TMEM43, also known as LUMA, is a transmembrane protein encoded by a highly conserved gene, ubiquitously expressed from bacteria to humans. It is involved in multiple biological processes and is associated with pathways related to cardiac function, metabolism, and cell growth. Genetic models, such as knockout mouse models, have been crucial in understanding its functions [2,3,6].

In mouse models, TMEM43 knockdown in hearts deteriorated lipopolysaccharide (LPS)-induced cardiac injury and dysfunction, while overexpression alleviated these effects by inhibiting ferroptosis, a form of cell death. Mechanistically, TMEM43 regulated the expression of proteins like P53, ferritin, Gpx4, and SLC7A11 [1]. Mutant mouse models with the TMEM43-S358L mutation showed classic pathologies of arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C), including structural abnormalities, cardiac fibrofatty changes, and hyper-activated NF-κB-TGFβ signal cascade [4,5]. In zebrafish, overexpression of wild-type and mutant TMEM43 led to cardiac morphological and ultrastructural changes, along with dysregulated gene expression [7].

In conclusion, TMEM43 plays essential roles in protecting against sepsis-induced cardiac injury via inhibiting ferroptosis and is involved in the pathogenesis of ARVD/C. The use of KO/CKO mouse models and other genetic models has significantly contributed to understanding its functions in these disease-related processes, which may provide potential therapeutic strategies for related diseases in the future [1,4,5].

References:

1. Chen, Zhen, Cao, Zhe, Gui, Feng, Ai, Fen, Zhang, Jun. 2022. TMEM43 Protects against Sepsis-Induced Cardiac Injury via Inhibiting Ferroptosis in Mice. In Cells, 11, . doi:10.3390/cells11192992. https://pubmed.ncbi.nlm.nih.gov/36230956/

2. Heller, Scott A, Shih, Renata, Kalra, Raghav, Kang, Peter B. 2019. Emery-Dreifuss muscular dystrophy. In Muscle & nerve, 61, 436-448. doi:10.1002/mus.26782. https://pubmed.ncbi.nlm.nih.gov/31840275/

3. Zhang, Nannan, Wang, Feiran, Yang, Xiaobing, Feitelson, Mark A, Chen, Zhong. 2024. TMEM43 promotes the development of hepatocellular carcinoma by activating VDAC1 through USP7 deubiquitination. In Translational gastroenterology and hepatology, 9, 9. doi:10.21037/tgh-23-108. https://pubmed.ncbi.nlm.nih.gov/38317750/

4. Zheng, Guoxing, Jiang, Changying, Li, Yulin, Du, Jie, Lin, Xin. 2018. TMEM43-S358L mutation enhances NF-κB-TGFβ signal cascade in arrhythmogenic right ventricular dysplasia/cardiomyopathy. In Protein & cell, 10, 104-119. doi:10.1007/s13238-018-0563-2. https://pubmed.ncbi.nlm.nih.gov/29980933/

5. Orgil, Buyan-Ochir, Munkhsaikhan, Undral, Pierre, Joseph F, Towbin, Jeffrey A, Purevjav, Enkhsaikhan. 2023. The TMEM43 S358L mutation affects cardiac, small intestine, and metabolic homeostasis in a knock-in mouse model. In American journal of physiology. Heart and circulatory physiology, 324, H866-H880. doi:10.1152/ajpheart.00712.2022. https://pubmed.ncbi.nlm.nih.gov/37083466/

6. Ratnavadivel, Sandra, Dammeier, Joline, Gaertner, Anna, Paululat, Achim, Milting, Hendrik. 2024. Generation of a TMEM43 knockout human induced pluripotent stem cell line (HDZi003-A-1) using Nuclease technology. In Stem cell research, 76, 103354. doi:10.1016/j.scr.2024.103354. https://pubmed.ncbi.nlm.nih.gov/38430734/

7. Zink, Miriam, Seewald, Anne, Rohrbach, Mareike, Childs, Sarah J, Gerull, Brenda. 2022. Altered Expression of TMEM43 Causes Abnormal Cardiac Structure and Function in Zebrafish. In International journal of molecular sciences, 23, . doi:10.3390/ijms23179530. https://pubmed.ncbi.nlm.nih.gov/36076925/