| Popis: |
The intestinal epithelium is the fastest renewing tissue in mammals and has extensive flexibility to adapt to different types of damage. The orderly expression and activation of the YAP protein is the initial step in driving intestinal development and crucial for intestinal regenerative responses and regulating intestinal homeostasis[1–4]. However, the regulatory mechanisms controlling this process are still unknown. Mitochondria are enriched in the intestinal epithelium and particularly along the crypt-villus axis [5]. But we have little known about the role of mitochondria in maintaining intestinal homeostasis and regulating cell fate determination. In this study, we discovered that mitochondrial complex I assembly was the top enriched mitochondrial gene ontology (GO) along the crypt-villus axis, and ECSIT, the core subunit of Mitochondrial Complex I Intermediate Assembly (MCIA) complex [6, 7], was the top up-regulated mitochondrial factor I factor among this ontology. Intestinal cell-specific ablation of ECSIT results in the dysregulation of intestinal epithelial cell (IEC) differentiation and the development of a spontaneous intestinal inflammation phenotype. Single-cell RNA sequencing also revealed that mice lacking ECSIT in intestinal cells displayed a distinct, early proliferation- type signature in all the major intestinal cells, which we term “-like” cells. The “-like” cells are marked by high YAP protein and downstream YAP transcriptional programs but have no alteration in Yap mRNA level. Mechanistically, we show that the absence of ECSIT in intestinal cells promotes YAP translation initiation through the upregulation of the eIF4F complex. This upregulation is due to the reduced DNA methylation in genes encoding eIF4A1 and eIF4G2. Such DNA methylation reduction is caused by the increased a-ketoglutarate (a-KG): succinate ratio activating Ten-eleven translocation (TET)-dependent DNA demethylation in ECSIT deficient cells. Moreover, decreased ECSIT expression in intestinal cells enhanced susceptibility to tumorigenesis in the context of dysregulated WNT signaling, and the expression of ECSIT is positively correlated with the survival of patients with colorectal cancer. Together, our results reveal a novel and important role of the mitochondrial complex I assembly factor ECSIT and mitochondrial metabolism in maintaining optimal intestinal homeostasis and controlling the development of tumorigenesis by critical regulation of the eIF4F-YAP signalling axis. |
