TFAM is required for maturation of the fetal and adult intestinal epithelium

During development, the embryo transitions from a metabolism favoring glycolysis to a metabolism favoring mitochondrial respiration. How metabolic shifts regulate developmental processes, or how developmental processes regulate metabolic shifts, remains unclear. To test the requirement of mitochondrial function in developing endoderm-derived tissues, we genetically inactivated the mitochondrial transcription factor, Tfam, using the Shh-Cre driver. Tfam mutants did not survive postnatally, exhibiting defects in lung development. In the developing intestine, TFAM-loss was tolerated until late fetal development, during which the process of villus elongation was compromised. While progenitor cell populations appeared unperturbed, markers of enterocyte maturation were diminished and villi were blunted. Loss of TFAM was also tested in the adult intestinal epithelium, where enterocyte maturation was similarly dependent upon the mitochondrial transcription factor. While progenitor cells in the transit amplifying zone of the adult intestine remained proliferative, intestinal stem cell renewal was dependent upon TFAM, as indicated by molecular profiling and intestinal organoid formation assays. Taken together, these studies point to critical roles for the mitochondrial regulator TFAM for multiple aspects of intestinal development and maturation, and highlight the importance of mitochondrial regulators in tissue development and homeostasis. •The mitochondrial transcription factor TFAM is required for proper lung development and post-natal survival.•TFAM is dispensable early in intestinal development, but required for tissue maturation and enterocyte differentiation.•In the adult, TFAM loss leads to expansion of cells in the crypt progenitor zone at the expense of villus differentiation.•Intestinal stem cell renewal also depends upon TFAM, highlighting complex functions for the mitochondrial regulator.•Stem, progenitor, and differentiated intestinal epithelial cells exhibit unique dependencies on mitochondrial regulators.