmacology 16 28800400
2019 Edition of TFAM gene by CRISPR/Cas9 technology in bovine model. PloS one 15 30845180
2024 Nicorandil mitigates arsenic trioxide-induced lung injury via modulating vital signalling pathways SIRT1/PGC-1α/TFAM, JAK1/STAT3, and miRNA-132 expression. British journal of pharmacology 12 38741475
2023 Reduced acetylation of TFAM promotes bioenergetic dysfunction in the failing heart. iScience 12 37305705
2022 TFAM's Contributions to mtDNA Replication and OXPHOS Biogenesis Are Genetically Separable. Cells 12 36497015
2021 Knock out hepatic Krüppel-like factor 16 (KLF16) improve myocardial damage and promoted myocardial protection of myocardial ischemia-reperfusion via anti-oxidative and anti-inflammation effects by TFAM/PPARβ signal passage. Bioengineered 12 34823421
2024 TRAP1 modulates mitochondrial biogenesis via PGC-1α/TFAM signalling pathway in colorectal cancer cells. Journal of molecular medicine (Berlin, Germany) 11 39210159