Loss of TMEM126A promotes extracellular matrix remodeling, epithelial-to-mesenchymal transition, and breast cancer metastasis by regulating mitochondrial retrograde signaling

TMEM126A is a mitochondrial transmembrane protein, and its functions in breast cancer progression remain unclear. In this study, via the iTRAQ assay using primary and metastatic breast cancer cell models, we found that TMEM126A expression decreased in metastatic cells. We further confirmed that low TMEM126A expression correlated with tumor progression and poor prognosis in patients. The downregulation of TMEM126A in breast cancer cell lines significantly enhanced the metastatic properties in vitro and in vivo, whereas its overexpression decreased the metastatic potential of cell lines. Mechanistic studies based on RNA-sequencing indicated that TMEM126A might regulate cell metastasis via ECM-receptor interaction, focal adhesions, and actin cytoskeleton, among other processes. Furthermore, the loss of TMEM126A activated extracellular matrix (ECM) remodeling and promoted epithelial-to-mesenchymal transition (EMT). Moreover, TMEM126A silencing induced reactive oxygen species (ROS) production and mitochondrial membrane potential depolarization. The ROS scavengers reversed ECM remodeling and EMT mediated by TMEM126A. Collectively, our findings show that the loss of TMEM126A induces mitochondrial dysfunction and subsequently metastasis by activating ECM remodeling and EMT. These findings suggest that TMEM126A is a novel suppressor of metastasis and that it can be a potential prognostic indicator for patients with breast cancer.