Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: TFAM
Cytogenetic location: 10q21.1 Genomic coordinates (GRCh38): 10:58,385,410-58,399,220 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10q21.1 | ?Mitochondrial DNA depletion syndrome 15 (hepatocerebral type) | 617156 | Autosomal recessive | 3 |
The TFAM gene encodes mitochondrial transcription factor A, which is essential for transcription, replication, and packaging of mtDNA into nucleoids, as well as critical for mitochondrial biogenesis (summary by Stiles et al., 2016).
The mature TCF6 gene product, mitochondrial transcription factor A (TFAM; also known as mtTF1 or mtTFA), is a 162-amino acid protein that activates transcription of each mitochondrial DNA (mtDNA) strand by binding to an element of approximately 30 nucleotides present in both the light-strand and the heavy-strand promoters (Parisi and Clayton, 1991).
Mitochondrial transcription factor A is a key activator of mitochondrial transcription in mammals. It also has a role in mitochondrial DNA replication, since transcription generates an RNA primer necessary for initiation of mtDNA replication. In the mouse, testis-specific mtTFA transcripts encode a protein isoform that is imported to the nucleus, rather than into mitochondria, of spermatocytes and elongating spermatids. Larsson et al. (1997) reported molecular characterization of human mtTFA expression in somatic tissues and male germ cells. Similarly to the mouse, analysis of cDNAs and Northern blots identified abundant testis-specific transcript isoforms generated by use of alternate transcription initiation sites. However, unlike the mouse, none of the testis-specific transcripts predicted a nuclear protein isoform, and Western blot analysis identified only the mitochondrial form of mtTFA in human testis. Immunohistochemistry and in situ hybridization were used to compare the distribution of mtTFA protein, testis-specific mtTFA transcripts, mtDNA, and mtRNA in sections of human testis. Their results showed that mtTFA protein and mtDNA exhibit parallel gradients with high levels in undifferentiated male germ cells and low levels or an absence in differentiated male germ cells. Testis-specific transcripts exhibited the opposite pattern, suggesting to Larsson et al. (1997) that in both humans and mice, these testis-specific mtTFA transcripts downregulate mtTFA protein levels in mammalian mitochondria. Their findings demonstrated that mtTFA does not have a critical role in nucleus, suggested a mechanism for reducing mtDNA copy number during spermatogenesis, and had implications for the understanding of strictly maternal transmission of mtDNA.
Mitochondrial nucleoids are large complexes containing, on average, 5 to 7 mtDNA genomes and several proteins involved in mtDNA replication and transcription, as well as related processes. Bogenhagen et al. (2008) had previously shown that TFAM was associated with native purified HeLa cell nucleoids. Using a formaldehyde crosslinking technique, they found that TFAM copurified with mtDNA and was a core nucleoid protein. Bogenhagen et al. (2008) confirmed these findings by Western blot analysis.
Yamamoto et al. (2012) observed upregulated expression of Foxj3 (616035) and mtTFA in differentiated mouse C2C12 myotubes, concomitant with downregulation of the regulatory microRNA Mir494 (616036). Knockdown and overexpression studies with Western blot, microarray, and reporter gene analyses showed that Mir494 downregulated translation of Foxj3 and mtTFA mRNAs in proliferating C2C12 myoblasts by binding to conserved target sequences in their 3-prime UTRs. Mir494 did not cause mRNA degradation. Endurance exercise in mice stimulated mitochondrial biogenesis in skeletal muscle, concomitant with decreased expression of Mir494 and elevated expression of Foxj3 and mtTFA. Yamamoto et al. (2012) concluded that FOXJ3 and mtTFA promote mitochondrial biogenesis and that MIR494 inhibits their expression and activity.
West et al. (2015) showed that moderate mtDNA stress elicited by TFAM deficiency engages cytosolic antiviral signaling to enhance the expression of a subset of interferon-stimulated genes. Mechanistically, the authors found that aberrant mtDNA packaging promotes escape of mtDNA into the cytosol, where it engages the DNA sensor cGAS (613973) and promotes STING (612374)/IRF3 (603734)-dependent signaling to elevate interferon-stimulated gene expression, potentiate type I interferon responses, and confer broad viral resistance. Furthermore, West et al. (2015) demonstrated that herpes viruses induce mtDNA stress, which enhances antiviral signaling and type I interferon responses during infection. West et al. (2015) concluded that their results further demonstrated that mitochondria are central participants in innate immunity, identified mtDNA stress as a cell-intrinsic trigger of antiviral signaling, and suggested that cellular monitoring of mtDNA homeostasis cooperates with canonical virus-sensing mechanisms to fully engage antiviral innate immunity.
By Southern blot analysis of restriction enzyme digests of human/Chinese hamster somatic cell hybrid lines, Milatovich et al. (1992) mapped TFAM sequences, which they called MTTF1, to 3 different chromosomes: chromosomes 10, 7p, and 11q.
By PCR-based screening of a somatic cell hybrid panel and by fluorescence in situ hybridization, Tiranti et al. (1995) assigned the TFAM gene to 10q21.
Scott (2007) stated that the sequences mapped to chromosomes 7p (TCF6L1) and 11q (MTTF1, or TCF6L3) are pseudogenes.
Larsson et al. (1997) mapped the mouse mitochondrial transcription factor A gene (Tfam) to the central part of mouse chromosome 10. This region exhibits syntenic homology with human 10q21.
In 2 sibs, born of consanguineous parents of Colombian-Basque descent, with mitochondrial DNA depletion syndrome-15 (MTDPS15; 617156), Stiles et al. (2016) identified a homozygous missense mutation in the TFAM gene (P178L; 600438.0001). The mutation, which was found by exome sequencing, segregated with the disorder in the family. Patient fibroblasts showed increased TFAM mRNA but decreased protein levels, consistent with a compensatory mechanism. Patient fibroblasts also had decreased mtDNA copy number, decreased basal respiration, decreased number of nucleoids, and presence of abnormal nucleoid aggregates compared to controls, all indicative of mitochondrial dysfunction. The patients had neonatal onset of rapidly progressive liver failure, resulting in death in infancy.
The regulation of mitochondrial DNA expression is crucial for mitochondrial biogenesis during development and differentiation. Larsson et al. (1998) disrupted the mouse Tfam gene by gene targeting. Heterozygous mice exhibited reduced mtDNA copy number and respiratory chain deficiency in heart. Homozygous knockout embryos exhibited a severe mtDNA depletion with abolished oxidative phosphorylation. Mutant embryos proceed through implantation and gastrulation, but die before embryonic day (E)10.5. Thus, Tfam is the first mammalian protein demonstrated to regulate mtDNA copy number in vivo and is essential for mitochondrial biogenesis and embryonic development.
Wang et al. (1999) reported that hallmarks of mtDNA mutation disorders can be reproduced in the mouse using a conditional mutation strategy to manipulate the expression of the gene encoding mitochondrial transcription factor A (Tfam), which regulates transcription and replication of mtDNA. Using a loxP-flanked Tfam allele in combination with a cre-recombinase transgene under control of the muscle creatine kinase promoter, they disrupted Tfam in heart and muscle. Mutant animals developed a mosaic cardiac-specific progressive respiratory chain deficiency, dilated cardiomyopathy, and atrioventricular heart conduction blocks, and died at 2 to 4 weeks of age. This animal model reproduced biochemical, morphologic, and physiologic features of the dilated cardiomyopathy of Kearns-Sayre syndrome (530000). The findings provided genetic evidence that the respiratory chain is critical for normal heart function. The method should make it possible to disrupt oxidative phosphorylation in virtually any organ of the mouse by expressing cre-recombinase in a tissue-specific manner. This system might shed light on the role of oxidative phosphorylation in aging and in the pathogenesis of common human disorders such as heart failure, diabetes mellitus, and neurodegenerative diseases.
Li et al. (2000) described a heart-knockout strain obtained by mating Tfam(loxP) mice to animals expressing cre-recombinase from the alpha-myosin heavy chain (Myhca; 160710) promoter. This promoter is active from embryonic day 8, and the knockouts had onset of mitochondrial cardiomyopathy during embryogenesis. The age of onset of cardiac respiratory chain dysfunction could thus be controlled by temporal regulation of cre-recombinase expression. Approximately 75% of the knockouts died in the neonatal period, whereas, surprisingly, approximately 25% survived for several months before dying from dilated cardiomyopathy with atrioventricular heart conduction blocks. Modifying genes affect the life span of knockouts, because approximately 95% of the knockout offspring from an intercross of the longer-living knockouts survived the neonatal period. Thus, the tissue-specific knockouts described by Li et al. (2000) not only reproduced important pathophysiologic features of mitochondrial cardiomyopathy but also provided a powerful system by which to identify modifying genes of potential therapeutic value.
Ekstrand et al. (2004) generated PAC transgenic mice ubiquitously expressing human TFAM. Expression of the human TFAM protein in the mouse did not result in downregulation of endogenous Tfam expression, thus resulting in a general increase of mtDNA copy number. Using a combination of mice with TFAM overexpression and TFAM knockout, the authors demonstrated that mtDNA copy number is directly proportional to the total TFAM protein levels. The expression of human TFAM in the mouse resulted in upregulation of mtDNA copy number without increasing respiratory chain capacity or mitochondrial mass. The authors proposed a novel role for TFAM in direct regulation of mtDNA copy number in mammals.
Aydin et al. (2009) used mice with skeletal muscle-specific disruption of Tfam to study whether change in cellular Ca2+ handling is part of the mechanism of muscle dysfunction in mitochondrial myopathy. Muscles of Tfam knockout mice show a progressive deterioration in respiratory chain function over their approximately 4-month life span. Force measurements were combined with measurements of cytosolic Ca2+, mitochondrial Ca2+, and membrane potential and reactive oxygen species in intact adult muscle fibers. There was reduced sarcoplasmic reticulum Ca2+ storage capacity in Tfam knockout muscles due to a decreased expression of calsequestrin-1 (CASQ1; 114250). There were no signs of oxidative stress in Tfam knockout cells, whereas they displayed increased mitochondrial Ca2+ levels during repeated contractions. Mitochondrial Ca2+ levels remained elevated long after the end of stimulation in muscle cells from Tfam knockout mice, and the increase was smaller in the presence of the cyclophilin D (601753)-binding inhibitor cyclosporin A. The mitochondrial membrane potential in Tfam knockout cells did not decrease during repeated contractions. The authors suggested that the observed changes in Ca2+ handling may be adaptive responses with long-term detrimental effects. Reduced sarcoplasmic reticulum Ca2+ release may decrease ATP expenditure, but it also induces muscle weakness. Increased Ca2+ levels in the mitochondrial matrix may stimulate mitochondrial metabolism acutely, but may also trigger cell damage.
Desdin-Mico et al. (2020) found that mice with T cell-specific deletion of Tfam had T cells with dysfunctional mitochondria that acted as accelerators of senescence. These cells instigated multiple aging-related features in mutant mice, including metabolic, cognitive, physical, and cardiovascular alterations, that resulted in premature death. T-cell metabolic failure induced accumulation of circulating cytokines, resembling chronic inflammation characteristic of aging, and this cytokine storm acted as a systemic inducer of senescence. Blocking Tnf (191160) signaling or preventing senescence with nicotinamide adenine dinucleotide precursors partially rescued premature aging in mutant mice. Desdin-Mico et al. (2020) concluded that T cells can regulate organismal fitness and life span, highlighting the importance of tight immunometabolic control in both aging and the onset of age-associated diseases.
In 2 sibs, born of consanguineous parents of Colombian-Basque descent, with mitochondrial DNA depletion syndrome-15 (MTDPS15; 617156), Stiles et al. (2016) identified a homozygous c.533C-T transition (c.533C-T, NM_003201.2) in the TFAM gene, resulting in a pro178-to-leu (P178L) substitution in the HMG box B domain, which is involved in mtDNA binding and compaction. The mutation was predicted to result in steric hindrance and decreased binding ability of TFAM to mtDNA. The mutation, which was found by exome sequencing, segregated with the disorder in the family, and was found in 2 of 118,504 chromosomes in the ExAC database. Patient fibroblasts showed increased TFAM mRNA but decreased protein levels, consistent with a compensatory mechanism. Patient cells also had decreased mtDNA copy number, decreased basal respiration, decreased number of nucleoids, and presence of abnormal nucleoid aggregates compared to controls. The patients had neonatal onset of rapidly progressive liver failure, resulting in death in infancy.
Aydin, J., Andersson, D. C., Hanninen, S. L., Wredenberg, A., Tavi, P., Park, C. B., Larsson, N.-G., Bruton, J. D., Westerblad, H. Increased mitochondrial Ca2+ and decreased sarcoplasmic reticulum Ca2+ in mitochondrial myopathy. Hum. Molec. Genet. 18: 278-288, 2009. [PubMed: 18945718] [Full Text: https://doi.org/10.1093/hmg/ddn355]
Bogenhagen, D. F., Rousseau, D., Burke, S. The layered structure of human mitochondrial DNA nucleoids. J. Biol. Chem. 283: 3665-3675, 2008. [PubMed: 18063578] [Full Text: https://doi.org/10.1074/jbc.M708444200]
Desdin-Mico, G., Soto-Heredero, G., Aranda, J. F., Oller, J., Carrasco, E., Gabande-Rodriguez, E., Blanco, E. M., Alfranca, A., Cusso, L., Desco, M., Ibanez, B., Gortazar, A. R., Fernandez-Marcos, P., Navarro, M. N., Hernaez, B., Alcami, A., Baixauli, F., Mittelbrunn, M. T cells with dysfunctional mitochondria induce multimorbidity and premature senescence. Science 368: 1371-1376, 2020. [PubMed: 32439659] [Full Text: https://doi.org/10.1126/science.aax0860]
Ekstrand, M. I., Falkenberg, M., Rantanen, A., Park, C. B., Gaspari,P M., Hultenby, K., Rustin, P., Gustafsson, C. M., Larsson, N.-G. Mitochondrial transcription factor A regulates mtDNA copy number in mammals. Hum. Molec. Genet. 13: 935-944, 2004. [PubMed: 15016765] [Full Text: https://doi.org/10.1093/hmg/ddh109]
Larsson, N.-G., Barsh, G. S., Clayton, D. A. Structure and chromosomal localization of the mouse mitochondrial transcription factor A gene (Tfam). Mammalian Genome 8: 139-140, 1997. [PubMed: 9060414] [Full Text: https://doi.org/10.1007/s003359900373]
Larsson, N.-G., Oldfors, A., Garman, J. D., Barsh, G. S., Clayton, D. A. Down-regulation of mitochondrial transcription factor A during spermatogenesis in humans. Hum. Molec. Genet. 6: 185-191, 1997. [PubMed: 9063738] [Full Text: https://doi.org/10.1093/hmg/6.2.185]
Larsson, N.-G., Wang, J., Wilhelmsson, H., Oldfors, A., Rustin, P., Lewandoski, M., Barsh, G. S., Clayton, D. A. Mitochondrial transcription factor A is necessary for mtDNA maintenance and embryogenesis in mice. Nature Genet. 18: 231-236, 1998. [PubMed: 9500544] [Full Text: https://doi.org/10.1038/ng0398-231]
Li, H., Wang, J., Wilhelmsson, H., Hansson, A., Thoren, P., Duffy, J., Rustin, P., Larsson, N.-G. Genetic modification of survival in tissue-specific knockout mice with mitochondrial cardiomyopathy. Proc. Nat. Acad. Sci. 97: 3467-3472, 2000. [PubMed: 10737799] [Full Text: https://doi.org/10.1073/pnas.97.7.3467]
Milatovich, A., Parisi, M. A., Poulton, J., Clayton, D. A., Francke, U. Sequences homologous to MTTF1, mitochondrial transcription factor 1, are located on human chromosomes 7 (7pter-cen), 10 and 11 (11cen-qter). (Abstract) Cytogenet. Cell Genet. 58: 1924 only, 1992.
Parisi, M. A., Clayton, D. A. Similarity of human mitochondrial transcription factor 1 to high mobility group proteins. Science 252: 965-969, 1991. [PubMed: 2035027] [Full Text: https://doi.org/10.1126/science.2035027]
Scott, A. F. Personal Communication. Baltimore, Md. 9/20/2007.
Stiles, A. R., Simon, M. T., Stover, A., Eftekharian, S., Khanlou, N., Wang, H. L., Magaki, S., Lee, H., Partynski, K., Dorrani, N., Chang, R., Martinez-Agosto, J. A., Abdenur, J. E. Mutations in TFAM, encoding mitochondrial transcription factor A, cause neonatal liver failure associated with mtDNA depletion. Molec. Genet. Metab. 119: 91-99, 2016. [PubMed: 27448789] [Full Text: https://doi.org/10.1016/j.ymgme.2016.07.001]
Tiranti, V., Rossi, E., Ruiz-Carrillo, A., Rossi, G., Rocchi, M., DiDonato, S., Zuffardi, O., Zeviani, M. 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 25: 559-564, 1995. [PubMed: 7789991] [Full Text: https://doi.org/10.1016/0888-7543(95)80058-t]
Tominaga, K., Akiyama, S., Kagawa, Y., Ohta, S. Upstream region of a genomic gene for human mitochondrial transcription factor 1. Biochim. Biophys. Acta 1131: 217-219, 1992. [PubMed: 1610904] [Full Text: https://doi.org/10.1016/0167-4781(92)90082-b]
Wang, J., Wilhelmsson, H., Graff, C., Li, H., Oldfors, A., Rustin, P., Bruning, J. C., Kahn, C. R., Clayton, D. A., Barsh, G. S., Thoren, P., Larsson, N.-G. Dilated cardiomyopathy and atrioventricular conduction blocks induced by heart-specific inactivation of mitochondrial DNA gene expression. Nature Genet. 21: 133-137, 1999. [PubMed: 9916807] [Full Text: https://doi.org/10.1038/5089]
West, A. P., Khoury-Hanold, W., Staron, M., Tal, M. C., Pineda, C. M., Lang, S. M., Bestwick, M., Duguay, B. A., Raimundo, N., MacDuff, D. A., Kaech, S. M., Smiley, J. R., Means, R. E., Iwasaki, A., Shadel, G. S. Mitochondrial DNA stress primes the antiviral innate immune response. Nature 520: 553-557, 2015. [PubMed: 25642965] [Full Text: https://doi.org/10.1038/nature14156]
Yamamoto, H., Morino, K., Nishio, Y., Ugi, S., Yoshizaki, T., Kashiwagi, A., Maegawa, H. MicroRNA-494 regulates mitochondrial biogenesis in skeletal muscle through mitochondrial transcription factor A and forkhead box j3. Am. J. Physiol. Endocr. Metab. 303: E1419-E1427, 2012. Note: Electronic Article. [PubMed: 23047984] [Full Text: https://doi.org/10.1152/ajpendo.00097.2012]