Draft:TFAM

Mitochondrial transcription factor A, abbreviated as TFAM or mtTFA, is a protein that in humans is encoded by the TFAM gene.

Function
This gene encodes a mitochondrial transcription factor that is a key activator of mitochondrial transcription as well as a participant in mitochondrial genome replication. TFAM binds mitochondrial promoter DNA to aid transcription of the mitochondrial genome. Although commonly thought of as the powerhouse of the cell, the mitochondria should be viewed as a complex network including many mitochondrial genes and proteins such as TFAM. Figure 2 from Damirichi et al. shows the process of TFAM maturing. TFAM is an important part of the mitochondrial biogenesis process. TFAM is a double box High-mobility group DNA-binding and bending protein. This bending action is important for mitochondrial transcription initiation in mammals, but not in yeasts with the homolog Abf2. TFAM may also participate in the packaging of the mitochondrial genome, as its binding activity is non-sequence-specific.

Interactions
The initial creation of TFAM occurs in the nucleus. It is shortly after transported to the mitochondria. Nuclear respiratory factors such as NRF-1 and NRF-2 monitor the creation of TFAM starting in the nucleus. TFAM has been shown to interact with TFB1M and TFB2M. TFAM is transcriptionally controlled by NRF-1 and NRF-2. PGC-1α is a mediator for TFAM. NRF-1 activates TFAM which allows proteins synthesis in the mitochondria to progress. TFAM interacts with other proteins involved in transcription such as specific zinc fingers. Interactions with deficiency of FOXP1 is linked to mitochondrial disfunction. TFAM packages human mitochondrial DNA. The maintenance of mitochondrial DNA requires the use of TFAM. Higher levels of TFAM help to alleviate cardiac dysfunction. Looking at more specific interactions of TFAM can open more doors of research in animals and human health.

Researched in Animal Models
TFAM has been used in mitochondrial research in mice, rats , zebra finches , and other model animals. Studies in mice have demonstrated that this gene product is required to regulate the mitochondrial genome copy number and is essential for embryonic development. A mouse model for Kearns–Sayre syndrome was produced when expression of this gene was eliminated by targeted disruption in heart and muscle cells. By looking at levels of TFAM, estimates can be made on mitochondrial efficiency, ATP production, and mitochondrial biogenesis. Faster energy turnover is associated with higher mitochondria amounts and levels of TFAM. Figure 10 from Sun et al. 2024 showed evidence of TFAM reducing chaperone mediated autophagy. Another study in mice has found that deficits in TFAM are correlated with FOXP1 syndrome, deficits in memory, and deficits in learning. Animal model research allows ethical exploration of complex questions involving intricate areas of molecular Biology such as TFAM involvement in mitochondrial efficiency.

Health Research
TFAM is imperative to many areas of health, from day to day exercise to research of diseases. Increased activity and exercise has been observed to have increases in TFAM activity. In figure 8 from Sun et al. 2024, TFAM levels were seen to mediate Cd related mitochondrial damage. Baicalin and NAC regulate metabolism through TFAM activity. Cd levels alone will reduce TFAM activity. Mediation of Baicalin and NAC will negate Cd from negatively impacting TFAM. TFAM regulates PLD1 to regulate mitochondrial structure and function. Knockouts of TFAM in embryonic research have been seen to be fatal. Reductions in TFAM have been seen to be correlated with mitochondrial activity reductions. Even when individuals have a high fat diet, TFAM has mediated diet induced insulin resistance. Disease research that has looked at TFAM has found it to be the missing link to finding improved health. For example, a close inspection of the interaction of TFAM with Zinc finger protein 468 has contributed to research on breast cancer as a potential therapeutic option for patients. Levels of TFAM can even be a mediator for symptoms of diabetes. In FOXP1 syndrome, TFAM was dysregulated along with other genes involved in mitochondrial biogenesis. Further research of diseases should consider interactions of TFAM as an important area of interest. Other health related areas of research involving TFAM include aging, stress, metabolism and cardiac research. Reduced levels of TFAM can cause heart dysfunction and aging.

Aging Research
Mitochondrial efficiency has been found to decline with age. Research on aging looks closely at mitochondrial biogenesis including involvement of TFAM. Aging is directly impacted by cardiac mitochondrial activity. Lower mitochondrial efficiency has been associated with aging in research using zebra finches. Effects of aging are seen in poor quality of mitochondria and increased LEAK which leads to overall less efficiency of mitochondria. Healthy lifestyle characteristics such as low caloric diet and/or regular exercise can delay the effects of aging on mitochondria. Regular exercise in older adults is correlated with higher mitochondrial efficiency.

Stress
TFAM has been used as a biomarker of oxidative stress related to environmental pollution. Environmental stress factors such as different temperature extremes have been associated with lower mitochondrial efficiency. Future research should investigate if increasing TFAM could alleviate symptoms of stress. Stress can manifest from different environmental or internal factors within an individual animal. Stress can come from dietary issues, temperature, social aspects and more. Throughout all four complexes of the mitochondria, mitochondrial oxygen consumption was higher under heat stress conditions in mice. In zebra finches, heat stress is associated with lower mitochondrial efficiency. The natural habitat of zebra finches, Australia, undergoes moments of extreme heat. King penguins, living in the opposite extreme habitat, have decreases in oxidative damages related to maintaining mitochondrial efficiency despite the harsh stressors of their habitat. Glucocorticoid hormones such as corticosterone were higher in response to the stresses the king penguins went through. Increasing CORT levels lead to decreases in mitochondrial efficiency within the penguins, but this also resulted in less oxidative stress. Depending on the type of stress, mitochondrial efficiency levels may be needed to fluctuate higher or lower to coincide with the stress.

Metabolism
Mitochondrial metabolism depends on high levels of TFAM in order to maintain homeostasis. Metabolism related diseases and disorders can be mediated by increasing levels of TFAM. The maintenance of all of the areas of the body, or metabolism, are reliant on mitochondrial functions. Homeostasis of the body throughout all its activity is easily impacted. Increased temperature and decreased pH, experimental conditions mimicking exercise, results in reduced mitochondrial efficiency. This study showed the impact of mitochondrial efficiency on exercise metabolism. Throughout any changes in the body metabolism is able to fluctuate based on the changing needs. During pregnancies, for example, cardiac mitochondrial metabolism fluctuates as the body of the mother undergoes significant changes. Within some health conditions such as obesity and asthma, mitochondrial dysfunction can reprogram the metabolism of an individual. Metabolic diseases can be caused or impacted by changes in mitochondrial efficiency. Cellular metabolism requires healthy mitochondria. Metabolism for each health condition is reliant on healthy mitochondria functions.

Cardiac Research
TFAM is involved in pathways that lead to recovery from cardiac dysfunction. A biomarker of heart failure is lower levels of TFAM. A newer treatment involves increasing levels of TFAM which leads to increases in mitochondrial biogenesis and stabilizes cardiomyocyte functions. TFAM is associated with protecting the heart from oxidative stress and damage. There are many connections between cardiovascular disease and mitochondrial dysfunction. Environmental stressors can lead to increased activation of inflammatory pathways involved with mitochondria that lead to heart diseases. One of the main features of heart failure is mitochondrial dysfunction. Signs of stress, aging and inefficient metabolism can all be factors leading to heart disease. Dysfunction in mitochondria can lead to heart failure, but heart failure can also cause mitochondria dysfunction. Damage associated molecular patterns that involve the mitochondria can lead to inflammation from NLRP3 inflammasomes. Activation of these associated molecular pathways can lead to stressors on the heart, such as hypertension, differences in blood pressure, cardiomyocyte hypertrophy, and more. The NLRP3 pathway, that involves the mitochondria and leads to inflammation, is involved in brain and heart communication of stress. Environmental stress such as extreme heat or cold can alter mitochondrial activity increasing the likelihood of activation of the NLRP3 pathway, leading to higher potential of heart disease or failure. Higher activation of the NLRP3 inflammasome can increase hypertension and spread damaging effects throughout the whole cardiovascular system. Future research should continue to build a deeper understanding of complex molecular pathways that involve cardiac mitochondria because of how impactful the mitochondria are to heart health.

Further Research
Viewing the proteins and genes such as TFAM that are part of the complexity of mitochondrial biogenesis can shed light on more complex disease questions, animal behavioral questions , and metabolism questions. Understanding how TFAM is involved in complex molecular pathways can lead to the discoveries of unique strategies to improve health.