bims-polyam 2024-11-24 papers

Issue of 2024–11–24
five papers selected by
Sebastian J. Hofer, University of Graz

PLoS Pathog. 2024 Nov 18. 20(11): e1012711

Polyamines mediate cellular energetics and lipid metabolism through mitochondrial respiration to facilitate virus replication.

Yazmin E Cruz-Pulido, Natalie J LoMascolo, Delaina May, Jomana Hatahet, Caroline E Thomas, Andrea K W Chu, Samantha P Stacey, Maria Del Mar Villanueva Guzman, Gregory Aubert, Bryan C Mounce.

Polyamines are critical cellular components that regulate a variety of processes, including translation, cell cycling, and nucleic acid metabolism. The polyamines, putrescine, spermidine, and spermine, are found abundantly within cells and are positively-charged at physiological pH. Polyamine metabolism is connected to distinct other metabolic pathways, including nucleotide and amino acid metabolism. However, the breadth of the effect of polyamines on cellular metabolism remains to be fully understood. We recently demonstrated a role for polyamines in cholesterol metabolism, and following these studies, we measured the impact of polyamines on global lipid metabolism. We find that lipid droplets increase in number and size with polyamine depletion. We further demonstrate that lipid anabolism is markedly decreased, and lipid accumulation is due to reduced mitochondrial fatty acid oxidation. In fact, mitochondrial structure and function are largely ablated with polyamine depletion. To compensate, cells depleted of polyamines switch from aerobic respiration to glycolysis in a polyamine depletion-mediated Warburg-like effect. Finally, we show that inhibitors of lipid metabolism are broadly antiviral, suggesting that polyamines and lipids are promising antiviral targets. Together, these data demonstrate a novel role for polyamines in mitochondrial function, lipid metabolism, and cellular energetics.

DOI: https://doi.org/10.1371/journal.ppat.1012711

J Clin Invest. 2024 Nov 19. pii: e177824. [Epub ahead of print]

Tumor cell-derived spermidine promotes a pro-tumorigenic immune microenvironment in glioblastoma via CD8+ T cell inhibition.

The glioblastoma (GBM) microenvironment is enriched in immunosuppressive factors that potently interfere with the function of cytotoxic T lymphocytes. Cancer cells can directly impact the immune system, but the mechanisms driving these interactions are not completely clear. Here we demonstrate that the polyamine metabolite spermidine (SPD) is elevated in the GBM tumor microenvironment. Exogenous administration of SPD drives tumor aggressiveness in an immune-dependent manner in pre-clinical mouse models via reduction of CD8+ T cell frequency and reduced cytotoxic function. Knockdown of ornithine decarboxylase, the rate-limiting enzyme in spermidine synthesis, did not impact cancer cell growth in vitro but did result in extended survival. Furthermore, glioblastoma patients with a more favorable outcome had a significant reduction in spermidine compared to patients with a poor prognosis. Our results demonstrate that spermidine functions as a cancer cell-derived metabolite that drives tumor progression by reducing CD8+ T cell number and function.

Keywords: Adaptive immunity; Brain cancer; Immunology; Oncology; Polyamines

DOI: https://doi.org/10.1172/JCI177824

ACS Infect Dis. 2024 Nov 19.

Polyamine-Enriched Exosomes from Leishmania donovani Drive Host Macrophage Polarization via Immunometabolism Reprogramming.

Prince Sebastian, Madhulika Namdeo, Moodu Devender, Anjali Anand, Krishan Kumar, Jalaja Veronica, Radheshyam Maurya.

Leishmania donovani (Ld) promastigotes secrete exosomes that are crucial in host-pathogen interactions and intercellular communication by carrying parasite-specific molecules. Although the composition of cargos in Leishmania exosomes is known, the effects of the unique metabolic repertoire on immunometabolism rewiring of macrophage polarization are poorly understood. Interestingly, we found the enrichment of polyamines (PAs) such as spermidine and putrescine in the Ld-exosomes. Herein, we investigate the critical polycationic molecules and their crucial role in parasite survival. Our study shows that PA inhibition or depletion significantly impairs parasite growth and fitness, particularly in drug-resistant strains. Furthermore, we aimed to elucidate the impact of PAs-enriched Ld-exosomes on host macrophages. The data demonstrated that macrophages efficiently internalized these exosomes, leading to heightened phagocytic activity and infectivity. In addition, internalized Ld-exosomes induced M2 macrophage polarization characterized by elevated Arginase-1 expression and activity. The increased expression of the solute carrier gene (SLC3A2) and elevated intracellular spermidine levels suggest that Ld-exosomes contribute to the host PAs pool and create an anti-inflammatory milieu. These findings highlight the essential role of PAs-enriched Ld-exosomes in parasite survival and establishing a pro-parasitic environment in the host macrophage.

Keywords: Anti-inflammatory; Arginase-1; Exosomes; Immunometabolism; Macrophage polarization; Polyamines

DOI: https://doi.org/10.1021/acsinfecdis.4c00738

Nutr Res. 2024 Oct 23. pii: S0271-5317(24)00141-6. [Epub ahead of print]132 125-135

Absorption, anti-inflammatory, antioxidant, and cardioprotective impacts of a novel fasting mimetic containing spermidine, nicotinamide, palmitoylethanolamide, and oleoylethanolamide: A pilot dose-escalation study in healthy young adult men.

Christopher H Rhodes, Brian V Hong, Xinyu Tang, Cheng-Yu Weng, Jea Woo Kang, Joanne K Agus, Carlito B Lebrilla, Angela M Zivkovic.

This pilot dose-escalation study evaluated the absorption and metabolism of a novel fasting mimetic formulation containing spermidine, nicotinamide, palmitoylethanolamide (PEA), and oleoylethanolamide (OEA) taken as oral supplements in young adults. Five healthy men consumed a standardized breakfast, followed by control (wheat flour) or low, medium, or high doses of supplements containing spermidine, nicotinamide, PEA, and OEA 2 hours later. Blood was drawn at 0, 1, 2, and 4 hours after the supplement (2, 3, 4, and 6 hours postprandial). Plasma concentrations of spermidine, 1-methylnicotinamide, PEA and OEA were quantified by liquid chromatography-mass spectrometry. The secretion of tumor necrosis factor alpha and production of reactive oxygen species by stimulated macrophages incubated with plasma, and cholesterol efflux capacity of plasma were analyzed. Plasma 1-methylnicotinamide, PEA, and OEA concentrations increased after supplement intake (P < .05). Spermidine concentrations decreased in the control arm (P < .05) but not the supplement arms. Net incremental area under the curve for tumor necrosis factor alpha and reactive oxygen species in stimulated macrophages decreased when incubated with plasma following supplement intake (P < .05). Intake of the combined supplements showed they were bioavailable and increased in plasma in a dose-dependent manner and provide preliminary data showing enhanced plasma anti-inflammatory and antioxidant functions. This trial was registered at clinicaltrials.gov (NCT05017428).

Keywords: 1-methlynicotinamide; Anti-inflammatory; Antioxidant; Cholesterol efflux capacity (CEC); Nicotinamide; OEA; Oleoylethanolamide; PEA; Palmitoylethanolamide; Postprandial inflammation; Spermidine

DOI: https://doi.org/10.1016/j.nutres.2024.10.006

Discov Oncol. 2024 Nov 16. 15(1): 666

Single-cell expression and immune infiltration analysis of polyamine metabolism in breast cancer.

Xiliang Zhang, Hanjie Guo, Xiaolong Li, Wei Tao, Xiaoqing Ma, Yuxing Zhang, Weidong Xiao.

Breast cancer is one of the most threatening women health diseases worldwide and its molecular heterogeneity offers a range of response to therapy. The role of polyamine metabolism is receiving increasing attention. Polyamine metabolism not only plays an important role in the occurrence and development of breast cancer, but also interacts with tumor immune microenvironment. In this work, we applied single-cell RNA-sequencing (scRNA-seq) and systems immunological approaches to interrogate immune cell infiltration gene-to-gene co-expressions in the bulk tumor transcriptomes of breast cancer. We acquired breast cancer sample data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), evaluated the infiltration status of 22 immune cell types using CIBERSORTx tool, respectively. By leveraging the Retrospective Breast sample of various technologies including gene expression and methylation, we identified 46 breast cancer proliferation-associated co-expression modules using weighted gene coexpression network analysis (WGCNA) approach along with machine learning models which in turn delineated single cell level expressions features that these selected module possessed. We observed substantial cellular heterogeneity in the breast cancer microenvironment, where lineage-specific gene expression patterns were highly associated with tumor progression. Moreover, we also identified the gene modules correlated with immune cell infiltration level that could function as regulators in response to tumors for immune therapy. Moreover, risk scores were correlated with immune cell function in different patient groups defined by high- and low-risk. The findings of this study shed a new light upon molecular classification prognostic assessment and personalized treatment in breast cancer.

Keywords: Breast cancer; Gene co-expression network; Immune microenvironment; Machine learning; Personalized treatment; Single-cell RNA sequencing

DOI: https://doi.org/10.1007/s12672-024-01524-w