PGC-1β promotes enterocyte lifespan and tumorigenesis in the intestine

Elena Bellafante, Annalisa Morgano, Lorena Salvatore, Stefania Murzilli, Giuseppe Di Tullio, Andria D'Orazio, Dominga Latorre, Gaetano Villani, Antonio Moschetta

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

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-γ coactivator-1β (PGC-1β) 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-1β gain and loss of function in the gut, we generated both intestinal-specific PGC-1β transgenic and PGC-1β knockout mice. Mice overexpressing PGC-1β 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-1β knockout mice are protected from carcinogenesis. We show that PGC-1β triggers mitochondrial respiration while protecting enterocytes from ROS-driven macromolecule damage and consequent apoptosis in both normal and dysplastic mucosa. Therefore, PGC-1β 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.

Original languageEnglish (US)
Pages (from-to)E4523-E4531
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number42
DOIs
StatePublished - Oct 21 2014

Keywords

  • Colon cancer
  • Gene expression
  • Molecular pathology
  • Nuclear receptors

ASJC Scopus subject areas

  • General

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  • Cite this

    Bellafante, E., Morgano, A., Salvatore, L., Murzilli, S., Di Tullio, G., D'Orazio, A., Latorre, D., Villani, G., & Moschetta, A. (2014). PGC-1β promotes enterocyte lifespan and tumorigenesis in the intestine. Proceedings of the National Academy of Sciences of the United States of America, 111(42), E4523-E4531. https://doi.org/10.1073/pnas.1415279111