Mitochondria regulate intestinal stem cell proliferation and epithelial homeostasis through FOXO

Zhang, Fan; Pirooznia, Mehdi; Xu, Hong

doi:10.1091/mbc.e19-10-0560

Cited by 33 publications

(28 citation statements)

References 64 publications

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“…In contrast, the evolutionarily primitive zebrafish lack butyrate-producing bacterial organisms, as well as intestinal crypts. Second, the investigators demonstrated that exposure of intestinal stem cells to butyrate resulted in HDAC inhibition-mediated expression of Foxo3, a transcription factor that regulates cell cycle arrest and apoptosis through disruption of cellular metabolism [ 48 ]. When butyrate comes in contact with intestinal stem cells, such as under conditions of mucosal injury in crypt-containing mice, or from luminal infusion in crypt-less zebrafish, there is resulting inhibition of stem cell proliferation (see Figure 2 ).…”

Section: Butyrate and Intestinal Epithelial Proliferationmentioning

confidence: 99%

“…Notably, Foxo3 upregulation has not been specifically observed in colon cancer cells treated with butyrate, although Foxo3 expression does modulate a number of pro-apoptotic genes associated with butyrate’s antineoplastic effects [ 48 ]. The importance of this transcription factor in intestinal stem cell cycle arrest, and the similarities in cellular metabolism between stem cells and neoplastic cells, call for further characterization of the antiproliferative pathways activated by butyrate in cancer cells.…”

Section: Butyrate and Intestinal Epithelial Proliferationmentioning

confidence: 99%

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Butyrate and the Intestinal Epithelium: Modulation of Proliferation and Inflammation in Homeostasis and Disease

Salvi

Cowles

2021

Cells

236

114

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The microbial metabolite butyrate serves as a link between the intestinal microbiome and epithelium. The monocarboxylate transporters MCT1 and SMCT1 are the predominant means of butyrate transport from the intestinal lumen to epithelial cytoplasm, where the molecule undergoes rapid β-oxidation to generate cellular fuel. However, not all epithelial cells metabolize butyrate equally. Undifferentiated colonocytes, including neoplastic cells and intestinal stem cells at the epithelial crypt base preferentially utilize glucose over butyrate for cellular fuel. This divergent metabolic conditioning is central to the phenomenon known as “butyrate paradox”, in which butyrate induces contradictory effects on epithelial proliferation in undifferentiated and differentiated colonocytes. There is evidence that accumulation of butyrate in epithelial cells results in histone modification and altered transcriptional activation that halts cell cycle progression. This manifests in the apparent protective effect of butyrate against colonic neoplasia. A corollary to this process is butyrate-induced inhibition of intestinal stem cells. Yet, emerging research has illustrated that the evolution of the crypt, along with butyrate-producing bacteria in the intestine, serve to protect crypt base stem cells from butyrate’s anti-proliferative effects. Butyrate also regulates epithelial inflammation and tolerance to antigens, through production of anti-inflammatory cytokines and induction of tolerogenic dendritic cells. The role of butyrate in the pathogenesis and treatment of intestinal neoplasia, inflammatory bowel disease and malabsorptive states is evolving, and holds promise for the potential translation of butyrate’s cellular function into clinical therapies.

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Section: Butyrate and Intestinal Epithelial Proliferationmentioning

confidence: 99%

Section: Butyrate and Intestinal Epithelial Proliferationmentioning

confidence: 99%

Butyrate and the Intestinal Epithelium: Modulation of Proliferation and Inflammation in Homeostasis and Disease

Salvi

Cowles

2021

Cells

236

114

View full text Add to dashboard Cite

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“…Therefore, by limiting mitochondrial pyruvate flux, MPC plays a cell-autonomous role in maintaining the proliferation of ISCs ( Schell et al, 2017 ). However, a very recent study demonstrates that mitochondrial Oxphos is essential for Drosophila ISC proliferation ( Zhang et al, 2020 ). Genetic disruption of the mitochondrial ETC in the ISCs by manipulating the mitochondrial genome retards their proliferation rate, leading to the production of a limited number of EBs, which eventually fails to differentiate into ECs ( Figure 3B ).…”

Section: Intestinal Stem Cells Of the Midgut And Their Regulation By Mitochondriamentioning

confidence: 99%

“…Furthermore, knocking down foxo in these ISCs markedly suppresses the proliferation and lineage specification defects associated with the ETC disruption. Therefore, mitochondrial respiration is critical for Drosophila ISC proliferation and lineage specification and acts at least partially by repressing endogenous FOXO signaling ( Zhang et al, 2020 ).…”

Section: Intestinal Stem Cells Of the Midgut And Their Regulation By Mitochondriamentioning

confidence: 99%

Mitochondrial Control of Stem Cell State and Fate: Lessons From Drosophila

Tiwari

Mandal

2021

Front. Cell Dev. Biol.

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Over the years, Drosophila has served as a wonderful genetically tractable model system to unravel various facets of tissue-resident stem cells in their microenvironment. Studies in different stem and progenitor cell types of Drosophila have led to the discovery of cell-intrinsic and extrinsic factors crucial for stem cell state and fate. Though initially touted as the ATP generating machines for carrying various cellular processes, it is now increasingly becoming clear that mitochondrial processes alone can override the cellular program of stem cells. The last few years have witnessed a surge in our understanding of mitochondria’s contribution to governing different stem cell properties in their subtissular niches in Drosophila. Through this review, we intend to sum up and highlight the outcome of these in vivo studies that implicate mitochondria as a central regulator of stem cell fate decisions; to find the commonalities and uniqueness associated with these regulatory mechanisms.

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“…Reduced mitochondrial function, specifically the inhibition of the electron transport chain and oxidative phosphorylation, has been shown to limit proliferation in a variety of cell types such as intestinal stem cells (Zhang et al, 2020), Jurkat cells (Birsoy et al, 2015), vascular smooth muscle cells (Chiong et al, 2014), and human colon cancer cells HCT116 (Wheaton et al, 2014). Additionally, PGE2 has been shown to limit oxidative phosphorylation in human monocyte-derived macrophages (Minhas et al, 2021).…”

Section: Pge2 Signaling Alters the Mitochondrial Fitness Of Amsmentioning

confidence: 99%

Age-elevated prostaglandin E₂enhances mortality to influenza infection

Chen

Deng

Zemans

et al. 2021

Preprint

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SummaryAging impairs the immune responses to influenza A virus (IAV), resulting in increased mortality to IAV infections in older adults. With aging, there is reduced number and impaired function of alveolar macrophages (AMs), cells critical for defense against IAV. However, factors within the aged lung that impair AMs are not fully known. Using a murine model of IAV infection, we observed that aging increased the level of prostaglandin E2 (PGE2) in the bronchoalveolar lavage fluid (BALF) of aged mice compared to young mice. Blockade of the PGE2 receptor EP2 in aged mice increased AM numbers and subsequently enhanced survival to IAV. Additionally, PGE2 impaired the mitochondrial health of AMs. We also identified senescent type II alveolar epithelial cells (AECs) as a source of the aged-associated PGE2 in the lung. Our results reveal a crosstalk between AECs and AMs, via PGE2, that compromises host defense to IAV infection with aging.

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Mitochondria regulate intestinal stem cell proliferation and epithelial homeostasis through FOXO

Abstract: Deficiencies in electron transport chain complexes increase the activity of FOXO transcription factor in Drosophila midgut stem cells, which impairs stem cell proliferation and enterocyte specification.

Cited by 33 publications

References 64 publications

Butyrate and the Intestinal Epithelium: Modulation of Proliferation and Inflammation in Homeostasis and Disease

Butyrate and the Intestinal Epithelium: Modulation of Proliferation and Inflammation in Homeostasis and Disease

Mitochondrial Control of Stem Cell State and Fate: Lessons From Drosophila

Age-elevated prostaglandin E₂enhances mortality to influenza infection

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Mitochondria regulate intestinal stem cell proliferation and epithelial homeostasis through FOXO

Abstract: Deficiencies in electron transport chain complexes increase the activity of FOXO transcription factor in Drosophila midgut stem cells, which impairs stem cell proliferation and enterocyte specification.

Cited by 33 publications

References 64 publications

Butyrate and the Intestinal Epithelium: Modulation of Proliferation and Inflammation in Homeostasis and Disease

Butyrate and the Intestinal Epithelium: Modulation of Proliferation and Inflammation in Homeostasis and Disease

Mitochondrial Control of Stem Cell State and Fate: Lessons From Drosophila

Age-elevated prostaglandin E2enhances mortality to influenza infection

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Product

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Age-elevated prostaglandin E₂enhances mortality to influenza infection