TMEM126A, a mitochondrial transmembrane protein, is involved in multiple biological functions and disease-related processes. It participates in the assembly of mitochondrial complex I, especially in the ND4-module assembly, and is also associated with cotranslational quality control in mitochondria. In macrophages, it couples with the TLR4 signal transduction pathway, and may contribute to the up-regulation of genes related to antigen presentation. Additionally, in breast cancer, it is considered a suppressor of metastasis, regulating extracellular matrix remodeling and epithelial-to-mesenchymal transition through mitochondrial retrograde signaling [2,3,4].

Loss-of-function studies, though not specifically mentioned as KO/CKO mouse models in the given references, have shown that loss of TMEM126A leads to destabilization of mitochondrial translation products, triggering inner membrane quality control processes where newly synthesized proteins are degraded by the mitochondrial iAAA protease. In breast cancer cell lines, down-regulation of TMEM126A enhanced metastatic properties, while overexpression decreased them [1,4].

In conclusion, TMEM126A plays essential roles in mitochondrial protein insertion, complex I assembly, immune-related signaling, and breast cancer metastasis. These functions are revealed through functional studies, providing insights into its importance in normal biological processes and disease conditions, especially in optic atrophy and breast cancer [1,2,3,4].