| First Author | Bellafante E | Year | 2014 |
| Journal | Proc Natl Acad Sci U S A | Volume | 111 |
| Issue | 42 | Pages | E4523-31 |
| PubMed ID | 25288742 | Mgi Jnum | J:216428 |
| Mgi Id | MGI:5608804 | Doi | 10.1073/pnas.1415279111 |
| Citation | Bellafante E, et al. (2014) PGC-1beta promotes enterocyte lifespan and tumorigenesis in the intestine. Proc Natl Acad Sci U S A 111(42):E4523-31 |
| abstractText | The mucosa of the small intestine is renewed completely every 3-5 d throughout the entire lifetime by small populations of adult stem cells that are believed to reside in the bottom of the crypts and to migrate and differentiate into all the different populations of intestinal cells. When the cells reach the apex of the villi and are fully differentiated, they undergo cell death and are shed into the lumen. Reactive oxygen species (ROS) production is proportional to the electron transfer activity of the mitochondrial respiration chain. ROS homeostasis is maintained to control cell death and is finely tuned by an inducible antioxidant program. Here we show that peroxisome proliferator-activated receptor-gamma coactivator-1beta (PGC-1beta) is highly expressed in the intestinal epithelium and possesses dual activity, stimulating mitochondrial biogenesis and oxygen consumption while inducing antioxidant enzymes. To study the role of PGC-1beta gain and loss of function in the gut, we generated both intestinal-specific PGC-1beta transgenic and PGC-1beta knockout mice. Mice overexpressing PGC-1beta present a peculiar intestinal morphology with very long villi resulting from increased enterocyte lifespan and also demonstrate greater tumor susceptibility, with increased tumor number and size when exposed to carcinogens. PGC-1beta knockout mice are protected from carcinogenesis. We show that PGC-1beta triggers mitochondrial respiration while protecting enterocytes from ROS-driven macromolecule damage and consequent apoptosis in both normal and dysplastic mucosa. Therefore, PGC-1beta in the gut acts as an adaptive self-point regulator, capable of providing a balance between enhanced mitochondrial activity and protection from increased ROS production. |
