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Cell Metabolism Nov 2023The intestinal epithelium has a high turnover rate and constantly renews itself through proliferation of intestinal crypt cells, which depends on insufficiently...
The intestinal epithelium has a high turnover rate and constantly renews itself through proliferation of intestinal crypt cells, which depends on insufficiently characterized signals from the microenvironment. Here, we showed that colonic macrophages were located directly adjacent to epithelial crypt cells in mice, where they metabolically supported epithelial cell proliferation in an mTORC1-dependent manner. Specifically, deletion of tuberous sclerosis complex 2 (Tsc2) in macrophages activated mTORC1 signaling that protected against colitis-induced intestinal damage and induced the synthesis of the polyamines spermidine and spermine. Epithelial cells ingested these polyamines and rewired their cellular metabolism to optimize proliferation and defense. Notably, spermine directly stimulated proliferation of colon epithelial cells and colon organoids. Genetic interference with polyamine production in macrophages altered global polyamine levels in the colon and modified epithelial cell proliferation. Our results suggest that macrophages act as "commensals" that provide metabolic support to promote efficient self-renewal of the colon epithelium.
Topics: Mice; Animals; Spermine; Polyamines; Colon; Intestinal Mucosa; Homeostasis; Macrophages; Mechanistic Target of Rapamycin Complex 1
PubMed: 37804836
DOI: 10.1016/j.cmet.2023.09.010 -
Nature Aging Nov 2023Advanced age is a primary risk factor for female infertility due to reduced ovarian reserve and declining oocyte quality. However, as an important contributing factor,...
Advanced age is a primary risk factor for female infertility due to reduced ovarian reserve and declining oocyte quality. However, as an important contributing factor, the role of metabolic regulation during reproductive aging is poorly understood. Here, we applied untargeted metabolomics to identify spermidine as a critical metabolite in ovaries to protect oocytes against aging. In particular, we found that the spermidine level was reduced in ovaries of aged mice and that supplementation with spermidine promoted follicle development, oocyte maturation, early embryonic development and female fertility of aged mice. By microtranscriptomic analysis, we further discovered that spermidine-induced recovery of oocyte quality was mediated by enhancement of mitophagy activity and mitochondrial function in aged mice, and this mechanism of action was conserved in porcine oocytes under oxidative stress. Altogether, our findings suggest that spermidine supplementation could represent a therapeutic strategy to ameliorate oocyte quality and reproductive outcome in cis-gender women and other persons trying to conceive at an advanced age. Future work is needed to test whether this approach can be safely and effectively translated to humans.
Topics: Pregnancy; Female; Humans; Mice; Animals; Swine; Spermidine; Polyamines; Mitophagy; Oocytes; Aging
PubMed: 37845508
DOI: 10.1038/s43587-023-00498-8 -
Immunity Nov 2023Cyclic guanosine monophosphate (GMP)-AMP (cGAMP) synthase (cGAS) is a universal double-stranded DNA (dsDNA) sensor that recognizes foreign and self-DNA in the cytoplasm...
Cyclic guanosine monophosphate (GMP)-AMP (cGAMP) synthase (cGAS) is a universal double-stranded DNA (dsDNA) sensor that recognizes foreign and self-DNA in the cytoplasm and initiates innate immune responses and has been implicated in various infectious and non-infectious contexts. cGAS binds to the backbone of dsDNA and generates the second messenger, cGAMP, which activates the stimulator of interferon genes (STING). Here, we show that the endogenous polyamines spermine and spermidine attenuated cGAS activity and innate immune responses. Mechanistically, spermine and spermidine induced the transition of B-form DNA to Z-form DNA (Z-DNA), thereby decreasing its binding affinity with cGAS. Spermidine/spermine N1-acetyltransferase 1 (SAT1), the rate-limiting enzyme in polyamine catabolism that decreases the cellular concentrations of spermine and spermidine, enhanced cGAS activation by inhibiting cellular Z-DNA accumulation; SAT1 deficiency promoted herpes simplex virus 1 (HSV-1) replication in vivo. The results indicate that spermine and spermidine induce dsDNA to adopt the Z-form conformation and that SAT1-mediated polyamine metabolism orchestrates cGAS activity.
Topics: Spermine; Spermidine; DNA, Z-Form; DNA, B-Form; DNA; Nucleotidyltransferases; Polyamines; Immunity, Innate
PubMed: 37848037
DOI: 10.1016/j.immuni.2023.09.012 -
Trends in Cell Biology May 2024Polyamines - putrescine, spermidine, and spermine - are widely distributed aliphatic compounds known to regulate important biological processes in prokaryotic and... (Review)
Review
Polyamines - putrescine, spermidine, and spermine - are widely distributed aliphatic compounds known to regulate important biological processes in prokaryotic and eukaryotic cells. Therefore, spermidine insufficiency is associated with various physio-pathological processes, such as aging and cancers. Recent advances in immuno-metabolism and immunotherapy shed new light on the role of spermidine in immune cell regulation and anticancer responses. Here, we review novel works demonstrating that spermidine is produced by collective metabolic pathways of gut bacteria, bacteria-host co-metabolism, and by the host cells, including activated immune cells. We highlight the effectiveness of spermidine in enhancing antitumor responses in aged animals otherwise nonresponsive to immune checkpoint therapy and propose that spermidine supplementation could be used to enhance the efficacy of anti-PD-1 treatment.
Topics: Spermidine; Humans; Animals; Aging; Gastrointestinal Microbiome; Neoplasms; Immunotherapy
PubMed: 37723019
DOI: 10.1016/j.tcb.2023.08.002 -
Cell Mar 2024The repertoire of modifications to bile acids and related steroidal lipids by host and microbial metabolism remains incompletely characterized. To address this knowledge...
The repertoire of modifications to bile acids and related steroidal lipids by host and microbial metabolism remains incompletely characterized. To address this knowledge gap, we created a reusable resource of tandem mass spectrometry (MS/MS) spectra by filtering 1.2 billion publicly available MS/MS spectra for bile-acid-selective ion patterns. Thousands of modifications are distributed throughout animal and human bodies as well as microbial cultures. We employed this MS/MS library to identify polyamine bile amidates, prevalent in carnivores. They are present in humans, and their levels alter with a diet change from a Mediterranean to a typical American diet. This work highlights the existence of many more bile acid modifications than previously recognized and the value of leveraging public large-scale untargeted metabolomics data to discover metabolites. The availability of a modification-centric bile acid MS/MS library will inform future studies investigating bile acid roles in health and disease.
Topics: Animals; Humans; Bile Acids and Salts; Metabolomics; Polyamines; Tandem Mass Spectrometry; Gastrointestinal Microbiome; Databases, Chemical
PubMed: 38471500
DOI: 10.1016/j.cell.2024.02.019 -
Gastroenterology Sep 2023The amino acid hypusine, synthesized from the polyamine spermidine by the enzyme deoxyhypusine synthase (DHPS), is essential for the activity of eukaryotic translation...
BACKGROUND & AIMS
The amino acid hypusine, synthesized from the polyamine spermidine by the enzyme deoxyhypusine synthase (DHPS), is essential for the activity of eukaryotic translation initiation factor 5A (EIF5A). The role of hypusinated EIF5A (EIF5A) remains unknown in intestinal homeostasis. Our aim was to investigate EIF5A in the gut epithelium in inflammation and carcinogenesis.
METHODS
We used human colon tissue messenger RNA samples and publicly available transcriptomic datasets, tissue microarrays, and patient-derived colon organoids. Mice with intestinal epithelial-specific deletion of Dhps were investigated at baseline and in models of colitis and colon carcinogenesis.
RESULTS
We found that patients with ulcerative colitis and Crohn's disease exhibit reduced colon levels of DHPS messenger RNA and DHPS protein and reduced levels of EIF5A. Similarly, colonic organoids from colitis patients also show down-regulated DHPS expression. Mice with intestinal epithelial-specific deletion of Dhps develop spontaneous colon hyperplasia, epithelial proliferation, crypt distortion, and inflammation. Furthermore, these mice are highly susceptible to experimental colitis and show exacerbated colon tumorigenesis when treated with a carcinogen. Transcriptomic and proteomic analysis on colonic epithelial cells demonstrated that loss of hypusination induces multiple pathways related to cancer and immune response. Moreover, we found that hypusination enhances translation of numerous enzymes involved in aldehyde detoxification, including glutathione S-transferases and aldehyde dehydrogenases. Accordingly, hypusination-deficient mice exhibit increased levels of aldehyde adducts in the colon, and their treatment with a scavenger of electrophiles reduces colitis.
CONCLUSIONS
Hypusination in intestinal epithelial cells has a key role in the prevention of colitis and colorectal cancer, and enhancement of this pathway via supplementation of spermidine could have a therapeutic impact.
Topics: Humans; Animals; Mice; Spermidine; Proteomics; Peptide Initiation Factors; Carcinogenesis; Colitis; Homeostasis; Inflammation
PubMed: 37271289
DOI: 10.1053/j.gastro.2023.05.041 -
International Journal of Molecular... Oct 2023Ovarian aging and disease-related decline in fertility are challenging medical and economic issues with an increasing prevalence. Polyamines are a class of polycationic... (Review)
Review
Ovarian aging and disease-related decline in fertility are challenging medical and economic issues with an increasing prevalence. Polyamines are a class of polycationic alkylamines widely distributed in mammals. They are small molecules essential for cell growth and development. Polyamines alleviate ovarian aging through various biological processes, including reproductive hormone synthesis, cell metabolism, programmed cell death, etc. However, an abnormal increase in polyamine levels can lead to ovarian damage and promote the development of ovarian disease. Therefore, polyamines have long been considered potential therapeutic targets for aging and disease, but their regulatory roles in the ovary deserve further investigation. This review discusses the mechanisms by which polyamines ameliorate human ovarian aging and disease through different biological processes, such as autophagy and oxidative stress, to develop safe and effective polyamine targeted therapy strategies for ovarian aging and the diseases.
Topics: Animals; Female; Humans; Polyamines; Ovary; Aging; Reproduction; Fertility; Mammals
PubMed: 37895010
DOI: 10.3390/ijms242015330 -
Nature Metabolism Jan 2024The global loss of heterochromatin during ageing has been observed in eukaryotes from yeast to humans, and this has been proposed as one of the causes of ageing....
The global loss of heterochromatin during ageing has been observed in eukaryotes from yeast to humans, and this has been proposed as one of the causes of ageing. However, the cause of this age-associated loss of heterochromatin has remained enigmatic. Here we show that heterochromatin markers, including histone H3K9 di/tri-methylation and HP1, decrease with age in muscle stem cells (MuSCs) as a consequence of the depletion of the methyl donor S-adenosylmethionine (SAM). We find that restoration of intracellular SAM in aged MuSCs restores heterochromatin content to youthful levels and rejuvenates age-associated features, including DNA damage accumulation, increased cell death, and defective muscle regeneration. SAM is not only a methyl group donor for transmethylation, but it is also an aminopropyl donor for polyamine synthesis. Excessive consumption of SAM in polyamine synthesis may reduce its availability for transmethylation. Consistent with this premise, we observe that perturbation of increased polyamine synthesis by inhibiting spermidine synthase restores intracellular SAM content and heterochromatin formation, leading to improvements in aged MuSC function and regenerative capacity in male and female mice. Together, our studies demonstrate a direct causal link between polyamine metabolism and epigenetic dysregulation during murine MuSC ageing.
Topics: Humans; Female; Male; Mice; Animals; Aged; Heterochromatin; S-Adenosylmethionine; Aging; Polyamines; Cellular Senescence; Muscles
PubMed: 38243132
DOI: 10.1038/s42255-023-00955-z -
Nature Communications Mar 2024Targeting ferroptosis, an iron-dependent form of regulated cell death triggered by the lethal overload of lipid peroxides, in cancer therapy is impeded by our limited...
Targeting ferroptosis, an iron-dependent form of regulated cell death triggered by the lethal overload of lipid peroxides, in cancer therapy is impeded by our limited understanding of the intersection of tumour's metabolic feature and ferroptosis vulnerability. In the present study, arginine is identified as a ferroptotic promoter using a metabolites library. This effect is mainly achieved through arginine's conversion to polyamines, which exerts their potent ferroptosis-promoting property in an HO-dependent manner. Notably, the expression of ornithine decarboxylase 1 (ODC1), the critical enzyme catalysing polyamine synthesis, is significantly activated by the ferroptosis signal--iron overload--through WNT/MYC signalling, as well as the subsequent elevated polyamine synthesis, thus forming a ferroptosis-iron overload-WNT/MYC-ODC1-polyamine-HO positive feedback loop that amplifies ferroptosis. Meanwhile, we notice that ferroptotic cells release enhanced polyamine-containing extracellular vesicles into the microenvironment, thereby further sensitizing neighbouring cells to ferroptosis and accelerating the "spread" of ferroptosis in the tumour region. Besides, polyamine supplementation also sensitizes cancer cells or xenograft tumours to radiotherapy or chemotherapy through inducing ferroptosis. Considering that cancer cells are often characterized by elevated intracellular polyamine pools, our results indicate that polyamine metabolism exposes a targetable vulnerability to ferroptosis and represents an exciting opportunity for therapeutic strategies for cancer.
Topics: Humans; Polyamines; Ferroptosis; Hydrogen Peroxide; Cell Line, Tumor; Arginine; Iron Overload; Neoplasms
PubMed: 38504107
DOI: 10.1038/s41467-024-46776-w -
Natural Product Reports Apr 2024Covering: 2005 to August, 2023Polyamine-containing natural products (NPs) have been isolated from a wide range of terrestrial and marine organisms and most of them... (Review)
Review
Covering: 2005 to August, 2023Polyamine-containing natural products (NPs) have been isolated from a wide range of terrestrial and marine organisms and most of them exhibit remarkable and diverse activities, including antimicrobial, antiprotozoal, antiangiogenic, antitumor, antiviral, iron-chelating, anti-depressive, anti-inflammatory, insecticidal, antiobesity, and antioxidant properties. Their extraordinary activities and potential applications in human health and agriculture attract increasing numbers of studies on polyamine-containing NPs. In this review, we summarized the source, structure, classification, bioactivities and biosynthesis of polyamine-containing NPs, focusing on the biosynthetic mechanism of polyamine itself and representative polyamine alkaloids, polyamine-containing siderophores with catechol/hydroxamate/hydroxycarboxylate groups, nonribosomal peptide-(polyketide)-polyamine (NRP-(PK)-PA), and NRP-PK-long chain poly-fatty amine (lcPFAN) hybrid molecules.
Topics: Alkaloids; Anti-Infective Agents; Antineoplastic Agents; Biological Products; Molecular Structure; Polyamines; Siderophores
PubMed: 37873660
DOI: 10.1039/d2np00087c