TMEM126A, a mitochondrial transmembrane protein, has multiple essential functions. It is involved in mitochondrial protein insertion into the membrane, cooperating with OXA1L, and participates in the assembly of the ND4-module of mitochondrial complex I. It also couples with the TLR4 signal transduction pathway in macrophages, influencing antigen-presentation-related gene expression. Mutations in TMEM126A are associated with autosomal-recessive optic atrophy, indicating its importance in maintaining normal optic function [1,2,3].

Loss-of-function studies have provided insights into its role. In breast cancer cell models, down-regulation of TMEM126A enhanced metastatic properties, while overexpression decreased metastatic potential. This was associated with extracellular matrix remodeling, epithelial-to-mesenchymal transition, and mitochondrial retrograde signaling. In macrophages, TMEM126A-deficient cells showed diminished responses to TLR4 activation [4].

In conclusion, TMEM126A is crucial for mitochondrial protein-related processes and has implications in diseases such as autosomal-recessive optic atrophy and breast cancer metastasis. The use of cell models in functional studies of TMEM126A has revealed its role in specific biological processes and disease-associated mechanisms, providing a basis for further understanding of these diseases.

References:

1. Poerschke, Sabine, Oeljeklaus, Silke, Cruz-Zaragoza, Luis Daniel, Dennerlein, Sven, Rehling, Peter. 2024. Identification of TMEM126A as OXA1L-interacting protein reveals cotranslational quality control in mitochondria. In Molecular cell, 84, 345-358.e5. doi:10.1016/j.molcel.2023.12.013. https://pubmed.ncbi.nlm.nih.gov/38199007/

2. Formosa, Luke E, Reljic, Boris, Sharpe, Alice J, Stroud, David A, Ryan, Michael T. . Optic atrophy-associated TMEM126A is an assembly factor for the ND4-module of mitochondrial complex I. In Proceedings of the National Academy of Sciences of the United States of America, 118, . doi:10.1073/pnas.2019665118. https://pubmed.ncbi.nlm.nih.gov/33879611/

3. Kim, Eun-Cheol, Moon, Ji-Hoi, Kang, Sang W, Kwon, Byungsuk, Lee, Hyeon-Woo. 2014. TMEM126A, a CD137 ligand binding protein, couples with the TLR4 signal transduction pathway in macrophages. In Molecular immunology, 64, 244-51. doi:10.1016/j.molimm.2014.12.001. https://pubmed.ncbi.nlm.nih.gov/25549946/

4. Sun, He-Fen, Yang, Xue-Li, Zhao, Yang, Zhao, Yuan-Yuan, Jin, Wei. 2018. Loss of TMEM126A promotes extracellular matrix remodeling, epithelial-to-mesenchymal transition, and breast cancer metastasis by regulating mitochondrial retrograde signaling. In Cancer letters, 440-441, 189-201. doi:10.1016/j.canlet.2018.10.018. https://pubmed.ncbi.nlm.nih.gov/30393159/