TFAM

Summary

TFAM (transcription factor A, mitochondrial, HGNC:11741) is a protein-coding gene on chromosome 10q21.1, encoding Transcription factor A, mitochondrial (Q00059). Binds to the mitochondrial light strand promoter and functions in mitochondrial transcription regulation. It is a selective cancer dependency (DepMap: 65.1% of cell lines).

This gene encodes a key mitochondrial transcription factor containing two high mobility group motifs. The encoded protein also functions in mitochondrial DNA replication and repair. Sequence polymorphisms in this gene are associated with Alzheimer’s and Parkinson’s diseases. There are pseudogenes for this gene on chromosomes 6, 7, and 11. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 7019 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial DNA depletion syndrome 15 (hepatocerebral type) (Strong, GenCC)
• GWAS associations: 6
• Clinical variants (ClinVar): 105 total — 2 likely-pathogenic
• Phenotypes (HPO): 28
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 65.1% of screened cell lines
• Transcription factor: yes — 17 downstream targets (CollecTRI)
• MANE Select transcript: NM_003201

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11741
Approved symbol	TFAM
Name	transcription factor A, mitochondrial
Location	10q21.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000108064
Ensembl biotype	protein_coding
OMIM	600438
Entrez	7019

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 6 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000373895, ENST00000373899, ENST00000395377, ENST00000487519, ENST00000909231, ENST00000935269, ENST00000935270

RefSeq mRNA: 2 — MANE Select: NM_003201 NM_001270782, NM_003201

CCDS: CCDS59217, CCDS7253

Canonical transcript exons

ENST00000487519 — 7 exons

Exon	Start	End
ENSE00001849163	58394928	58399220
ENSE00001854885	58385410	58385648
ENSE00003493428	58394358	58394414
ENSE00003599654	58388670	58388819
ENSE00003628587	58390765	58390860
ENSE00003665581	58388190	58388260
ENSE00003667136	58386220	58386338

Expression profiles

Bgee: expression breadth ubiquitous, 284 present calls, max score 95.53.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 54.1160 / max 813.3107, expressed in 1821 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
104998	52.0816	1821
104999	1.7572	799
104995	0.1466	48
104997	0.1053	27
104996	0.0253	6

Top tissues by expression

293 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right testis	UBERON:0004534	95.53	gold quality
left testis	UBERON:0004533	95.37	gold quality
secondary oocyte	CL:0000655	94.52	gold quality
testis	UBERON:0000473	94.24	gold quality
calcaneal tendon	UBERON:0003701	92.65	gold quality
adrenal tissue	UBERON:0018303	92.63	gold quality
ventricular zone	UBERON:0003053	91.64	gold quality
monocyte	CL:0000576	91.49	gold quality
germinal epithelium of ovary	UBERON:0001304	91.38	gold quality
tendon	UBERON:0000043	91.36	gold quality
mononuclear cell	CL:0000842	90.96	gold quality
ganglionic eminence	UBERON:0004023	90.93	gold quality
mucosa of sigmoid colon	UBERON:0004993	90.88	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	90.78	gold quality
leukocyte	CL:0000738	90.76	gold quality
oocyte	CL:0000023	90.66	gold quality
medial globus pallidus	UBERON:0002477	90.51	gold quality
lymph node	UBERON:0000029	89.99	gold quality
rectum	UBERON:0001052	89.65	gold quality
islet of Langerhans	UBERON:0000006	89.35	gold quality
globus pallidus	UBERON:0001875	89.12	gold quality
cortical plate	UBERON:0005343	89.06	gold quality
tonsil	UBERON:0002372	88.64	gold quality
vermiform appendix	UBERON:0001154	88.40	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	88.38	gold quality
caecum	UBERON:0001153	88.37	gold quality
colonic mucosa	UBERON:0000317	88.32	gold quality
parietal pleura	UBERON:0002400	88.16	gold quality
embryo	UBERON:0000922	88.03	gold quality
body of tongue	UBERON:0011876	87.90	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.81

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

17 targets.

Target	Regulation
ACADM	Unknown
ATP2A2
AVPR2
BCL2L1
BIRC5
GFM1
GHRHR
HSP90B2P
HSPA4
INS
MT-CO1
NOS2
NRF1
SLC25A5
TFAM
TFB1M
UCP1	Activation

Upstream regulators (CollecTRI, top): E2F4, FOXC1, MYC, NFE2L2, NRF1, PDX1, PPARG, PPARGC1A, TFAM, ZNF143

miRNA regulators (miRDB)

167 targeting TFAM, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4481	100.00	66.42	1669
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 65.1% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• the effects of mitochondrial transcription factor A (TFAM) and single-stranded DNA-binding protein (mtSSB) on D-loops (PMID:11964388)
• mtTFA plays an important role in the recognition of oxidative DNA damage. (PMID:12127986)
• both the mitochondrial transcription factor TFAM and mitochondrial single-stranded DNA-binding protein colocalize with Twinkle in intramitochondrial foci (PMID:12686611)
• Tfam interacts with p53 protein and helps regulate DNA damage. (PMID:12839966)
• TFB1 interacts with the C-terminal activation region of h-mtTFA and stimulates transcription independently of its RNA methyltransferase activity (PMID:12897151)
• This study describe a family with autosomal dominant progressive external ophthalmoplegia caused by a novel heterozygous A to C transversion at nucleotide 956 of the Twinkle gene. (PMID:12921794)
• There was an association of genotype rs1937G/G with Alzheimer disease in females and an association of a TFAM haplotype with Alzheimer disease both in the whole sample and in females. (PMID:15464268)
• mtDNA amount is finely correlated with the amount of TFAM but not with the transcription level (PMID:15509786)
• TFAM induces a structural change of the promoter that is required for POLRMT-dependent promoter recognition (PMID:15526033)
• Overexpression of mitochondrial transcription factor A (TFAM) stimulates mitochondrial DNA transcription, but is not sufficient to stimulate mitochondrial DNA replication. (PMID:15547250)
• Overexpression of TFAM in transgenic mice inhibited left ventricular remodeling after myocardial infarct and may provide a novel therapeutic strategy of cardiac failure. (PMID:16043643)
• we have determined its chromosomal localization, suggesting that its locus is highly conserved; we have searched for the presence of the delta5 isoform, demonstrating that it is present only in hominids (PMID:16202542)
• PDIP38 is located in the mitochondrial matrix. TFAM and mitochondrial single-stranded DNA binding protein (mtSSB) are co-immunoprecipitated with PDIP38 (PMID:16428295)
• These results suggest that PGC-1alpha variants with Gly/Gly at 482nd amino acid may impair the Tfam transcription, a regulatory function of mitochondrial biogenesis, resulting in dysfunctional mtDNA replication. (PMID:16631115)
• the C-terminal tail of TFAM is important for the strong general binding to mtDNA; this strong DNA-binding conferred by the C-tail may play an important role in the nucleoid structure (PMID:17167045)
• We have determined whether POLG and TFAM have functional roles in post-ejaculatory sperm mtDNA. (PMID:17339235)
• Three polymorphisms in the TFAM gene rs1937, rs2306604 and rs1049432 do not predict endurance capacity/trainability in Chinese males. (PMID:17497594)
• rs2306604 A-allele of mitochondrial transcription factor A could be a moderate risk factor for Alzheimer’s diseae (PMID:17537576)
• Transcription factor ZNF143 is required for expression of TFAM gene. (PMID:17707600)
• Data suggested that the mitochondrial targeting sequence of hTFAM may extend beyond the cleavable presequence. (PMID:18028422)
• TFAM-variants did not contribute to the risk of developing Parkinson disease (PMID:18248889)
• PHB1 maintains the organization and copy number of the mtDNA through both TFAM-independent and -dependent pathways. (PMID:18258228)
• The nigral dopamine neurons of MitoPark mice show respiratory chain dysfunction, accompanied by the development of intraneuronal inclusions and cell death. In early adulthood, the mice show progressing loss of motor function. (PMID:18642640)
• Overexpression of TFAM is therefore considered to ameliorate age-dependent impairment of the brain functions through the prevention of oxidative stress and mitochondrial dysfunctions in microglia. (PMID:18716221)
• determined the variation in the TFAM, TFB1M, and TFB2M genes in cardiac hypertrophy (PMID:19096125)
• Data show that overexpression of delta 5Tfam causes an increase of mitochondrial transcription, so also this isoform as a role in the mitochondrial process. (PMID:19192634)
• The X-ray crystal structure of h-mtTFA box B, revealed the features of a noncanonical HMG box. (PMID:19304746)
• Data suggest that Tfam overexpression protects mitochondria against Abeta-induced oxidative damage in SH-SY5Y cells. (PMID:19496804)
• On supercoiled templates, the promoter-independent activity was strongly suppressed by a putatively physiological amount of TFAM, while promoter-dependent transcription was inhibited to a lesser extent. (PMID:19624753)
• TFAM protein levels are higher in conditions with enhanced oxidative capacity (PMID:19681768)
• These results suggest that TRX2 not only functions as an antioxidant, but also supports mtTFA functions (PMID:19885567)
• Potentially functional polymorphic TFAM variants might influence PD risk alone or depending on mitochondrial haplogroup/haplogroup cluster background. (PMID:19925850)
• Our findings suggest a potential role of promoter TFAM methylation in the pathogenesis of insulin resistance in adolescents. (PMID:20202876)
• only two essential initiation factors, TFAM and TFB2M, and two promoters, LSP and HSP1, are required to drive transcription of the mitochondrial genome (PMID:20410300)
• TFAM gene Ser12Thr polymorphism is associated with physical performance of athletes. (PMID:20432700)
• POLG expression was related to decreased mtDNA copy number, and its overexpression associated with TFAM expression levels also have an impact on long-term survival among GBM type diffusely infiltrating astrocytomas patients. (PMID:20643228)
• TFAM modulates mitochondrial base excision repair by virtue of its DNA binding activity and protein interactions. (PMID:20739229)
• We found four common TFAM polymorphisms, with allele/genotype frequencies that did not differ between early onset myocardial infarction patients and controls. (PMID:20863902)
• This study provides the evidence that variations in TFAM are involved in the pathogenesis of sporadic LOAD in the Han Chinese population. (PMID:20977898)
• comparison between the 5’UTR length and the distribution of the different transcripts showed that the transcripts with the shortest TFAM 5’UTR are present in all the investigated tissues, while the longest 5’UTR seems to be related to tissue-specificity (PMID:21081181)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	tfam	ENSDARG00000063145
mus_musculus	Tfam	ENSMUSG00000003923
rattus_norvegicus	Tfam	ENSRNOG00000000613
caenorhabditis_elegans	hmg-3	WBGENE00001973
caenorhabditis_elegans		WBGENE00001974

Paralogs (20): HMGB3 (ENSG00000029993), HMG20B (ENSG00000064961), SP100 (ENSG00000067066), SMARCE1 (ENSG00000073584), SP140 (ENSG00000079263), TOX4 (ENSG00000092203), HMGXB4 (ENSG00000100281), TOX3 (ENSG00000103460), UBTF (ENSG00000108312), HMGB1P1 (ENSG00000124097), TOX2 (ENSG00000124191), SP110 (ENSG00000135899), HMG20A (ENSG00000140382), SSRP1 (ENSG00000149136), HMGB2 (ENSG00000164104), HMGB4 (ENSG00000176256), SP140L (ENSG00000185404), HMGB1 (ENSG00000189403), TOX (ENSG00000198846), UBTFL1 (ENSG00000255009)

Protein

Protein identifiers

Transcription factor A, mitochondrial — Q00059 (reviewed: Q00059)

Alternative names: Mitochondrial transcription factor 1, Transcription factor 6, Transcription factor 6-like 2

All UniProt accessions (3): Q00059, E5KSU5, H7BYN3

UniProt curated annotations — full annotation on UniProt →

Function. Binds to the mitochondrial light strand promoter and functions in mitochondrial transcription regulation. Component of the mitochondrial transcription initiation complex, composed at least of TFB2M, TFAM and POLRMT that is required for basal transcription of mitochondrial DNA. In this complex, TFAM recruits POLRMT to a specific promoter whereas TFB2M induces structural changes in POLRMT to enable promoter opening and trapping of the DNA non-template strand. Required for accurate and efficient promoter recognition by the mitochondrial RNA polymerase. Promotes transcription initiation from the HSP1 and the light strand promoter by binding immediately upstream of transcriptional start sites. Is able to unwind DNA. Bends the mitochondrial light strand promoter DNA into a U-turn shape via its HMG boxes. Required for maintenance of normal levels of mitochondrial DNA. May play a role in organizing and compacting mitochondrial DNA.

Subunit / interactions. Monomer; binds DNA as a monomer. Homodimer. Component of the mitochondrial transcription initiation complex, composed at least of TFB2M, TFAM and POLRMT. In this complex TFAM recruits POLRMT to the promoter whereas TFB2M induces structural changes in POLRMT to enable promoter opening and trapping of the DNA non-template strand. Upon metabolic stress, forms a complex composed of FOXO3, SIRT3, TFAM and POLRMT. Interacts with TFB1M and TFB2M. Interacts with CLPX; this enhances DNA-binding.

Subcellular location. Mitochondrion. Mitochondrion matrix. Mitochondrion nucleoid.

Post-translational modifications. Phosphorylation by PKA within the HMG box 1 impairs DNA binding and promotes degradation by the AAA+ Lon protease.

Disease relevance. Mitochondrial DNA depletion syndrome 15, hepatocerebral type (MTDPS15) [MIM:617156] An autosomal recessive mitochondrial disorder characterized by severe intrauterine growth restriction, neonatal-onset hypoglycemia and liver dysfunction, mitochondrial DNA depletion in liver and skeletal muscle, and abnormal mitochondrial morphology observed in skeletal muscle. Hepatic pathology includes cirrhosis, steatosis and cholestasis. Progression to liver failure and death is rapid with no evidence of neurological impairment or other organ involvement. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. Binds DNA via its HMG boxes. When bound to the mitochondrial light strand promoter, bends DNA into a U-turn shape, each HMG box bending the DNA by 90 degrees.

Isoforms (2)

UniProt ID	Names	Canonical?
Q00059-1	1	yes
Q00059-2	2

RefSeq proteins (2): NP_001257711, NP_003192* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR009071	HMG_box_dom	Domain
IPR036910	HMG_box_dom_sf	Homologous_superfamily
IPR050342	HMGB	Family

Pfam: PF00505, PF09011

UniProt features (30 total): helix 9, modified residue 7, sequence variant 2, mutagenesis site 2, DNA-binding region 2, strand 2, site 2, transit peptide 1, chain 1, splice variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

16 structures.

PDB	Method	Resolution (Å)
3FGH	X-RAY DIFFRACTION	1.35
3TQ6	X-RAY DIFFRACTION	2.45
3TMM	X-RAY DIFFRACTION	2.5
7LBX	X-RAY DIFFRACTION	2.7
4NNU	X-RAY DIFFRACTION	2.81
7LBW	X-RAY DIFFRACTION	2.84
4NOD	X-RAY DIFFRACTION	2.9
9MN5	ELECTRON MICROSCOPY	3.04
6HB4	X-RAY DIFFRACTION	3.05
9MN4	ELECTRON MICROSCOPY	3.05
6HC3	X-RAY DIFFRACTION	3.1
9R96	ELECTRON MICROSCOPY	3.1
9R95	ELECTRON MICROSCOPY	3.2
9GZM	ELECTRON MICROSCOPY	3.4
6ERQ	X-RAY DIFFRACTION	4.5
6ERP	X-RAY DIFFRACTION	4.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q00059-F1	86.06	0.78

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (2): 58 (intercalates between bases and promotes dna bending); 182 (intercalates between bases and promotes dna bending)

Post-translational modifications (7): 160, 193, 195, 55, 56, 61, 122

Mutagenesis-validated functional residues (2):

Position	Phenotype
77	moderate reduction in dna bending.
162	moderate reduction in dna bending.

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-163282	Mitochondrial transcription initiation
R-HSA-2151201	Transcriptional activation of mitochondrial biogenesis
R-HSA-9837999	Mitochondrial protein degradation
R-HSA-1592230	Mitochondrial biogenesis
R-HSA-1852241	Organelle biogenesis and maintenance
R-HSA-392499	Metabolism of proteins
R-HSA-74160	Gene expression (Transcription)
R-HSA-75944	Transcription from mitochondrial promoters

MSigDB gene sets: 278 (showing top): GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_UP, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOBP_MITOCHONDRIAL_RESPIRATORY_CHAIN_COMPLEX_ASSEMBLY, DACOSTA_UV_RESPONSE_VIA_ERCC3_UP, chr10q21, PUJANA_CHEK2_PCC_NETWORK, WEI_MYCN_TARGETS_WITH_E_BOX, GOBP_RESPONSE_TO_OXYGEN_LEVELS, KEGG_HUNTINGTONS_DISEASE, GOBP_MITOCHONDRIAL_RNA_METABOLIC_PROCESS, GOTZMANN_EPITHELIAL_TO_MESENCHYMAL_TRANSITION_DN, GOBP_DNA_TEMPLATED_TRANSCRIPTION_INITIATION, GARY_CD5_TARGETS_DN, DACOSTA_UV_RESPONSE_VIA_ERCC3_COMMON_UP, GOBP_RESPONSE_TO_ABIOTIC_STIMULUS

GO Biological Process (5): response to hypoxia (GO:0001666), mitochondrial transcription (GO:0006390), transcription initiation at mitochondrial promoter (GO:0006391), response to nutrient (GO:0007584), mitochondrial respiratory chain complex assembly (GO:0033108)

GO Molecular Function (9): mitochondrial promoter sequence-specific DNA binding (GO:0001018), transcription coactivator binding (GO:0001223), chromatin binding (GO:0003682), RNA binding (GO:0003723), heat shock protein binding (GO:0031072), mitochondrial transcription factor activity (GO:0034246), sequence-specific DNA binding (GO:0043565), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (6): nucleus (GO:0005634), mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), cytosol (GO:0005829), protein-containing complex (GO:0032991), mitochondrial nucleoid (GO:0042645)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Transcription from mitochondrial promoters	1
Mitochondrial biogenesis	1
Metabolism of proteins	1
Organelle biogenesis and maintenance	1
Gene expression (Transcription)	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
mitochondrion	5
mitochondrial RNA metabolic process	2
mitochondrial transcription	2
binding	2
nucleic acid binding	2
intracellular membrane-bounded organelle	2
cytoplasm	2
response to stress	1
response to decreased oxygen levels	1
DNA-templated transcription	1
mitochondrial gene expression	1
DNA-templated transcription initiation	1
response to nutrient levels	1
response to chemical	1
mitochondrion organization	1
protein-containing complex assembly	1
transcription cis-regulatory region binding	1
transcription coregulator binding	1
protein binding	1
mitochondrial single-subunit type RNA polymerase binding	1
mitochondrial promoter sequence-specific DNA binding	1
transcription regulator activity	1
DNA binding	1
intracellular organelle lumen	1
cellular anatomical structure	1
cellular_component	1
mitochondrial matrix	1
nucleoid	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

3958 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TFAM	POLRMT	O00411	999
TFAM	TFB2M	Q9H5Q4	997
TFAM	TFB1M	Q8WVM0	995
TFAM	NRF1	Q16656	977
TFAM	TP53	P04637	958
TFAM	SSBP1	Q04837	940
TFAM	HSPA5	P11021	936
TFAM	POLG	P54098	929
TFAM	GABPB1	Q06547	928
TFAM	TWNK	Q96RR1	921
TFAM	SIRT1	Q96EB6	899
TFAM	PPARGC1A	Q9UBK2	894
TFAM	GABPA	Q06546	866
TFAM	PRKN	O60260	824
TFAM	PINK1	Q9BXM7	810

IntAct

224 interactions, top by confidence:

A	B	Type	Score
MGST3	TFAM	psi-mi:“MI:0915”(physical association)	0.660
ARL6IP1	TFAM	psi-mi:“MI:0915”(physical association)	0.560
AGTRAP	TFAM	psi-mi:“MI:0915”(physical association)	0.560
TFAM	AGTRAP	psi-mi:“MI:0915”(physical association)	0.560
TFAM	ARL6IP1	psi-mi:“MI:0915”(physical association)	0.560
TSPAN1	TFAM	psi-mi:“MI:0915”(physical association)	0.560
TFAM	COL8A2	psi-mi:“MI:0915”(physical association)	0.560
STATH	TFAM	psi-mi:“MI:0915”(physical association)	0.560
TFAM	TECR	psi-mi:“MI:0915”(physical association)	0.560
POLRMT	TFAM	psi-mi:“MI:0915”(physical association)	0.560
POLRMT	TFAM	psi-mi:“MI:0914”(association)	0.560
TFAM	TFB1M	psi-mi:“MI:0915”(physical association)	0.540
TFAM	TFB1M	psi-mi:“MI:0407”(direct interaction)	0.540
EGFR	NDUFA4	psi-mi:“MI:0914”(association)	0.530
RYK	PCDH7	psi-mi:“MI:0914”(association)	0.530
SYNGAP1	IGF2BP3	psi-mi:“MI:0914”(association)	0.530
KCTD17	CBX4	psi-mi:“MI:0914”(association)	0.530
NRAS	ESYT2	psi-mi:“MI:2364”(proximity)	0.480
LONP1	TFAM	psi-mi:“MI:0570”(protein cleavage)	0.440
TFAM	TFB2M	psi-mi:“MI:0407”(direct interaction)	0.440
ACOT2	TFAM	psi-mi:“MI:0915”(physical association)	0.400
	POLRMT	psi-mi:“MI:0915”(physical association)	0.400
NFKB1	NFKB1	psi-mi:“MI:0914”(association)	0.350
JUN		psi-mi:“MI:0914”(association)	0.350
HSCB	RBP5	psi-mi:“MI:0914”(association)	0.350
PPM1G	HADHA	psi-mi:“MI:0914”(association)	0.350

BioGRID (508): TFAM (Affinity Capture-MS), ARL6IP1 (Two-hybrid), AGTRAP (Two-hybrid), TFAM (Affinity Capture-MS), TFAM (Affinity Capture-MS), TFAM (Affinity Capture-MS), TFAM (Affinity Capture-MS), TFAM (Affinity Capture-MS), TFAM (Affinity Capture-MS), TFAM (Co-fractionation), TFAM (Affinity Capture-MS), TFAM (Affinity Capture-MS), TFAM (Affinity Capture-MS), TFAM (Affinity Capture-MS), TFAM (Affinity Capture-MS)

ESM2 similar proteins: A4D7T3, B5DF07, D4A7N1, O15091, O60308, P0CB47, P0CB48, P17480, P25976, P25977, P25979, P25980, P40630, Q00059, Q00PJ3, Q07617, Q07DZ7, Q07E43, Q0II87, Q0P4D6, Q0P4W3, Q108U1, Q16891, Q28IV3, Q2QLC6, Q32L34, Q3USZ2, Q4H0T5, Q4R366, Q5D144, Q5FVV3, Q5U509, Q5ZKQ3, Q63406, Q64096, Q68FQ7, Q6AX41, Q6AZF8, Q6DIJ5, Q6P8W9

Diamond homologs: A4QNP0, A9RA84, B0CM99, B1MTB0, B2RPK0, B7SBD2, O04235, O15347, O15405, O49596, O54879, O64702, O94842, O94900, P07746, P09429, P10103, P11632, P11633, P11873, P12682, P17480, P17741, P25976, P25977, P26583, P26584, P26585, P30681, P33417, P40618, P40619, P40620, P40622, P40623, P40625, P40626, P40630, P40644, P40673

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
PRKACA	up-regulates	TFAM	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 179 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Deactivation of the beta-catenin transactivating complex	6	10.4×	7e-03
Signaling by WNT	9	7.5×	3e-03
TCF dependent signaling in response to WNT	8	7.0×	7e-03

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of fibroblast proliferation	8	13.9×	8e-05
response to ethanol	9	7.8×	1e-03
negative regulation of apoptotic process	18	3.7×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

105 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	2
Uncertain significance	41
Likely benign	34
Benign	20

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
221285	NM_003201.3(TFAM):c.533C>T (p.Pro178Leu)	Likely pathogenic
2585248	NM_003201.3(TFAM):c.441del (p.Glu148fs)	Likely pathogenic

SpliceAI

1059 predictions. Top by Δscore:

Variant	Effect	Δscore
10:58386215:T:G	acceptor_gain	1.0000
10:58386218:A:AG	acceptor_gain	1.0000
10:58386219:G:GG	acceptor_gain	1.0000
10:58386219:GTTT:G	acceptor_gain	1.0000
10:58386219:GTTTT:G	acceptor_gain	1.0000
10:58388176:A:AG	acceptor_gain	1.0000
10:58388177:T:G	acceptor_gain	1.0000
10:58388181:A:AG	acceptor_gain	1.0000
10:58388182:T:G	acceptor_gain	1.0000
10:58388185:CATAG:C	acceptor_loss	1.0000
10:58388186:ATAG:A	acceptor_loss	1.0000
10:58388187:T:G	acceptor_gain	1.0000
10:58388187:TAG:T	acceptor_loss	1.0000
10:58388188:A:AG	acceptor_gain	1.0000
10:58388188:A:G	acceptor_loss	1.0000
10:58388188:AGAT:A	acceptor_gain	1.0000
10:58388189:G:GT	acceptor_gain	1.0000
10:58388189:GA:G	acceptor_gain	1.0000
10:58388189:GAT:G	acceptor_gain	1.0000
10:58388189:GATG:G	acceptor_gain	1.0000
10:58388189:GATGC:G	acceptor_gain	1.0000
10:58388256:AAAAA:A	donor_gain	1.0000
10:58388257:AAAA:A	donor_gain	1.0000
10:58388258:AAA:A	donor_gain	1.0000
10:58388258:AAAGT:A	donor_loss	1.0000
10:58388259:AA:A	donor_gain	1.0000
10:58388260:AGT:A	donor_loss	1.0000
10:58388261:G:GG	donor_gain	1.0000
10:58388667:TA:T	acceptor_loss	1.0000
10:58388668:A:AG	acceptor_gain	1.0000

AlphaMissense

1607 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:58386296:T:C	F60L	0.997
10:58386298:T:A	F60L	0.997
10:58386298:T:G	F60L	0.997
10:58394987:G:C	W218C	0.992
10:58394987:G:T	W218C	0.992
10:58388233:G:C	W88C	0.991
10:58388233:G:T	W88C	0.991
10:58386297:T:C	F60S	0.990
10:58388231:T:A	W88R	0.989
10:58388231:T:C	W88R	0.989
10:58394387:G:C	W189C	0.986
10:58394387:G:T	W189C	0.986
10:58395013:G:C	R227P	0.986
10:58394985:T:A	W218R	0.984
10:58394985:T:C	W218R	0.984
10:58388241:T:C	L91P	0.982
10:58390816:T:G	Y165D	0.981
10:58394385:T:A	W189R	0.981
10:58394385:T:C	W189R	0.981
10:58394943:G:C	A204P	0.979
10:58388232:G:C	W88S	0.978
10:58388257:A:C	K96N	0.976
10:58388257:A:T	K96N	0.976
10:58386281:A:C	S55R	0.975
10:58386283:T:A	S55R	0.975
10:58386283:T:G	S55R	0.975
10:58386297:T:G	F60C	0.975
10:58390785:A:C	K154N	0.975
10:58390785:A:T	K154N	0.975
10:58394962:G:C	R210P	0.975

dbSNP variants (sampled 300 via entrez): RS1000043515 (10:58390277 C>T), RS1000525527 (10:58383486 T>C), RS1000756200 (10:58388359 A>C,G), RS1000917854 (10:58394807 A>G), RS1001205711 (10:58389861 A>G), RS1001768579 (10:58399437 T>C), RS1002024844 (10:58387003 C>A), RS1002057418 (10:58387390 T>G), RS1002060633 (10:58396559 C>A,T), RS1002378684 (10:58396024 CTGTGAGCTAGGAAT>C), RS1002535053 (10:58386106 G>A,C,T), RS1002665286 (10:58398014 CT>C), RS1002695738 (10:58392881 A>C), RS1002759205 (10:58386019 G>A), RS1002780714 (10:58398277 A>T)

Disease associations

OMIM: gene MIM:600438 | disease phenotypes: MIM:617156

GenCC curated gene-disease

Disease	Classification	Inheritance
mitochondrial DNA depletion syndrome 15 (hepatocerebral type)	Strong	Autosomal recessive

Mondo (3): mitochondrial DNA depletion syndrome 15 (hepatocerebral type) (MONDO:0014943), premature menopause (MONDO:0001119), sensorineural hearing loss disorder (MONDO:0020678)

Orphanet (0):

HPO phenotypes

28 total (29 of 28 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000952	Jaundice
HP:0001254	Lethargy
HP:0001394	Cirrhosis
HP:0001396	Cholestasis
HP:0001399	Hepatic failure
HP:0001414	Microvesicular hepatic steatosis
HP:0001508	Failure to thrive
HP:0001511	Intrauterine growth retardation
HP:0001522	Death in infancy
HP:0001541	Ascites
HP:0001561	Polyhydramnios
HP:0001635	Congestive heart failure
HP:0001943	Hypoglycemia
HP:0002098	Respiratory distress
HP:0002904	Hyperbilirubinemia
HP:0002908	Conjugated hyperbilirubinemia
HP:0002910	Elevated circulating hepatic transaminase concentration
HP:0003073	Hypoalbuminemia
HP:0003155	Elevated circulating alkaline phosphatase concentration
HP:0003161	4-Hydroxyphenylpyruvic aciduria
HP:0003231	Hypertyrosinemia
HP:0003235	Hypermethioninemia
HP:0003270	Abdominal distention
HP:0003607	4-hydroxyphenylacetic aciduria
HP:0003623	Neonatal onset
HP:0003676	Progressive
HP:0009141	Depletion of mitochondrial DNA in muscle tissue
HP:0000407	Sensorineural hearing impairment

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST001885_10	Height	6.000000e-06
GCST004283_11	Midgestational circulating levels of PCBs	2.000000e-06
GCST005986_14	Blood urea nitrogen levels	2.000000e-09
GCST009391_40	Metabolite levels	8.000000e-06
GCST010002_288	Refractive error	2.000000e-44
GCST011878_1	Mitochondrial heteroplasmy measurement	2.000000e-223

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0007042	polychlorinated biphenyls measurement
EFO:0007964	gestational serum measurement
EFO:0010116	choline measurement
EFO:0600008	mitochondrial heteroplasmy measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D008594	Menopause, Premature	C12.050.351.500.056.630.250; C12.100.250.056.630.250; G08.686.157.500.500; G08.686.841.249.500.500

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067181 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

2 potent at pChembl≥5 of 4 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.31	Kd	48.7	nM	CHEMBL5653589
7.31	ED50	48.7	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 4 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149575: Binding affinity to human TFAM incubated for 45 mins by Kinobead based pull down assay	kd	0.0487	uM

CTD chemical–gene interactions

122 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Resveratrol	decreases reaction, increases expression, increases reaction, affects cotreatment, decreases expression	7
Rotenone	increases expression, decreases expression, decreases reaction, affects cotreatment	4
Arsenic	increases expression, decreases methylation	3
Doxorubicin	decreases expression, decreases reaction, increases expression, affects reaction	3
sodium arsenite	decreases expression, increases expression	2
Acetaminophen	affects cotreatment, increases expression, decreases expression	2
Acetylcysteine	decreases expression, decreases reaction	2
Atrazine	decreases expression	2
Benzo(a)pyrene	decreases expression, decreases reaction	2
Dichlorodiphenyl Dichloroethylene	increases activity, increases expression	2
Glucose	affects reaction, affects cotreatment, decreases expression, decreases reaction, increases reaction (+1 more)	2
Tetrachlorodibenzodioxin	affects expression, decreases expression	2
Cadmium Chloride	decreases expression, increases expression	2
Palmitic Acid	affects cotreatment, decreases expression, decreases reaction, increases reaction, affects reaction	2
PQQ Cofactor	decreases expression, decreases reaction	2
afuresertib	decreases expression	1
FR900359	increases phosphorylation	1
bisphenol F	increases expression	1
SR18292	decreases expression, decreases reaction	1
3-monochloropropane-1, 2 diol ester	increases expression, decreases reaction, increases phosphorylation, increases secretion	1
dicrotophos	decreases expression	1
methylmercuric chloride	decreases expression	1
oxybenzone	increases expression	1
triphenyl phosphate	affects expression	1
uranyl acetate	affects expression	1
3,4-dihydroxyphenylethanol	decreases expression, decreases reaction	1
kaempferol	increases expression	1
bisphenol A	increases expression	1
cobaltiprotoporphyrin	decreases reaction, increases expression	1
di-n-octyl phthalate	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652617	Binding	Binding affinity to human TFAM incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

171 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00417066	PHASE4	COMPLETED	Flexible GnRH Antagonist vs Flare up GnRH Agonist Protocol in Poor Responders
NCT00732693	PHASE4	COMPLETED	Evaluation of Physiologic and Standard Sex Steroid Replacement Regimens in Women With Premature Ovarian Failure
NCT00837616	PHASE4	COMPLETED	Estrogen Dosing in Turner Syndrome: Pharmacology and Metabolism
NCT01853501	PHASE4	UNKNOWN	Effects of ADSC Therapy in Women With POF
NCT02783937	PHASE4	COMPLETED	Filgrastim for Premature Ovarian Insufficiency
NCT03535480	PHASE4	UNKNOWN	Autologous Bone Marrow Stem Cell Ovarian Transplantation to Restore Ovarian Function in Premature Ovarian Failure
NCT00140998	PHASE3	COMPLETED	Estrogen Treatment (Oral vs. Patches) in Turner Syndrome
NCT01655212	PHASE3	TERMINATED	Congenital Cytomegalovirus: Efficacy of Antiviral Treatment in a Randomized Controlled Trial
NCT02005822	PHASE3	COMPLETED	Congenital Cytomegalovirus: Efficacy of Antiviral Treatment
NCT03374514	PHASE3	UNKNOWN	Cochlear Electrical Impedance and the Effect of Topical Dexamethasone on Cochlear Implant Surgery
NCT00001951	PHASE2	COMPLETED	Hormone Replacement in Young Women With Premature Ovarian Failure
NCT00370019	PHASE2	WITHDRAWN	Effects of an Estrogen Replacement Therapy Skin Patch on Ovulation in Women With Premature Ovarian Failure
NCT00429494	PHASE2	COMPLETED	GnRH Analogue for Ovarian Function Preservation in Hematopoietic Stem Cell Transplantation Patients
NCT03816852	PHASE2	SUSPENDED	The Safety and Efficiency Study of Mesenchymal Stem Cell (19#iSCLife®-POI) in Premature Ovarian Insufficiency
NCT04536467	PHASE2	UNKNOWN	Prevention of Chemotherapy-Induced Ovarian Failure With Goserelin in Premenopausal Lymphoma Patients
NCT06117982	PHASE2	COMPLETED	The Impact of Granulocyte Colony Stimulating Factor on Premature Ovarian Insufficiency
NCT02497690	PHASE2	COMPLETED	Effectiveness of Therapy Via Telemedicine Following Cochlear Implants
NCT03107871	PHASE2	ACTIVE_NOT_RECRUITING	Randomized Controlled Trial of Valganciclovir for Cytomegalovirus Infected Hearing Impaired Infants
NCT04120116	PHASE2	COMPLETED	FX-322 in Adults With Stable Sensorineural Hearing Loss
NCT05061758	PHASE2	WITHDRAWN	A Trial of LY3056480 in Patients With SNLH
NCT07364747	PHASE2	RECRUITING	Protective Effect of Acetylcysteine Against Cisplatinum-Induced Ototoxicity: A Randomized Controlled Trial
NCT02912104	PHASE1	COMPLETED	A Therapeutic Trial of Human Amniotic Epithelial Cells Transplantation for Primary Ovarian Failure
NCT03178695	PHASE1	COMPLETED	Inovium Ovarian Rejuvenation Trials
NCT04815213	PHASE1	ACTIVE_NOT_RECRUITING	The Use of Expandeded Mesenchymal Stromal Cells (MSC) in Premature Ovarian Failure (POF) in Adult Humans
NCT05138367	PHASE1	COMPLETED	Effects of UCA-PSCs in Women With POF
NCT06132542	PHASE1	UNKNOWN	Autologous ADMSC Transplantation in Patients With POI
NCT02259595	PHASE1	COMPLETED	Study to Determine the Safety, Tolerability, and Pharmacokinetic Profile of HPN-07 and HPN-07 Plus NAC
NCT00948857	PHASE2/PHASE3	TERMINATED	Dehydroepiandrosterone (DHEA) Treatment and Premature Ovarian Failure (POF)
NCT04031456	PHASE2/PHASE3	RECRUITING	Autologous PRP Infusion May Restore Ovarian Function and May Promote Folliculogenesis in POI Patients
NCT02043743	PHASE1/PHASE2	UNKNOWN	Autologous Stem Cells Transplantation in Patients With Idiopathic and Drug Induced Premature Ovarian Failure
NCT02062931	PHASE1/PHASE2	UNKNOWN	Autologous Mesenchymal Stem Cells Transplantation In Women With Premature Ovarian Failure
NCT02151890	PHASE1/PHASE2	COMPLETED	Pregnancy After Stem Cell Transplantation in Premature Ovarian Failure
NCT02372474	PHASE1/PHASE2	COMPLETED	It is a Real The First Baby Of Autologous Stem Cell Therapy in Premature Ovarian Failure
NCT02603744	PHASE1/PHASE2	UNKNOWN	Autologous Adipose Derived Mesenchymal Stromal Cells Transplantation in Women With Premature Ovarian Failure (POF)
NCT02644447	PHASE1/PHASE2	COMPLETED	Transplantation of HUC-MSCs With Injectable Collagen Scaffold for POF
NCT03069209	PHASE1/PHASE2	UNKNOWN	Autologous Bone Marrow-Derived Stem Cell Transplantation in Patients With Premature Ovarian Failure (POF)
NCT03985462	PHASE1/PHASE2	WITHDRAWN	Very Small Embryonic-like Stem Cells for Ovary
NCT04009473	PHASE1/PHASE2	UNKNOWN	Stem Cell Therapy and Growth Factor Ovarian in Vitro Activation
NCT04071574	PHASE1/PHASE2	COMPLETED	Comparative Study on the Efficacy of Ovarian Stimulation Protocols on the Success Rate of ICSI in Female Infertility
NCT04922398	PHASE1/PHASE2	UNKNOWN	Ovarian Injection of PRP (Platelet -Rich Plasma) Vs Normal Saline in Premature Ovarian Insufficiency