Affinage

TFAM

Transcription factor A, mitochondrial · UniProt Q00059

Length
246 aa
Mass
29.1 kDa
Annotated
2026-06-10
100 papers in source corpus 34 papers cited in narrative 34 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TFAM is a mitochondrial HMG-box DNA-binding protein that packages mtDNA into nucleoids and licenses its transcription, with its activities governed by the local TFAM-to-mtDNA ratio (PMID:22037171, PMID:34818548). Structurally, each of its two HMG-box domains wedges into the DNA minor groove to generate kinks while a positively charged α-helix on the opposite face acts as a bending platform, forcing promoter DNA into a U-turn; the inter-domain linker reversibly unfolds to stabilize this tight bend (PMID:22037171, PMID:29248151). TFAM recognizes a GN10G consensus and binds the LSP and HSP1 promoters in opposite orientations, explaining why LSP activation requires bending whereas HSP1 does not, and it bridges two DNA substrates (PMID:34928349, PMID:24435062). Beyond recruitment, TFAM has a post-recruitment role in transcription initiation: together with TFB2M it enables POLRMT to efficiently melt the LSP promoter and stabilizes the open complex for productive RNA synthesis (PMID:27903899). DNA-bound TFAM dimerization, dispensable for bending and transcription, drives the compaction that packages mtDNA into nucleoids, and TFAM:mtDNA ratio dictates whether individual nucleoids are transcriptionally active or silenced — at high relative abundance TFAM becomes a general transcriptional repressor (PMID:24435062, PMID:34818548, PMID:34462320). TFAM-DNA binding and stability are tuned by post-translational modification: PKA phosphorylation of HMG box 1 and lysine acetylation reduce DNA binding, with DNA-free phosphorylated TFAM selectively degraded by the Lon protease (PMID:23201127, PMID:29897602). TFAM also serves immune and quality-control functions, acting as an autophagy receptor through an LC3-interacting region that directs leaked cytoplasmic mtDNA to autolysosomes and thereby limits cGAS-STING inflammatory signaling (PMID:38783142, PMID:28902841).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2003 High

    Established that mtDNA exists essentially entirely complexed with TFAM in particulate nucleoids rather than as free molecules, defining TFAM as the principal packaging factor of the mitochondrial genome.

    Evidence Co-immunoprecipitation, subcellular fractionation, and DNase I digestion of human placental mitochondria

    PMID:12626705

    Open questions at the time
    • Did not resolve the molecular geometry of packaging
    • Did not separate transcription-competent from compacted states
  2. 2011 High

    Answered how TFAM physically remodels DNA, showing each HMG-box generates kinks and an α-helix platform forces a U-turn that reverses helix direction — the structural basis for bending-dependent promoter activation.

    Evidence X-ray crystallography of human TFAM bound to promoter DNA with domain-contribution validation

    PMID:22037171

    Open questions at the time
    • Single static conformation; bending dynamics unresolved
    • Did not address dimerization or packaging
  3. 2014 High

    Separated TFAM's two functions by showing HSP1 and LSP are bound in opposite orientations and that DNA-bound dimerization is dispensable for bending/transcription but required for compaction/packaging.

    Evidence Multiple crystal structures with transcription and DNA compaction assays

    PMID:24435062

    Open questions at the time
    • Stoichiometry of dimers on full nucleoids in vivo not defined
    • Dynamics of orientation selection unresolved
  4. 2012 High

    Defined how TFAM levels are controlled, showing PKA phosphorylation of HMG box 1 impairs DNA binding and that only DNA-free TFAM is degraded by Lon, coupling modification to turnover.

    Evidence In vitro kinase and protease assays, DNA-binding assays, and Lon depletion in cells

    PMID:23201127

    Open questions at the time
    • Upstream signals activating mitochondrial PKA not mapped
    • Quantitative contribution to steady-state TFAM in vivo unclear
  5. 2016 High

    Showed TFAM has a post-recruitment role in initiation, cooperating with TFB2M to enable POLRMT to melt the LSP promoter and stabilize the open complex for productive synthesis.

    Evidence 2-aminopurine fluorescence melting mapping, equilibrium binding, and abortive RNA synthesis in a reconstituted system

    PMID:27903899

    Open questions at the time
    • HSP1 initiation mechanism less defined
    • Order of assembly steps not fully kinetically resolved
  6. 2017 High

    Resolved the solution mechanism of the U-turn, demonstrating progressive cooperative binding of both HMG-boxes with reversible linker unfolding stabilizing the tight bend.

    Evidence Single-molecule FRET, SAXS, and molecular dynamics on TFAM/LSP complexes

    PMID:29248151

    Open questions at the time
    • Did not connect bending dynamics to transcriptional output
    • Behavior on packaged nucleoid DNA not examined
  7. 2017 High

    Linked TFAM's DNA-distorting activity to innate immunity, showing TFAM-induced U-turns pre-structure DNA to nucleate cGAS dimers and enhance cooperative cGAS-DNA network assembly.

    Evidence In vitro cGAS activity assays, structural analysis, and cellular cGAMP production

    PMID:28902841

    Open questions at the time
    • Did not establish in vivo relevance to mtDNA-driven inflammation
    • Did not address how leaked TFAM-mtDNA reaches cGAS
  8. 2018 High

    Quantified how PTMs tune TFAM-DNA engagement, showing acetylation lowers the on-rate while phosphorylation lowers on-rate, raises off-rate, and accelerates sliding, both weakening compaction.

    Evidence Single-molecule FRET and bulk binding assays with PTM-mimic mutants

    PMID:29897602

    Open questions at the time
    • Used PTM mimics rather than enzymatically modified protein
    • Did not identify the responsible cellular enzymes
  9. 2021 High

    Established the TFAM:mtDNA ratio as a master regulator: super-resolution imaging showed inactive nucleoids carry high TFAM:mtDNA, and in vivo overexpression showed excess TFAM acts as a general transcriptional repressor counterbalanced by LONP1 and POLRMT.

    Evidence Multi-color STED imaging of individual nucleoids; transgenic mouse overexpression across tissues

    PMID:34462320 PMID:34818548

    Open questions at the time
    • How nucleoids set their local TFAM:mtDNA ratio is unknown
    • Tissue-specific compensation mechanism not fully defined
  10. 2022 High

    Refined sequence recognition, showing TFAM reads a GN10G consensus, bridges two DNA substrates, and that these contacts are essential for transcription initiation.

    Evidence Crystal structure of TFAM on GN10G DNA with mutagenesis and transcription assays

    PMID:34928349

    Open questions at the time
    • Genome-wide impact of GN10G distribution not mapped
    • Relation of DNA bridging to nucleoid architecture unresolved
  11. 2023 High

    Uncovered a genome-maintenance liability, showing TFAM lysines and cysteines form covalent DNA-protein crosslinks at abasic sites and that TFAM cleaves AP-DNA to generate a reactive 3'pUA, with glutathione competing for resolution.

    Evidence In vitro DPC formation assays, residue mutagenesis, cellular AP-site DPC detection, and glutathione competition

    PMID:36583367

    Open questions at the time
    • Repair pathway resolving TFAM-DPCs not identified
    • Physiological frequency of these lesions unknown
  12. 2024 High

    Resolved how TFAM dynamically bends DNA in a sequence-dependent manner, with LSP forming the most stable fully bent, longest-lived complex, linking bending stability to binding affinity.

    Evidence Single-molecule FRET and PIFE across promoter and non-specific sequences

    PMID:38937458

    Open questions at the time
    • Link between bending lifetime and in vivo transcription rate not directly measured
  13. 2024 High

    Identified a moonlighting quality-control role, showing TFAM acts as a nucleoid-phagy autophagy receptor via an LC3-interacting region that targets leaked cytoplasmic mtDNA for autolysosomal degradation to limit inflammation.

    Evidence LIR-motif mutagenesis, LC3 co-IP, autolysosomal pathway analysis, and inflammatory signaling assays

    PMID:38783142

    Open questions at the time
    • How TFAM-mtDNA escapes mitochondria to engage LC3 is unresolved
    • Relationship to mitophagy of intact organelles not defined
  14. 2023 Medium

    Defined a regulatory acetylation/deacetylation axis, with GCN5L1 acetylating TFAM (K76 blocking TOM70-dependent import; other sites affecting cardiac mtDNA) and SIRT3 deacetylating N-terminal lysines to maintain mitochondrial function.

    Evidence Acetyl-proteomics, co-IP, proximity ligation, site-directed mutagenesis, and genetic knockout/knockdown of GCN5L1 and SIRT3

    PMID:36474281 PMID:37305705 PMID:38547618

    Open questions at the time
    • Each axis shown in single labs without cross-validation
    • Net effect of competing acetylation events on TFAM activity unintegrated
  15. 2022 Medium

    Connected TFAM loss to cytosolic mtDNA-driven cGAS-STING signaling in disease contexts, where TFAM deficiency promotes mtDNA leakage that alters tumor immunity and growth.

    Evidence Genetic TFAM knockout/knockdown in dendritic and cancer cells with STING inhibition or DNase I controls and tumor models

    PMID:35750756 PMID:36858460

    Open questions at the time
    • Context-dependent (immunostimulatory vs growth-promoting) outcomes not reconciled
    • Single-lab observations per cell type

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the cell sets and senses the TFAM:mtDNA ratio at individual nucleoids — integrating PTMs, Lon turnover, import control, and DNA bending kinetics into a unified set-point — remains unresolved.
  • No quantitative model linking PTM state to per-nucleoid activity
  • Mechanism coupling mtDNA copy number sensing to TFAM stability unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 6 GO:0005198 structural molecule activity 3 GO:0140110 transcription regulator activity 3 GO:0060090 molecular adaptor activity 1 GO:0140097 catalytic activity, acting on DNA 1
Localization
GO:0005739 mitochondrion 4 GO:0000228 nuclear chromosome 2 GO:0005829 cytosol 2
Pathway
R-HSA-1852241 Organelle biogenesis and maintenance 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-168256 Immune System 2 R-HSA-9612973 Autophagy 1
Partners
CGASGCN5L1LONP1MAP1LC3POLRMTSIRT3TFB2MTOM70
Complex memberships
mitochondrial nucleoid

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 X-ray crystallography revealed that human TFAM forces promoter DNA to undergo a U-turn, reversing the direction of the DNA helix. Each HMG-box domain wedges into the DNA minor groove to generate two kinks on one face of the DNA, while a positively charged α-helix on the opposite face serves as a platform to facilitate DNA bending. X-ray crystallography Nature structural & molecular biology High 22037171
2014 Crystal structures of TFAM bound to HSP1 and nonspecific DNA show that TFAM similarly distorts both into a U-turn, but binds HSP1 in the opposite orientation from LSP—explaining why transcription from LSP requires DNA bending whereas HSP1 does not. Additionally, DNA-bound TFAM dimerizes, and this dimerization is dispensable for DNA bending and transcriptional activation but is important for DNA compaction/packaging. X-ray crystallography, transcription assays, DNA compaction assays Nature communications High 24435062
2012 TFAM is phosphorylated within its HMG box 1 (HMG1) by cAMP-dependent protein kinase in mitochondria. HMG1 phosphorylation impairs TFAM's ability to bind DNA and to activate transcription. Only DNA-free TFAM is degraded by the Lon protease; in cells with normal mtDNA levels, HMG1-phosphorylated TFAM is preferentially degraded by Lon. In vitro kinase assay, DNA binding assays, in vitro protease assays, cell-based studies with Lon depletion Molecular cell High 23201127
2003 Human mtDNA is tightly packaged with TFAM in mitochondria: TFAM and mtDNA co-immunoprecipitate, and virtually all TFAM and mtDNA exist in a particulate (nucleoid) fraction that is solubilized by DNase I treatment, indicating few free molecules exist. Co-immunoprecipitation, subcellular fractionation, DNase I digestion Nucleic acids research High 12626705
2017 HMGB/TFAM proteins stimulate cGAS-mediated sensing of long DNA. TFAM induces U-turns and bends in DNA that pre-structure DNA to nucleate cGAS dimers, enhancing cooperative ladder-like cGAS-DNA network assembly and innate immune activation. In vitro cGAS activity assays, structural analysis, cell-based cGAMP production assays Nature High 28902841
2018 TFAM lysine acetylation within HMG box 1 reduces DNA binding affinity by decreasing the on-rate of TFAM binding to DNA. Serine phosphorylation at the same domain reduces binding via both decreased on-rate and increased off-rate, and additionally accelerates TFAM diffusion along DNA. Both modifications require higher protein concentrations to compact DNA to the same extent as wild-type. Single-molecule FRET, bulk DNA binding assays, phosphoserine and acetyl-lysine mimic mutagenesis Nucleic acids research High 29897602
2016 TFAM has post-recruitment roles in promoter melting during transcription initiation. POLRMT requires both TFB2M and TFAM to efficiently melt the LSP promoter; two-component complexes of POLRMT+TFB2M or POLRMT+TFAM alone lack the mechanism for efficient melting. TFAM also stabilizes the open complex and enables synthesis of RNAs longer than 2-mer abortives. 2-aminopurine fluorescence mapping, equilibrium binding assays, abortive RNA synthesis assays Nucleic acids research High 27903899
2021 The TFAM-to-mtDNA ratio is a critical regulator of mtDNA expression: when TFAM levels are very high relative to mtDNA, TFAM acts as a general repressor of mtDNA transcription. This repression can be counterbalanced tissue-specifically by induction of LONP1 protease and mitochondrial RNA polymerase. In vivo mouse transgenic overexpression, tissue-specific analysis of mtDNA expression and OXPHOS Life science alliance High 34462320
2024 TFAM acts as an autophagy receptor (nucleoid-phagy) for cytoplasmic mtDNA. TFAM contains an LC3-interacting region (LIR) motif that binds LC3 to direct leaked mtDNA to autolysosomes for degradation. Mutating the LIR motif does not affect TFAM's normal mitochondrial functions but causes cytoplasmic mtDNA accumulation and inflammatory signaling. LIR motif mutagenesis, co-immunoprecipitation with LC3, autolysosomal pathway analysis, cytoplasmic mtDNA quantification, inflammatory signaling assays Nature cell biology High 38783142
2017 Single-molecule FRET on freely diffusing TFAM/LSP complexes confirmed that the DNA U-turn is induced by progressive and cooperative binding of both TFAM HMG-box domains and the linker between them. The linker undergoes reversible unfolding to stabilize tight DNA bending, as supported by SAXS (protein compaction on complex formation) and molecular dynamics simulations. Single-molecule FRET, SAXS, molecular dynamics simulations Biophysical journal High 29248151
2021 Only a minority of nucleoids are transcriptionally and replicationally active. Inactivity correlates with a high TFAM-to-mtDNA ratio within individual nucleoids, indicating that TFAM-induced compaction regulates nucleoid activity in vivo. Multi-color STED super-resolution microscopy of individual nucleoids in primary human cells Cell reports High 34818548
2023 TFAM forms covalent DNA-protein cross-links (DPCs) with abasic (AP) sites in mtDNA. Lys residues of TFAM are critical for DPC formation. TFAM cleaves AP-DNA and generates a reactive 3'-phospho-α,β-unsaturated aldehyde (3'pUA) residue at single-strand breaks, which then reacts with two Cys residues of TFAM to stabilize DPC formation. Glutathione competes with this reaction. In vitro DPC formation assays, mutagenesis of Lys and Cys residues, cellular AP-site DPC detection, glutathione competition assays Nucleic acids research High 36583367
2022 Crystal structure of TFAM bound to a non-sequence-specific DNA containing the GN10G consensus shows TFAM bridging two DNA substrates while maintaining two guanine-specific interactions separated by 10 random nucleotides. Mutagenesis of GN10G contacts demonstrated this consensus is essential for transcriptional initiation and facilitates TFAM binding. X-ray crystallography, biochemical binding assays, mutagenesis, transcription initiation assays Nucleic acids research High 34928349
2024 TFAM-DNA complexes dynamically transition between partially and fully bent DNA conformational states. The bending/unbending transition rates and bending stability are DNA sequence-dependent: LSP forms the most stable fully bent complex, correlating with highest TFAM affinity and longest lifetime. Non-specific sequences form least stable complexes. Single-molecule FRET (smFRET), single-molecule protein-induced fluorescence enhancement (smPIFE) Nature communications High 38937458
2017 TFAM binds to the mitochondrial Lon protease substrate channel and blocks Lon-mediated TFAM degradation when bound to the small molecule TMP (tetramethylpyrazine). TMP does not directly inhibit Lon but instead interacts with TFAM protein to confer resistance to degradation, leading to TFAM accumulation and mtDNA copy number upregulation. In vitro Lon protease assays, pull-down assay with biotinylated TMP, cell-based TFAM and mtDNA copy number measurements Bioscience reports Medium 28465355
2010 TFAM and TFB2M bind to the Serca2 gene promoter at specific regions (-122 to -114 nt and -122 to -117 nt respectively) and regulate nuclear Serca2 gene transcription, as demonstrated by ChIP assay and fluorescence correlation spectroscopy. Mutation of these binding sites decreased Serca2 transcription. Chromatin immunoprecipitation (ChIP), fluorescence correlation spectroscopy, promoter mutation analysis, overexpression studies Cardiovascular research Medium 21113058
2014 Nuclear TFAM suppresses its own gene (TFAM) promoter activity in a dose-dependent manner by acting as a co-repressor of NRF-1. TFAM does not directly bind the NRF-1 binding site in the TFAM promoter, but co-immunoprecipitates with NRF-1, indicating protein-protein interaction mediates repression. Subcellular fractionation, GFP-fusion localization, luciferase promoter assay, co-immunoprecipitation, mitochondria-targeting sequence deletion mutant Biochemical and biophysical research communications Medium 24875355
2011 Truncating frameshift mutations in TFAM reduce TFAM protein abundance and mtDNA copy number in microsatellite-unstable colorectal cancer cells. Mutant TFAM exhibits reduced binding to the heavy-strand promoter (HSP) of mtDNA, leading to reduced cytochrome b transcription. Wild-type TFAM re-expression suppressed tumor growth and increased cisplatin sensitivity via cytochrome b-mediated apoptosis. TFAM binding assay to HSP, overexpression rescue experiments, xenograft tumor assay, apoptosis assays Cancer research Medium 21467167
2022 TFAM deficiency blocks the TCA cycle, increases intracellular malonyl-CoA, which causes malonylation of mDia2 (a formin that drives actin assembly), promoting mDia2 nuclear translocation and nuclear actin polymerization. This nuclear actin drives chromatin remodeling and pro-metastatic gene expression in liver cancer cells. In vivo metastasis models, malonyl-CoA measurement, mDia2 malonylation detection, nuclear actin polymerization assays, chromatin accessibility analysis The EMBO journal Medium 35451091
2022 GCN5L1 acetyltransferase acetylates TFAM at lysine K76, which inhibits TFAM interaction with the mitochondrial import receptor TOM70, thereby reducing TFAM import into mitochondria and diminishing mitochondrial biogenesis. Acetylated proteomics, co-immunoprecipitation, Duolink proximity ligation assay, site-directed K76 mutagenesis, knockdown of GCN5L1 Journal of translational medicine Medium 36474281
2023 SIRT3 deacetylates TFAM at K5, K7, and K8 residues. Decreased SIRT3 expression leads to hyper-acetylated TFAM and mitochondrial dysfunction. SIRT3-mediated deacetylation of TFAM was confirmed by immunoprecipitation and mass spectrometry. Co-immunoprecipitation, mass spectrometry identification of acetylation sites, SIRT3 knockdown and inhibitor experiments Phytomedicine Medium 38547618
2023 GCN5L1 knockout in cardiomyocytes leads to decreased acetylation of TFAM after hemodynamic stress (TAC), which is linked to reduced mtDNA levels and impaired bioenergetic output. Loss of GCN5L1-mediated TFAM acetylation thus contributes to heart failure progression. Cardiomyocyte-specific GCN5L1 knockout, TAC model, TFAM acetylation status measurement, mtDNA quantification, bioenergetics assay iScience Medium 37305705
2015 H2S maintains mtDNA replication by inhibiting DNA methyltransferase 3a (Dnmt3a) expression through S-sulfhydration of the transcription repressor IRF-1, which enhances IRF-1 binding to the Dnmt3a promoter. Reduced Dnmt3a leads to demethylation of the TFAM promoter and restored TFAM expression, thereby maintaining mtDNA copy number. TFAM promoter methylation assays, Dnmt3a knockdown, IRF-1 S-sulfhydration detection, ChIP for IRF-1 at Dnmt3a promoter, CSE knockout mice Antioxidants & redox signaling Medium 25758951
2007 The transcription factor hStaf/ZNF143 binds to two conserved sites in the human TFAM gene promoter and is required for normal TFAM promoter activity. This was demonstrated by promoter binding assays, transient expression of mutant TFAM reporter constructs, and chromatin immunoprecipitation. Promoter binding assays, mutant TFAM reporter gene constructs, chromatin immunoprecipitation Gene Medium 17707600
2020 ATF4 represses transcription of NRF1 by binding to the NRF1 promoter region, thereby disrupting the NRF1-TFAM pathway and impairing mitochondrial biogenesis and respiratory function in alcohol-induced liver disease. Hepatocyte-specific ATF4 knockout mice, liver-specific TFAM overexpression mice, ChIP assay for ATF4 at NRF1 promoter, cell-based rescue experiments Gut Medium 33177163
2018 In vitro chromatin immunoprecipitation experiments identified Tfam as a direct transcriptional target of Notch signaling (via the Jag1/Notch2 pathway) in renal tubular cells. Re-expression of Tfam in Notch-activated tubule cells prevented Notch-induced metabolic and profibrotic reprogramming, and tubule-specific deletion of Tfam caused renal fibrosis. Chromatin immunoprecipitation, genome-wide expression studies, tubule-specific knockout mice, rescue experiments PLoS biology Medium 30226866
2011 TFAM-interacting proteins ERAL1 and p32 were identified by co-immunoprecipitation. ERAL1 binds to mitochondrial rRNA of the small ribosomal subunit and is a component of that subunit; p32 is involved in mitochondrial translation. Co-immunoprecipitation, biochemical characterization of interaction partners Biochimica et biophysica acta Low 21920408
2023 Vitamin D receptor (VDR) physically interacts with TFAM and their binding sites are located in close proximity in the mtDNA D-loop. This interaction was supported by co-localization of VDR with mitochondria and mtDNA by confocal microscopy, and by mtDNA chromatin immunoprecipitation. Confocal microscopy, mtDNA-ChIP, electrophoretic mobility shift assay, co-localization analysis The Journal of nutritional biochemistry Low 36963731
2018 TFAM released from apoptotic cells acts as a mitochondrial damage-associated molecular pattern (DAMP) that triggers immunogenic cancer cell death via the receptor AGER. Neutralization of TFAM or AGER abrogated the immunogenic effect of spautin-1-treated cancer cells in vivo. Antibody neutralization of TFAM and AGER, in vivo vaccination assay, in vitro apoptosis assays Oncoimmunology Low 29872558
2018 TFAM was found to localize to the nucleus in addition to mitochondria in rat neonatal cardiac myocytes, and TFAM protein knockdown via CRISPR-Cas9 in HL-1 cardiomyocytes increased expression of NFAT4, Calpain1, and MMP9, while TFAM overexpression normalized NFAT4 under oxidative stress conditions. CRISPR-Cas9 knockdown, Western blotting, confocal microscopy, overexpression studies Canadian journal of physiology and pharmacology Low 28800400
2018 HuR RNA-binding protein binds and stabilizes TFAM mRNA in cancer cells following ionizing radiation. ATM/p38 signaling promotes nuclear-to-cytosol translocation of HuR, enhancing its binding to and stabilization of TFAM mRNA without affecting TFAM transcription or TFAM mRNA intrinsic stability. RNA immunoprecipitation, mRNA stability assays, HuR translocation analysis, ATM/p38 pathway inhibition Cancer science Low 29856906
2022 TFAM deficiency in dendritic cells causes mtDNA cytosolic leakage that activates the cGAS-STING pathway, enhancing antigen presentation and antitumor immunity. STING inhibitors abrogated the enhanced immune activation in TFAM-deficient DCs. Myeloid-specific Tfam knockout mice, tumor models, STING inhibitor treatment, DC functional assays Journal for immunotherapy of cancer Medium 36858460
2022 TFAM reduction in ESCC cells promotes mtDNA release into the cytosol, activating the cGAS-STING signaling pathway and stimulating autophagy and tumor cell growth. DNase I degradation of cytoplasmic mtDNA or STING depletion abrogated this effect. TFAM knockdown, cytoplasmic mtDNA quantification, STING depletion, DNase I treatment, autophagy and growth assays Oncogene Medium 35750756
2001 Downregulation of mitochondrial Tfam protein during mammalian spermatogenesis is accompanied by reduced mtDNA copy number, representing a conserved mechanism across rat, mouse, and human. The nuclear Tfam isoform found in mouse is absent in rat and human, demonstrating it is dispensable for spermatogenesis. Western blotting of testis fractions, mtDNA copy number quantification, comparison across species Mammalian genome Low 11668394

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 646 33408785
2017 cGAS senses long and HMGB/TFAM-bound U-turn DNA by forming protein-DNA ladders. Nature 434 28902841
2006 Mitochondrial transcription factor A (TFAM): roles in maintenance of mtDNA and cellular functions. Mitochondrion 372 17280879
2003 Human mitochondrial DNA is packaged with TFAM. Nucleic acids research 305 12626705
2012 Phosphorylation of human TFAM in mitochondria impairs DNA binding and promotes degradation by the AAA+ Lon protease. Molecular cell 266 23201127
2018 The mitochondrial transcription factor TFAM in neurodegeneration: emerging evidence and mechanisms. FEBS letters 252 29364506
2015 Regulation of mitochondrial biogenesis through TFAM-mitochondrial DNA interactions: Useful insights from aging and calorie restriction studies. Mitochondrion 246 26437364
2011 The mitochondrial transcription and packaging factor Tfam imposes a U-turn on mitochondrial DNA. Nature structural & molecular biology 238 22037171
2014 Distinct structural features of TFAM drive mitochondrial DNA packaging versus transcriptional activation. Nature communications 203 24435062
2023 Melatonin attenuates sepsis-induced acute kidney injury by promoting mitophagy through SIRT3-mediated TFAM deacetylation. Autophagy 138 37651673
2020 ATF4 activation promotes hepatic mitochondrial dysfunction by repressing NRF1-TFAM signalling in alcoholic steatohepatitis. Gut 127 33177163
2015 Overexpression of TFAM or twinkle increases mtDNA copy number and facilitates cardioprotection associated with limited mitochondrial oxidative stress. PloS one 125 25822152
2017 The Role of Exercise and TFAM in Preventing Skeletal Muscle Atrophy. Journal of cellular physiology 122 27966783
2024 TFAM is an autophagy receptor that limits inflammation by binding to cytoplasmic mitochondrial DNA. Nature cell biology 121 38783142
2019 Role of mitochondria in diabetic peripheral neuropathy: Influencing the NAD+-dependent SIRT1-PGC-1α-TFAM pathway. International review of neurobiology 108 31208524
2011 Frequent truncating mutation of TFAM induces mitochondrial DNA depletion and apoptotic resistance in microsatellite-unstable colorectal cancer. Cancer research 97 21467167
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 89 37030337
2016 Mitochondrial pathways to cardiac recovery: TFAM. Heart failure reviews 87 27166683
1995 Chromosomal localization of mitochondrial transcription factor A (TCF6), single-stranded DNA-binding protein (SSBP), and endonuclease G (ENDOG), three human housekeeping genes involved in mitochondrial biogenesis. Genomics 84 7789991
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 74 29897602
2017 MiR-199a-3p enhances breast cancer cell sensitivity to cisplatin by downregulating TFAM (TFAM). Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 72 28126676
2016 Human mitochondrial transcription factors TFAM and TFB2M work synergistically in promoter melting during transcription initiation. Nucleic acids research 72 27903899
2021 High levels of TFAM repress mammalian mitochondrial DNA transcription in vivo. Life science alliance 71 34462320
2011 Overexpression of TFAM, NRF-1 and myr-AKT protects the MPP(+)-induced mitochondrial dysfunctions in neuronal cells. Biochimica et biophysica acta 71 21856379
2015 Hydrogen Sulfide Maintains Mitochondrial DNA Replication via Demethylation of TFAM. Antioxidants & redox signaling 69 25758951
2018 Jagged1/Notch2 controls kidney fibrosis via Tfam-mediated metabolic reprogramming. PLoS biology 65 30226866
2017 TP73-AS1 promotes breast cancer cell proliferation through miR-200a-mediated TFAM inhibition. Journal of cellular biochemistry 65 28639399
2021 The TFAM-to-mtDNA ratio defines inner-cellular nucleoid populations with distinct activity levels. Cell reports 62 34818548
2022 TFAM loss induces nuclear actin assembly upon mDia2 malonylation to promote liver cancer metastasis. The EMBO journal 60 35451091
2001 Downregulation of Tfam and mtDNA copy number during mammalian spermatogenesis. Mammalian genome : official journal of the International Mammalian Genome Society 59 11668394
2022 TFAM downregulation promotes autophagy and ESCC survival through mtDNA stress-mediated STING pathway. Oncogene 58 35750756
2023 TFAM deficiency in dendritic cells leads to mitochondrial dysfunction and enhanced antitumor immunity through cGAS-STING pathway. Journal for immunotherapy of cancer 54 36858460
2012 Age- and calorie restriction-related changes in rat brain mitochondrial DNA and TFAM binding. Age (Dordrecht, Netherlands) 54 22945739
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 47 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 44 35210991
2021 Mitochondrial TFAM as a Signaling Regulator between Cellular Organelles: A Perspective on Metabolic Diseases. Diabetes & metabolism journal 42 34847642
2010 Mitochondrial DNA depletion and its correlation with TFAM, TFB1M, TFB2M and POLG in human diffusely infiltrating astrocytomas. Mitochondrion 42 20643228
2017 Role of microRNA-130b in placental PGC-1α/TFAM mitochondrial biogenesis pathway. Biochemical and biophysical research communications 40 28433632
2016 Failed upregulation of TFAM protein and mitochondrial DNA in oxidatively deficient fibers of chronic obstructive pulmonary disease locomotor muscle. Skeletal muscle 38 26893822
2015 Dietary isoflavone daidzein promotes Tfam expression that increases mitochondrial biogenesis in C2C12 muscle cells. The Journal of nutritional biochemistry 38 26166229
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 37 29259235
2018 TFAM is a novel mediator of immunogenic cancer cell death. Oncoimmunology 36 29872558
2008 Expression of mitochondrial transcription factor A (TFAM) during porcine gametogenesis and preimplantation embryo development. Journal of cellular physiology 36 18636550
2007 TFAM 1.0: an online tRNA function classifier. Nucleic acids research 36 17591612
2021 Mitochondrial genome and its regulator TFAM modulates head and neck tumourigenesis through intracellular metabolic reprogramming and activation of oncogenic effectors. Cell death & disease 35 34663785
2020 TFAM depletion overcomes hepatocellular carcinoma resistance to doxorubicin and sorafenib through AMPK activation and mitochondrial dysfunction. Gene 35 32461017
2020 The interaction between C/EBPβ and TFAM promotes acute kidney injury via regulating NLRP3 inflammasome-mediated pyroptosis. Molecular immunology 35 32971400
2018 Resistin destroys mitochondrial biogenesis by inhibiting the PGC-1α/ NRF1/TFAM signaling pathway. Biochemical and biophysical research communications 35 30172371
2014 A comparison among the tissue-specific effects of aging and calorie restriction on TFAM amount and TFAM-binding activity to mtDNA in rat. Biochimica et biophysica acta 35 24631828
2023 The Protective Mechanism of TFAM on Mitochondrial DNA and its Role in Neurodegenerative Diseases. Molecular neurobiology 34 38087167
2015 The regulation of mitochondrial transcription factor A (Tfam) expression during skeletal muscle cell differentiation. Bioscience reports 34 26182383
2010 Mitochondrial DNA and TFAM gene variation in early-onset myocardial infarction: evidence for an association to haplogroup H. Mitochondrion 34 20863902
2022 TFAM-Dependent Mitochondrial Metabolism Is Required for Alveolar Macrophage Maintenance and Homeostasis. Journal of immunology (Baltimore, Md. : 1950) 33 35165165
2021 Integrated Genomics Identifies miR-181/TFAM Pathway as a Critical Driver of Drug Resistance in Melanoma. International journal of molecular sciences 33 33670365
2018 KLF16 suppresses human glioma cell proliferation and tumourigenicity by targeting TFAM. Artificial cells, nanomedicine, and biotechnology 33 29374989
2021 The HIF-1/SNHG1/miR-199a-3p/TFAM axis explains tumor angiogenesis and metastasis under hypoxic conditions in breast cancer. BioFactors (Oxford, England) 32 34003544
2014 Upregulation of TFAM and mitochondria copy number in human lymphoblastoid cells. Mitochondrion 32 24462998
2003 Expression of the mitochondrial ATPase6 gene and Tfam in Down syndrome. Molecules and cells 31 12803480
2023 Vitamin D receptor regulates transcription of mitochondrial DNA and directly interacts with mitochondrial DNA and TFAM. The Journal of nutritional biochemistry 30 36963731
2018 HuR stabilizes TFAM mRNA in an ATM/p38-dependent manner in ionizing irradiated cancer cells. Cancer science 30 29856906
2023 35 Years of TFAM Research: Old Protein, New Puzzles. Biology 28 37372108
2018 TFAM overexpression reduces pathological cardiac remodeling. Molecular and cellular biochemistry 28 30353496
2017 Mitochondrial transcription factor A (TFAM) is upregulated in glioma. Molecular medicine reports 28 28440425
2024 Gastrodin alleviates mitochondrial dysfunction by regulating SIRT3-mediated TFAM acetylation in vascular dementia. Phytomedicine : international journal of phytotherapy and phytopharmacology 26 38547618
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
2014 Negative transcriptional regulation of mitochondrial transcription factor A (TFAM) by nuclear TFAM. Biochemical and biophysical research communications 26 24875355
2008 Mitochondrial transcription factor A (TFAM) gene variation and risk of late-onset Alzheimer's disease. Journal of Alzheimer's disease : JAD 26 18430995
2023 DNA-protein cross-links between abasic DNA damage and mitochondrial transcription factor A (TFAM). Nucleic acids research 25 36583367
2023 TFAM-Mediated mitochondrial transfer of MSCs improved the permeability barrier in sepsis-associated acute lung injury. Apoptosis : an international journal on programmed cell death 25 37060506
2018 TFAM is required for maturation of the fetal and adult intestinal epithelium. Developmental biology 25 29684311
2022 Mitochondrial dysfunction by TFAM depletion disrupts self-renewal and lineage differentiation of human PSCs by affecting cell proliferation and YAP response. Redox biology 24 35091324
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
2017 Mitochondrial DNA depletion, mitochondrial mutations and high TFAM expression in hepatocellular carcinoma. Oncotarget 24 29137431
2011 The role of TFAM-associated proteins in mitochondrial RNA metabolism. Biochimica et biophysica acta 24 21920408
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
2019 Effect of cholestasis and NeuroAid treatment on the expression of Bax, Bcl-2, Pgc-1α and Tfam genes involved in apoptosis and mitochondrial biogenesis in the striatum of male rats. Metabolic brain disease 23 31773435
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 22 38593898
2018 TGF-β and BMP signals regulate insect diapause through Smad1-POU-TFAM pathway. Biochimica et biophysica acta. Molecular cell research 22 29902488
2017 Polymorphisms in the TFAM and PGC1-α genes and their association with polycystic ovary syndrome among South Indian women. Gene 22 29030253
2017 Tetramethylpyrazine blocks TFAM degradation and up-regulates mitochondrial DNA copy number by interacting with TFAM. Bioscience reports 21 28465355
2024 Sequence-specific dynamic DNA bending explains mitochondrial TFAM's dual role in DNA packaging and transcription initiation. Nature communications 20 38937458
2021 Mitochondrial functional resilience after TFAM ablation in the adult heart. American journal of physiology. Cell physiology 20 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 19 38346661
2022 GCN5L1-mediated TFAM acetylation at K76 participates in mitochondrial biogenesis in acute kidney injury. Journal of translational medicine 19 36474281
2019 Down-regulation of TFAM increases the sensitivity of tumour cells to radiation via p53/TIGAR signalling pathway. Journal of cellular and molecular medicine 19 31062473
2017 Protein Flexibility and Synergy of HMG Domains Underlie U-Turn Bending of DNA by TFAM in Solution. Biophysical journal 19 29248151
2022 A minimal motif for sequence recognition by mitochondrial transcription factor A (TFAM). Nucleic acids research 18 34928349
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
2022 Agrimol B inhibits colon carcinoma progression by blocking mitochondrial function through the PGC-1α/NRF1/TFAM signaling pathway. Frontiers in oncology 17 36591497
2018 TFAM overexpression diminishes skeletal muscle atrophy after hindlimb suspension in mice. Archives of biochemistry and biophysics 17 30553768
2017 Mechanisms of TFAM-mediated cardiomyocyte protection. Canadian journal of physiology and pharmacology 16 28800400
2023 TFAM-mediated intercellular lipid droplet transfer promotes cadmium-induced mice nonalcoholic fatty liver disease. Journal of hazardous materials 15 38113736
2019 Edition of TFAM gene by CRISPR/Cas9 technology in bovine model. PloS one 15 30845180
2025 TFAM Deficiency Triggers mtDNA Leakage and cGAS-STING-Mediated Intestinal Ischemia-Reperfusion Injury. Inflammation 13 40257650
2023 Reduced acetylation of TFAM promotes bioenergetic dysfunction in the failing heart. iScience 13 37305705
2022 Circ_0002476 regulates cell growth, invasion, and mtDNA damage in non-small cell lung cancer by targeting miR-1182/TFAM axis. Thoracic cancer 13 36056804

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