Peroxisome proliferator-activated receptor-γ coactivator 1-α (PGC1α) is a metabolic regulator of intestinal epithelial cell fate

Peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC1 alpha) is a transcriptional coactivator able to up-regulate mitochondrial biogenesis, respiratory capacity, oxidative phosphorylation, and fatty acid beta-oxidation with the final aim of providing a more efficient pathway for aerobic energy production. In the continuously renewed intestinal epithelium, proliferative cells in the crypts migrate along the villus axis and differentiate into mature enterocytes, increasing their respiratory capacity and finally undergoing apoptosis. Here we show that in the intestinal epithelial surface, PGC1 alpha drives mitochondrial biogenesis and respiration in the presence of reduced antioxidant enzyme activities, thus determining the accumulation of reactive oxygen species and fostering the fate of enterocytes toward apoptosis. Combining gain-and loss-of-function genetic approaches in human cells and mouse models of intestinal cancer, we present an intriguing scenario whereby PGC1 alpha regulates enterocyte cell fate and protects against tumorigenesis.