Tfam-KO Mouse

TFAM, also known as transcription factor A, mitochondrial, is a crucial protein for maintaining mitochondrial DNA (mtDNA) stabilization, initiating mtDNA replication and transcription [5,6]. It is essential for cellular bioenergetics as it contributes to mtDNA maintenance and expression, thus being vital for cell survival [6]. TFAM is involved in pathways such as autophagy, inflammation regulation, and is associated with cellular responses to stress [1]. Genetic models, like knockout (KO) mouse models, have been instrumental in studying its functions.

In various disease-related studies, TFAM shows diverse impacts. In ischemic acute kidney injury, mitochondrial ROS (mtROS) promote injury by suppressing TFAM-mediated mtDNA maintenance, suggesting TFAM could be a target for renal repair [2]. In alcoholic steatohepatitis, ATF4 activation promotes hepatic mitochondrial dysfunction by repressing NRF1-TFAM signalling [3]. TFAM deficiency in dendritic cells leads to mitochondrial dysfunction and enhanced antitumor immunity through the cGAS-STING pathway [5]. Also, TFAM loss in liver cancer cells induces nuclear actin assembly promoting metastasis [4], while TFAM downregulation in esophageal squamous cell carcinoma promotes autophagy and cancer cell survival via the mtDNA stress-mediated STING pathway [7].

In conclusion, TFAM is essential for mitochondrial function and bioenergetics. Through model-based research, especially KO/CKO mouse models, we've learned that TFAM plays a significant role in multiple disease areas including kidney injury, liver diseases, cancer metastasis, and immune-related cancers. Understanding TFAM's functions provides potential therapeutic targets for these diseases.

References:

1. Liu, Hao, Zhen, Cien, Xie, Jianming, He, Pengcheng, Feng, Du. 2024. TFAM is an autophagy receptor that limits inflammation by binding to cytoplasmic mitochondrial DNA. In Nature cell biology, 26, 878-891. doi:10.1038/s41556-024-01419-6. https://pubmed.ncbi.nlm.nih.gov/38783142/

2. Zhao, Meng, Wang, Yizhuo, Li, Ling, Lu, Yanrong, Liu, Jingping. 2021. Mitochondrial ROS promote mitochondrial dysfunction and inflammation in ischemic acute kidney injury by disrupting TFAM-mediated mtDNA maintenance. In Theranostics, 11, 1845-1863. doi:10.7150/thno.50905. https://pubmed.ncbi.nlm.nih.gov/33408785/

3. Hao, Liuyi, Zhong, Wei, Dong, Haibo, Song, Zhenyuan, Zhou, Zhanxiang. 2020. ATF4 activation promotes hepatic mitochondrial dysfunction by repressing NRF1-TFAM signalling in alcoholic steatohepatitis. In Gut, 70, 1933-1945. doi:10.1136/gutjnl-2020-321548. https://pubmed.ncbi.nlm.nih.gov/33177163/

4. Huang, Qichao, Wu, Dan, Zhao, Jing, Liu, Xiaoli, Xing, Jinliang. 2022. TFAM loss induces nuclear actin assembly upon mDia2 malonylation to promote liver cancer metastasis. In The EMBO journal, 41, e110324. doi:10.15252/embj.2021110324. https://pubmed.ncbi.nlm.nih.gov/35451091/

5. Lu, Tianqi, Zhang, Ziqi, Bi, Zhenfei, Luo, Min, Wei, Xiawei. . TFAM deficiency in dendritic cells leads to mitochondrial dysfunction and enhanced antitumor immunity through cGAS-STING pathway. In Journal for immunotherapy of cancer, 11, . doi:10.1136/jitc-2022-005430. https://pubmed.ncbi.nlm.nih.gov/36858460/

6. Kozhukhar, Natalya, Alexeyev, Mikhail F. 2023. 35 Years of TFAM Research: Old Protein, New Puzzles. In Biology, 12, . doi:10.3390/biology12060823. https://pubmed.ncbi.nlm.nih.gov/37372108/

7. Li, Yujia, Yang, Qi, Chen, Hui, Wang, Yanming, Bao, Dengke. 2022. TFAM downregulation promotes autophagy and ESCC survival through mtDNA stress-mediated STING pathway. In Oncogene, 41, 3735-3746. doi:10.1038/s41388-022-02365-z. https://pubmed.ncbi.nlm.nih.gov/35750756/