TFAM

Fig1. Working model explaining how TFAM could impact the progression of neurodegenerative diseases through alteration of mtDNA dynamics. (Inhae Kang, 2018)

What is TFAM protein?

TFAM (transcription factor A, mitochondrial) gene is a protein coding gene which situated on the long arm of chromosome 10 at locus 10q21. TFAM is a multifunctional DNA-binding protein that plays a crucial role in the maintenance and expression of mitochondrial DNA (mtDNA). It is essential for cellular bioenergetics and the survival of cells. TFAM contributes to mtDNA maintenance and expression, impacting the cellular energy production and the structural organization of mtDNA within the mitochondria. The TFAM protein is consisted of 246 amino acids and its molecular mass is approximately 29.1 kDa.

What is the function of TFAM protein?

TFAM is a protein that plays a critical role in regulating mitochondrial DNA (mtDNA) transcription and replication. It is a member of the mitochondrial transcription factor A (TFAM) family, which includes other proteins that also regulate mtDNA transcription and replication. TFAM is located in the nucleus and mitochondria, where it binds to mtDNA and promotes its transcription and replication. It also helps to protect mtDNA from damage and degradation. TFAM is essential for normal mitochondrial function, as it is required for the production of the mitochondrial proteins that are necessary for energy production.

TFAM Related Signaling Pathway

TFAM may transmit signals between organelles by regulating calcium ion levels. For example, it can regulate calcium ion signaling by influencing the dynamics of mitochondria-associated membrane structures. The reduction of TFAM can promote the release of mitochondrial DNA into the cytoplasm and activate the cGAS-STING signaling pathway, thus triggering the stress response of the cell. TFAM helps organize and protect the mitochondrial genome by binding to mtDNA. It is also involved in the process of mitochondrial DNA replication and transcription.

TFAM Related Diseases

Because TFAM proteins play a key role in regulating transcription and replication of mitochondrial DNA (mtDNA), mutations in TFAM genes may lead to mitochondrial diseases. These diseases include mitochondrial encephalomyopathy, lactic acidosis and stroke-like onset syndrome (MELAS), Leigh syndrome, and others. Some studies have shown that the expression level of TFAM protein in tumor cells generally increases, which may be related to the increased energy requirements of tumor cells. The expression level of TFAM protein may change in neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. TFAM protein may be related to the occurrence and development of cardiovascular diseases. For example, some studies have found that TFAM protein expression levels in cardiomyocytes increase significantly after a myocardial infarction.

Bioapplications of TFAM

In drug development, the recombinant TFAM protein can be used as a target for drug screening, helping researchers evaluate the impact of potential drugs on mitochondrial function, especially in the fields of neurodegenerative diseases, metabolic diseases, and tumor therapies. Since mitochondrial function is closely related to the aging process, TFAM protein is also an important research object in anti-aging research. By regulating the activity of TFAM, it may help to delay the aging process. The recombinant form of the TFAM protein could also be used to develop diagnostic tools to help doctors assess the status of mitochondrial function in patients, especially in the diagnosis of mitochondrial diseases or diseases related to mitochondrial dysfunction.

Case Study 1: Natalya Kozhukhar, 2019

Mitochondrial transcription factor A (TFAM) plays an important role in mitochondrial DNA (mtDNA) transcription and replication. In some experimental settings, TFAM expression parallels parameters of mitochondrial biogenesis, which led to a widespread acceptance of TFAM as marker of mitochondrial biogenesis. The researchers modulated TFAM expression in several experimental systems and observed that it fails to consistently parallel mtDNA copy number and expression of mtDNA-encoded polypeptides. They suggest that the use of TFAM as a marker of mitochondrial biogenesis should be avoided outside of systems in which its performance has been carefully validated.

Fig1. TFAM and MT-CO2 protein expression.

Fig2. Effects of endogenous human mitochondrial transcription factor A (hTFAM) overexpression in human cells.

Case Study 2: Wenyan Xu, 2019

MtDNA degradation has emerged as an essential quality control measure to maintain mtDNA and to cope with mtDNA damage resulting from endogenous and environmental factors. Among all types of DNA damage known, abasic (AP) sites, sourced from base excision repair and spontaneous base loss, are the most abundant endogenous DNA lesions in cells. In mitochondria, AP sites trigger rapid DNA loss; however, the mechanism and molecular factors involved in the process remain elusive. Herein, the researchers demonstrate that the stability of AP sites is reduced dramatically upon binding to a major mtDNA packaging protein, mitochondrial transcription factor A (TFAM). The half-life of AP lesions within TFAM-DNA complexes is 2 to 3 orders of magnitude shorter than that in free DNA, depending on their position. The TFAM-catalyzed AP-DNA destabilization occurs with nonspecific DNA or mitochondrial light-strand promoter sequence, yielding DNA single-strand breaks and DNA-TFAM cross-links. TFAM-DNA cross-link intermediates prior to the strand scission were also observed upon treating AP-DNA with mitochondrial extracts of human cells. In situ trapping of the reaction intermediates (DNA-TFAM cross-links) revealed that the reaction proceeds via Schiff base chemistry facilitated by lysine residues.

Fig3. TFAM induces the formation of DPCs and SSBs with AP1.

Fig4. Representative denaturing PAGE analysis of reactions of TFAM with AP15.

TFAM has several biochemical functions, for example, DNA binding, bending,RNA polymerase II core promoter proximal region sequence-specific DNA binding,chromatin binding. Some of the functions are cooperated with other proteins, some of the functions could acted by TFAM itself. We selected most functions TFAM had, and list some proteins which have the same functions with TFAM. You can find most of the proteins on our site.

TFAM has direct interactions with proteins and molecules. Those interactions were detected by several methods such as yeast two hybrid, co-IP, pull-down and so on. We selected proteins and molecules interacted with TFAM here. Most of them are supplied by our site. Hope this information will be useful for your research of TFAM.

ARL6IP1;AGTRAP;TFB1M;C1qbp;TFB2M;MCC;IKBKE;TNIK;ssrna_cg