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PGC-1Β Promotes Enterocyte Lifespan and Tumorigenesis in the Intestine

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PGC-1Β Promotes Enterocyte Lifespan and Tumorigenesis in the Intestine PGC-1β promotes enterocyte lifespan and PNAS PLUS tumorigenesis in the intestine Elena Bellafantea,1, Annalisa Morganoa, Lorena Salvatorea, Stefania Murzillia, Giuseppe Di Tullioa, Andria D’Orazioa, Dominga Latorreb, Gaetano Villanib,2, and Antonio Moschettac,d,2 aFondazione Mario Negri Sud, 66030 Santa Maria Imbaro (Chieti), Italy; bDepartment of Basic Medical Sciences, Neurosciences and Sense Organs, and cDepartment of Interdisciplinary Medicine, University of Bari Aldo Moro, 70121 Bari, Italy; and dNational Cancer Research Center, Istituto Oncologico “Giovanni Paolo II,” 70124 Bari, Italy Edited by Steven A. Kliewer, University of Texas Southwestern Medical Center, Dallas, TX, and accepted by the Editorial Board September 9, 2014 (received for review August 12, 2014) The mucosa of the small intestine is renewed completely every 3–5d as antioxidant defense. Both PGC-1α and PGC-1β are pref- throughout the entire lifetime by small populations of adult erentially expressed in tissues with high oxidative capacity where stem cells that are believed to reside in the bottom of the crypts they participate, through mitochondrial biogenesis, in the and to migrate and differentiate into all the different populations metabolic response to high energy demand (4), such as cold- of intestinal cells. When the cells reach the apex of the villi and are adapted thermogenesis in brown adipose tissue (5), fiber-type fully differentiated, they undergo cell death and are shed into the switching in striated muscle (6), and fatty acid β oxidation and lumen. Reactive oxygen species (ROS) production is proportional gluconeogenesis in liver during a fasting state (7, 8). The increase to the electron transfer activity of the mitochondrial respiration in mitochondrial biogenesis and activity stimulated by PGC-1 chain. ROS homeostasis is maintained to control cell death and is proteins may cause an increase in the production of ROS. However, finely tuned by an inducible antioxidant program. Here we show α γ β PGC-1 also has been shown to increase the expression of the that peroxisome proliferator-activated receptor- coactivator-1 major mitochondrial antioxidant enzyme superoxide dismutase 2 (PGC-1β) is highly expressed in the intestinal epithelium and pos- (Sod2) (3, 9). Therefore, PGC-1α is able to upgrade aerobic energy sesses dual activity, stimulating mitochondrial biogenesis and metabolism while preserving ROS homeostasis, by simultaneously oxygen consumption while inducing antioxidant enzymes. To study β promoting ROS formation and detoxification. Recently, it has been MEDICAL SCIENCES the role of PGC-1 gain and loss of function in the gut, we gener- Drosophila α ated both intestinal-specific PGC-1β transgenic and PGC-1β knock- shown in that the PGC-1 homolog spargel is able to out mice. Mice overexpressing PGC-1β present a peculiar intestinal induce mitochondrial function and oxygen consumption, which is morphology with very long villi resulting from increased entero- coupled to the induction of scavenger systems and ROS reduction, cyte lifespan and also demonstrate greater tumor susceptibility, finally leading to increased longevity (10). On the other hand, in the with increased tumor number and size when exposed to carcino- differentiated intestinal epithelium of mice, PGC-1α induces mito- gens. PGC-1β knockout mice are protected from carcinogenesis. chondrial biogenesis and oxygen consumption, but it is not able to We show that PGC-1β triggers mitochondrial respiration while pro- induce the ROS-scavenging apparatus, thus promoting ROS- tecting enterocytes from ROS-driven macromolecule damage and dependent apoptotic cell death (2). consequent apoptosis in both normal and dysplastic mucosa. Therefore, PGC-1β in the gut acts as an adaptive self-point regula- Significance tor, capable of providing a balance between enhanced mitochon- drial activity and protection from increased ROS production. The mucosa of the small intestine is renewed completely every 3–5 d during the entire lifetime through the continuous steps nuclear receptors | gene expression | molecular pathology | colon cancer of proliferation, migration, and differentiation of the cells of the mucosa from the crypt site on the bottom to the villus site he intestine represents the interface between the organism on the top of the mucosa. The factors that regulate enterocyte Tand its luminal environment and is constantly challenged by lifespan and aging are of special interest as related to colon mechanical stress, diet-derived toxins and oxidants, and endog- cancer susceptibility. Here, using genetically modified gain- enously generated reactive oxygen species (ROS), which can and loss-of-function models, we present the importance of the induce serious damage to all biological molecules and cell mitochondrial respiration chain and reactive oxygen species structures (1). To preserve cellular integrity and tissue homeo- homeostasis in the gut and identify the protein peroxisome stasis, the intestine possesses self-renewing capacity via the proliferator-activated receptor-γ coactivator-1β as a gene- continuous migration of new enterocytes that undergo differen- expression modulator of enterocyte lifespan in both normal tiation from the crypt to the apical compartment of the villus, and tumoral conditions. where they become competent to apoptosis and are shed into the Author contributions: E.B., G.V., and A. Moschetta designed research; E.B., A. Morgano, lumen. ROS accumulation within intestinal epithelial cells pro- L.S., S.M., G.D.T., A.D., and D.L. performed research; S.M., A.D., D.L., G.V., and A. Moschetta motes apoptotic cell death in the differentiated compartment contributed new reagents/analytic tools; E.B., G.V., and A. Moschetta analyzed data; and (2). The mitochondrial electron transport chain is a major site of E.B., G.V., and A. Moschetta wrote the paper. ROS production in the cells. Under physiological conditions, the The authors declare no conflict of interest. balance between ROS generation and detoxification is controlled This article is a PNAS Direct Submission. S.A.K. is a guest editor invited by the Editorial by a set of cellular enzymes including superoxide dismutase Board. and catalase. Important components of the ROS-scavenging Data deposition: The data reported in this paper have been deposited in the Gene Ex- pathways are linked to mitochondrial oxidative metabolism via pression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession no. GSE61643). γ 1Present address: Division of Women’s Health, Faculty of Life Sciences & Medicine, King’s the peroxisome proliferator-activated receptor- coactivators College London, London WC2R 2LS, United Kingdom 1α and 1β (PGC-1α and PGC-1β), apparently enabling cells to 2To whom correspondence may be addressed. Email: [email protected] or antonio. maintain normal redox status in response to changing oxida- [email protected]. α β tive capacity (3). PGC-1 and PGC-1 are master regulators This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. of mitochondrial biogenesis and oxidative metabolism as well 1073/pnas.1415279111/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1415279111 PNAS | Published online October 6, 2014 | E4523–E4531 Downloaded by guest on September 26, 2021 PGC-1β is highly similar to PGC-1α, both in amino acid se- antioxidant systems as well as decreased susceptibility to tumors. quence and ability to regulate several metabolic pathways (8, 11). Indeed, tumors may use adaptive mechanisms to keep their ROS Therefore, in the present study we focus on the function of PGC-1β burden within a range that permits their growth and survival. In in the intestinal epithelium, giving special attention to the such contest, PGC-1β acts as a gatekeeper of redox status, allowing effect of this coactivator in enterocyte homeostasis. We first enterocyte survival and, in cancer-promoting conditions, tumor show that PGC-1β is highly expressed in intestinal epithelium progression. with an almost ubiquitous pattern of localization along the entire crypt–villus axis. To study its activation, we generated mice Results overexpressing PGC-1β selectively in the enterocytes. We show PGC-1β Is Highly Expressed in the Intestinal Epithelium and Modulates that in these cells PGC-1β enhances mitochondrial biogenesis Intestinal Morphology. The role and the exact localization of and respiration and induces a parallel increase in antioxidant PGC-1β in the intestine is completely unknown. Thus, we first enzymes, such as Sod2 and glutathione peroxidase 4 (Gpx4), as investigated the expression levels of PGC-1β in the intestine and well as peroxiredoxins. As a result, the intestinal morphology is its exact localization in the crypt–villus axis of the intestinal severely affected, with significant increases in enterocyte lon- mucosa in wild-type mice. We found significant PGC-1β levels in gevity and mucosal villi length. Concomitantly, PGC-1β over- the entire gastrointestinal tract with clearly higher expression in expression leads to a significant increase in tumor number and the colon (Fig. 1A). Notably, PGC-1β is present along the entire size in two distinct models of intestinal carcinogenesis. More- crypt–villus axis, although it seems to be more highly expressed over, to confirm the role of PGC-1β activity in the intestine, we also in the lowest part of this axis, which corresponds to the villus– generated intestinal-specific PGC-1β (iPGC-1β) knockout mice crypt junction, and in the transit-amplifying
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