bims-mepmim 2024-09-29 papers

bims-mepmim

Biomed News

on Metabolites in pathological microenvironments and immunometabolism

Issue of 2024‒09‒29
twenty papers selected by
Erika Mariana Palmieri, NIH/NCI Laboratory of Cancer ImmunoMetabolism

Geranylgeranylated SCFFBXO10 regulates selective outer mitochondrial membrane proteostasis and function.
Myeloid beta-arrestin 2 depletion attenuates metabolic dysfunction-associated steatohepatitis via the metabolic reprogramming of macrophages.
Loss of embryonically-derived Kupffer cells during hypercholesterolemia accelerates atherosclerosis development.
Metabolic reprogramming of hypoxic tumor-associated macrophages through CSF-1R targeting favors treatment efficiency in colorectal cancers.
Inhibition of hepatic oxalate overproduction ameliorates metabolic dysfunction-associated steatohepatitis.
Specific activation of the integrated stress response uncovers regulation of central carbon metabolism and lipid droplet biogenesis.
The emerging role of ethanolamine phosphate phospholyase in regulating hepatic phosphatidylethanolamine and plasma lipoprotein metabolism in mice.
Phages reconstitute NAD+ to counter bacterial immunity.
Damaging mutations in liver X receptor-α are hepatotoxic and implicate cholesterol sensing in liver health.
Notch signaling regulates macrophage-mediated inflammation in metabolic dysfunction-associated steatotic liver disease.
Deficiency of metabolic regulator PKM2 activates the pentose phosphate pathway and generates TCF1+ progenitor CD8+ T cells to improve immunotherapy.
Interleukin-34-orchestrated tumor-associated macrophage reprogramming is required for tumor immune escape driven by p53 inactivation.
Pyruvate metabolism dictates fibroblast sensitivity to GLS1 inhibition during fibrogenesis.
Loss of synovial tissue macrophage homeostasis precedes rheumatoid arthritis clinical onset.
A transmitochondrial sodium gradient controls membrane potential in mammalian mitochondria.
Crosstalk between butyrate oxidation in colonocyte and butyrate-producing bacteria.
Extracellular vesicle transfer of miR-1 to adipose tissue modifies lipolytic pathways following resistance exercise.
Spermidine metabolism regulates leukemia stem and progenitor cell function through KAT7 expression in patient-derived mouse models.
Lysosomes in the immunometabolic reprogramming of immune cells in atherosclerosis.
Glutathione peroxidase 3 is essential for countering senescence in adipose remodelling by maintaining mitochondrial homeostasis.

Cell Rep. 2024 Sep 21. pii: S2211-1247(24)01134-3. [Epub ahead of print]43(10): 114783

Geranylgeranylated SCFFBXO10 regulates selective outer mitochondrial membrane proteostasis and function.

Sameer Ahmed Bhat, Zahra Vasi, Liping Jiang, Shruthi Selvaraj, Rachel Ferguson, Sanaz Salarvand, Anish Gudur, Ritika Adhikari, Veronica Castillo, Hagar Ismail, Avantika Dhabaria, Beatrix Ueberheide, Shafi Kuchay.

  Compartment-specific cellular membrane protein turnover is not well understood. We show that FBXO10, the interchangeable component of the cullin-RING-ligase 1 complex, undergoes lipid modification with geranylgeranyl isoprenoid at cysteine953, facilitating its dynamic trafficking to the outer mitochondrial membrane (OMM). FBXO10 polypeptide lacks a canonical mitochondrial targeting sequence (MTS); instead, its geranylgeranylation at C953 and interaction with two cytosolic factors, cytosolic factor-like δ subunit of type 6 phosphodiesterase (PDE6δ; a prenyl-group-binding protein) and heat shock protein 90 (HSP90; a chaperone), orchestrate specific OMM targeting of prenyl-FBXO10. The FBXO10(C953S) mutant redistributes away from the OMM, impairs mitochondrial ATP production and membrane potential, and increases fragmentation. Phosphoglycerate mutase-5 (PGAM5) was identified as a potential substrate of FBXO10 at the OMM using comparative quantitative proteomics of enriched mitochondria. FBXO10 loss or expression of prenylation-deficient FBXO10(C953S) inhibited PGAM5 degradation, disrupted mitochondrial homeostasis, and impaired myogenic differentiation of human induced pluripotent stem cells (iPSCs) and murine myoblasts. Our studies identify a mechanism for FBXO10-mediated regulation of selective mitochondrial proteostasis potentially amenable to therapeutic intervention.

Keywords:  CP: Metabolism; CP: Molecular biology; E3-ligase; F-box protein; FBXO10; HSP90; PDE6δ; mitochondria; prenylation; trafficking; ubiquitination

DOI:  https://doi.org/10.1016/j.celrep.2024.114783
Cell Metab. 2024 Sep 17. pii: S1550-4131(24)00362-0. [Epub ahead of print]

Myeloid beta-arrestin 2 depletion attenuates metabolic dysfunction-associated steatohepatitis via the metabolic reprogramming of macrophages.

Xiaoli Wei, Dongqing Wu, Jing Li, Miaomiao Wu, Qianhui Li, Zhaodi Che, Xu Cheng, Qianying Cheng, Fan Yin, Hao Zhang, Xuefu Wang, Shabnam Abtahi, Li Zuo, Lei Hang, Lili Ma, Wei-Ting Kuo, Xiaoying Liu, Jerrold R Turner, Hua Wang, Jia Xiao, Fei Wang.

  Macrophage-mediated inflammation has been implicated in the pathogenesis of metabolic dysfunction-associated steatohepatitis (MASH); however, the immunometabolic program underlying the regulation of macrophage activation remains unclear. Beta-arrestin 2, a multifunctional adaptor protein, is highly expressed in bone marrow tissues and macrophages and is involved in metabolism disorders. Here, we observed that β-arrestin 2 expression was significantly increased in the liver macrophages and circulating monocytes of patients with MASH compared with healthy controls and positively correlated with the severity of metabolic dysfunction-associated steatotic liver disease (MASLD). Global or myeloid Arrb2 deficiency prevented the development of MASH in mice. Further study showed that β-arrestin 2 acted as an adaptor protein and promoted ubiquitination of immune responsive gene 1 (IRG1) to prevent increased itaconate production in macrophages, which resulted in enhanced succinate dehydrogenase activity, thereby promoting the release of mitochondrial reactive oxygen species and M1 polarization. Myeloid β-arrestin 2 depletion may be a potential approach for MASH.

Keywords:  IRG1; MASLD; itaconate; macrophage polarization; metabolic reprogramming; β-arrestin 2

DOI:  https://doi.org/10.1016/j.cmet.2024.08.010
Nat Commun. 2024 Sep 27. 15(1): 8341

Loss of embryonically-derived Kupffer cells during hypercholesterolemia accelerates atherosclerosis development.

Rebecca Fima, Sébastien Dussaud, Cheïma Benbida, Margault Blanchet, François Lanthiez, Lucie Poupel, Claudia Brambilla, Adélaïde Gélineau, Mattia Dessena, Marina Blanc, Cédric Lerévérend, Martine Moreau, Alexandre Boissonnas, Emmanuel L Gautier, Thierry Huby.

Hypercholesterolemia is a major risk factor for atherosclerosis and associated cardiovascular diseases. The liver plays a key role in the regulation of plasma cholesterol levels and hosts a large population of tissue-resident macrophages known as Kupffer cells (KCs). KCs are located in the hepatic sinusoids where they ensure key functions including blood immune surveillance. However, how KCs homeostasis is affected by the build-up of cholesterol-rich lipoproteins that occurs in the circulation during hypercholesterolemia remains unknown. Here, we show that embryo-derived KCs (EmKCs) accumulate large amounts of lipoprotein-derived cholesterol, in part through the scavenger receptor CD36, and massively expand early after the induction of hypercholesterolemia. After this rapid adaptive response, EmKCs exhibit mitochondrial oxidative stress and their numbers gradually diminish while monocyte-derived KCs (MoKCs) with reduced cholesterol-loading capacities seed the KC pool. Decreased proportion of EmKCs in the KC pool enhances liver cholesterol content and exacerbates hypercholesterolemia, leading to accelerated atherosclerotic plaque development. Together, our data reveal that KC homeostasis is perturbed during hypercholesterolemia, which in turn alters the control of plasma cholesterol levels and increases atherosclerosis.

DOI: https://doi.org/10.1038/s41467-024-52735-2
J Immunother Cancer. 2024 Sep 24. pii: e009602. [Epub ahead of print]12(9):

Metabolic reprogramming of hypoxic tumor-associated macrophages through CSF-1R targeting favors treatment efficiency in colorectal cancers.

Khaldoun Gharzeddine, Cristina Gonzalez Prieto, Marie Malier, Clara Hennot, Renata Grespan, Yoshiki Yamaryo-Botté, Cyrille Y Botté, Fabienne Thomas, Marie-Hélène Laverriere, Edouard Girard, Gael Roth, Arnaud Millet.

  BACKGROUND: Tumor-associated macrophages participate in the complex network of support that favors tumor growth. Among the various strategies that have been developed to target these cells, the blockade of the colony-stimulating factor 1 receptor (CSF-1R) receptor is one of the most promising ones. Here, we characterize the resulting state of human macrophages exposed to a CSF-1R kinase inhibitor.METHODS: Using RNA sequencing and metabolomics approach, we characterize the reprogramming of human monocyte-derived macrophages under CSF-1R targeting.
RESULTS: We find that CSF-1R receptor inhibition in human macrophages is able to impair cholesterol synthesis, fatty acid metabolism and hypoxia-driven expression of dihydropyrimidine dehydrogenase, an enzyme responsible for the 5-fluorouracil macrophage-mediated chemoresistance. We show that this inhibition of the CSF-1R receptor leads to a downregulation of the expression of sterol regulatory element-binding protein 2, a transcription factor that controls cholesterol and fatty acid synthesis. We also show that the inhibition of extracellular signal-regulated kinase 1/2 phosphorylation resulting from targeting the CSF-1R receptor destabilizes the expression of hypoxic induced factor 2 alpha in hypoxia resulting in the downregulation of dihydropyrimidine dehydrogenase expression restoring the sensitivity to 5-fluorouracil in colorectal cancer.
CONCLUSIONS: These results reveal the unexpected metabolic rewiring resulting from the CSF-1R receptor targeting of human macrophages and its potential to reverse macrophage-mediated chemoresistance in colorectal tumors.

Keywords:  Chemotherapy; Cholesterol; Colorectal Cancer; Macrophage; Tumor microenvironment - TME

DOI:  https://doi.org/10.1136/jitc-2024-009602
Nat Metab. 2024 Sep 27.

Inhibition of hepatic oxalate overproduction ameliorates metabolic dysfunction-associated steatohepatitis.

Sandeep Das, Alexandra C Finney, Sumit Kumar Anand, Sumati Rohilla, Yuhao Liu, Nilesh Pandey, Alia Ghrayeb, Dhananjay Kumar, Kelley Nunez, Zhipeng Liu, Fabio Arias, Ying Zhao, Brenna H Pearson-Gallion, M Peyton McKinney, Koral S E Richard, Jose A Gomez-Vidal, Chowdhury S Abdullah, Elizabeth D Cockerham, Joseph Eniafe, Andrew D Yurochko, Tarek Magdy, Christopher B Pattillo, Christopher G Kevil, Babak Razani, Md Shenuarin Bhuiyan, Erin H Seeley, Gretchen E Galliano, Bo Wei, Lin Tan, Iqbal Mahmud, Ida Surakka, Minerva T Garcia-Barrio, Philip L Lorenzi, Eyal Gottlieb, Eduardo Salido, Jifeng Zhang, A Wayne Orr, Wanqing Liu, Monica Diaz-Gavilan, Y Eugene Chen, Nirav Dhanesha, Paul T Thevenot, Ari J Cohen, Arif Yurdagul, Oren Rom.

The incidence of metabolic dysfunction-associated steatohepatitis (MASH) is on the rise, and with limited pharmacological therapy available, identification of new metabolic targets is urgently needed. Oxalate is a terminal metabolite produced from glyoxylate by hepatic lactate dehydrogenase (LDHA). The liver-specific alanine-glyoxylate aminotransferase (AGXT) detoxifies glyoxylate, preventing oxalate accumulation. Here we show that AGXT is suppressed and LDHA is activated in livers from patients and mice with MASH, leading to oxalate overproduction. In turn, oxalate promotes steatosis in hepatocytes by inhibiting peroxisome proliferator-activated receptor-α (PPARα) transcription and fatty acid β-oxidation and induces monocyte chemotaxis via C-C motif chemokine ligand 2. In male mice with diet-induced MASH, targeting oxalate overproduction through hepatocyte-specific AGXT overexpression or pharmacological inhibition of LDHA potently lowers steatohepatitis and fibrosis by inducing PPARα-driven fatty acid β-oxidation and suppressing monocyte chemotaxis, nuclear factor-κB and transforming growth factor-β targets. These findings highlight hepatic oxalate overproduction as a target for the treatment of MASH.

DOI: https://doi.org/10.1038/s42255-024-01134-4
Nat Commun. 2024 Sep 27. 15(1): 8301

Specific activation of the integrated stress response uncovers regulation of central carbon metabolism and lipid droplet biogenesis.

Katherine Labbé, Lauren LeBon, Bryan King, Ngoc Vu, Emily H Stoops, Nina Ly, Austin E Y T Lefebvre, Phillip Seitzer, Swathi Krishnan, Jin-Mi Heo, Bryson Bennett, Carmela Sidrauski.

The integrated stress response (ISR) enables cells to cope with a variety of insults, but its specific contribution to downstream cellular outputs remains unclear. Using a synthetic tool, we selectively activate the ISR without co-activation of parallel pathways and define the resulting cellular state with multi-omics profiling. We identify time- and dose-dependent gene expression modules, with ATF4 driving only a small but sensitive subgroup that includes amino acid metabolic enzymes. This ATF4 response affects cellular bioenergetics, rerouting carbon utilization towards amino acid production and away from the tricarboxylic acid cycle and fatty acid synthesis. We also find an ATF4-independent reorganization of the lipidome that promotes DGAT-dependent triglyceride synthesis and accumulation of lipid droplets. While DGAT1 is the main driver of lipid droplet biogenesis, DGAT2 plays an essential role in buffering stress and maintaining cell survival. Together, we demonstrate the sufficiency of the ISR in promoting a previously unappreciated metabolic state.

DOI: https://doi.org/10.1038/s41467-024-52538-5
FASEB J. 2024 Sep 30. 38(18): e70063

The emerging role of ethanolamine phosphate phospholyase in regulating hepatic phosphatidylethanolamine and plasma lipoprotein metabolism in mice.

Kholoud A Elmihi, Kelly-Ann Leonard, Randy Nelson, Aducio Thiesen, Robin D Clugston, René L Jacobs.

  Ethanolamine phosphate phospholyase (ETNPPL) is an enzyme that irreversibly degrades phospho-ethanolamine (p-ETN), an intermediate in the Kennedy pathway of phosphatidylethanolamine (PE) biosynthesis. PE is the second most abundant phospholipid in mammalian membranes. Disturbance of hepatic phospholipid homeostasis has been linked to the development of metabolic dysfunction-associated steatotic liver disease (MASLD). We generated whole-body Etnppl knockout mice to investigate the impact of genetic deletion of Etnppl on hepatic lipid metabolism. Primary hepatocytes isolated from Etnppl-/- mice showed increased conversion of [3H]ethanolamine to [3H]p-ETN and [3H]PE compared to Etnppl+/+ mice. Male and female Etnppl+/+ and Etnppl-/- mice were fed either a chow or a western-type diet (WTD). Irrespective of diet, Etnppl-/- mice had elevated fasting levels of total plasma cholesterol, triglyceride (TG) and apolipoprotein B100 (VLDL particles). Interestingly, hepatic TG secretion was unchanged between groups. Although hepatic lipids (phosphatidylcholine (PC), PE, TG, and cholesterol) were not different between mice, RNA sequencing analysis showed downregulation in genes related to cholesterol biosynthesis in Etnppl-/- mice. Furthermore, hepatic low-density lipoprotein receptor-related protein1 (LRP1) protein level was lower in female Etnppl-/- mice, which may indicate reduced uptake of remnant VLDL particles from circulation. Hepatic PE levels were only increased in WTD-fed female Etnppl-/- mice, not chow diet-fed mice. However, hepatic lipid accumulation and metabolic dysfunction-associated steatohepatitis (MASH) development were unchanged between Etnppl+/+ and Etnppl-/- mice. To conclude, ETNPPL has a role in regulating plasma lipoprotein metabolism independent of hepatic TG levels.

Keywords:  ETNPPL; fatty liver; phosphatidylethanolamine; phospho‐ethanolamine; plasma cholesterol; very low‐density lipoprotein; western‐type diet

DOI:  https://doi.org/10.1096/fj.202401321R
Nature. 2024 Sep 25.

Phages reconstitute NAD+ to counter bacterial immunity.

Ilya Osterman, Hadar Samra, Francois Rousset, Elena Loseva, Maxim Itkin, Sergey Malitsky, Erez Yirmiya, Adi Millman, Rotem Sorek.

Bacteria defend against phage infection through a variety of antiphage defence systems1. Many defence systems were recently shown to deplete cellular nicotinamide adenine dinucleotide (NAD+) in response to infection, by cleaving NAD+ into ADP-ribose (ADPR) and nicotinamide2-7. It was demonstrated that NAD+ depletion during infection deprives the phage of this essential molecule and impedes phage replication. Here we show that a substantial fraction of phages possess enzymatic pathways allowing reconstitution of NAD+ from its degradation products in infected cells. We describe NAD+ reconstitution pathway 1 (NARP1), a two-step pathway in which one enzyme phosphorylates ADPR to generate ADPR pyrophosphate (ADPR-PP), and the second enzyme conjugates ADPR-PP and nicotinamide to generate NAD+. Phages encoding NARP1 can overcome a diverse set of defence systems, including Thoeris, DSR1, DSR2, SIR2-HerA and SEFIR, all of which deplete NAD+ as part of their defensive mechanism. Phylogenetic analyses show that NARP1 is primarily encoded on phage genomes, suggesting a phage-specific function in countering bacterial defences. A second pathway, NARP2, allows phages to overcome bacterial defences by building NAD+ using metabolites different from ADPR-PP. Our findings reveal a unique immune evasion strategy in which viruses rebuild molecules depleted by defence systems, thus overcoming host immunity.

DOI: https://doi.org/10.1038/s41586-024-07986-w
Nat Metab. 2024 Sep 25.

Damaging mutations in liver X receptor-α are hepatotoxic and implicate cholesterol sensing in liver health.

Sam M Lockhart, Milan Muso, Ilona Zvetkova, Brian Y H Lam, Alessandra Ferrari, Erik Schoenmakers, Katie Duckett, Jack Leslie, Amy Collins, Beatriz Romartínez-Alonso, John A Tadross, Raina Jia, Eugene J Gardner, Katherine Kentistou, Yajie Zhao, Felix Day, Alexander Mörseburg, Kara Rainbow, Debra Rimmington, Matteo Mastantuoni, James Harrison, Meritxell Nus, Khalid Guma'a, Sam Sherratt-Mayhew, Xiao Jiang, Katherine R Smith, Dirk S Paul, Benjamin Jenkins, Albert Koulman, Maik Pietzner, Claudia Langenberg, Nicholas Wareham, Giles S Yeo, Krishna Chatterjee, John Schwabe, Fiona Oakley, Derek A Mann, Peter Tontonoz, Anthony P Coll, Ken Ong, John R B Perry, Stephen O'Rahilly.

Liver X receptor-α (LXRα) regulates cellular cholesterol abundance and potently activates hepatic lipogenesis. Here we show that at least 1 in 450 people in the UK Biobank carry functionally impaired mutations in LXRα, which is associated with biochemical evidence of hepatic dysfunction. On a western diet, male and female mice homozygous for a dominant negative mutation in LXRα have elevated liver cholesterol, diffuse cholesterol crystal accumulation and develop severe hepatitis and fibrosis, despite reduced liver triglyceride and no steatosis. This phenotype does not occur on low-cholesterol diets and can be prevented by hepatocyte-specific overexpression of LXRα. LXRα knockout mice exhibit a milder phenotype with regional variation in cholesterol crystal deposition and inflammation inversely correlating with steatosis. In summary, LXRα is necessary for the maintenance of hepatocyte health, likely due to regulation of cellular cholesterol content. The inverse association between steatosis and both inflammation and cholesterol crystallization may represent a protective action of hepatic lipogenesis in the context of excess hepatic cholesterol.

DOI: https://doi.org/10.1038/s42255-024-01126-4
Immunity. 2024 Sep 19. pii: S1074-7613(24)00414-X. [Epub ahead of print]

Notch signaling regulates macrophage-mediated inflammation in metabolic dysfunction-associated steatotic liver disease.

Wei Guo, Ziyi Li, Gerasimos Anagnostopoulos, Wan Ting Kong, Shuangyan Zhang, Svetoslav Chakarov, Amanda Shin, Jiawen Qian, Yiwen Zhu, Wenjuan Bai, Olivier Cexus, Bin'en Nie, Jing Wang, Xiaoyu Hu, Camille Blériot, Zhaoyuan Liu, Baiyong Shen, Nicolas Venteclef, Bing Su, Florent Ginhoux.

  The liver macrophage population comprises resident Kupffer cells (KCs) and monocyte-derived macrophages with distinct pro- or anti-inflammatory properties that affect the severity and course of liver diseases. The mechanisms underlying macrophage differentiation and functions in metabolic dysfunction-associated steatotic liver disease and/or steatohepatitis (MASLD/MASH) remain mostly unknown. Using single-cell RNA sequencing (scRNA-seq) and fate mapping of hepatic macrophage subpopulations, we unraveled the temporal and spatial dynamics of distinct monocyte and monocyte-derived macrophage subsets in MASH. We revealed a crucial role for the Notch-Recombination signal binding protein for immunoglobulin kappa J region (RBPJ) signaling pathway in controlling the monocyte-to-macrophage transition, with Rbpj deficiency blunting inflammatory macrophages and monocyte-derived KC differentiation and conversely promoting the emergence of protective Ly6Clo monocytes. Mechanistically, Rbpj deficiency promoted lipid uptake driven by elevated CD36 expression in Ly6Clo monocytes, enhancing their protective interactions with endothelial cells. Our findings uncover the crucial role of Notch-RBPJ signaling in monocyte-to-macrophage transition and will aid in the design of therapeutic strategies for MASH treatment.

Keywords:  Kupffer cell; Ly6C(hi) monocyte; Ly6C(lo) monocyte; MASH; Notch; RBPJ; inflammation; liver; macrophage; monocyte

DOI:  https://doi.org/10.1016/j.immuni.2024.08.016
Nat Immunol. 2024 Oct;25(10): 1884-1899

Deficiency of metabolic regulator PKM2 activates the pentose phosphate pathway and generates TCF1+ progenitor CD8+ T cells to improve immunotherapy.

Geoffrey J Markowitz, Yi Ban, Diamile A Tavarez, Liron Yoffe, Enrique Podaza, Yongfeng He, Mitchell T Martin, Michael J P Crowley, Tito A Sandoval, Dingcheng Gao, M Laura Martin, Olivier Elemento, Juan R Cubillos-Ruiz, Timothy E McGraw, Nasser K Altorki, Vivek Mittal.

TCF1high progenitor CD8+ T cells mediate the efficacy of immunotherapy; however, the mechanisms that govern their generation and maintenance are poorly understood. Here, we show that targeting glycolysis through deletion of pyruvate kinase muscle 2 (PKM2) results in elevated pentose phosphate pathway (PPP) activity, leading to enrichment of a TCF1high progenitor-exhausted-like phenotype and increased responsiveness to PD-1 blockade in vivo. PKM2KO CD8+ T cells showed reduced glycolytic flux, accumulation of glycolytic intermediates and PPP metabolites and increased PPP cycling as determined by 1,2-13C glucose carbon tracing. Small molecule agonism of the PPP without acute glycolytic impairment skewed CD8+ T cells toward a TCF1high population, generated a unique transcriptional landscape and adoptive transfer of agonist-treated CD8+ T cells enhanced tumor control in mice in combination with PD-1 blockade and promoted tumor killing in patient-derived tumor organoids. Our study demonstrates a new metabolic reprogramming that contributes to a progenitor-like T cell state promoting immunotherapy efficacy.

DOI: https://doi.org/10.1038/s41590-024-01963-1
Immunity. 2024 Sep 14. pii: S1074-7613(24)00415-1. [Epub ahead of print]

Interleukin-34-orchestrated tumor-associated macrophage reprogramming is required for tumor immune escape driven by p53 inactivation.

Zhigang Nian, Yingchao Dou, Yiqing Shen, Jintang Liu, Xianghui Du, Yong Jiang, Yonggang Zhou, Binqing Fu, Rui Sun, Xiaohu Zheng, Zhigang Tian, Haiming Wei.

  As the most frequent genetic alteration in cancer, more than half of human cancers have p53 mutations that cause transcriptional inactivation. However, how p53 modulates the immune landscape to create a niche for immune escape remains elusive. We found that cancer stem cells (CSCs) established an interleukin-34 (IL-34)-orchestrated niche to promote tumorigenesis in p53-inactivated liver cancer. Mechanistically, we discovered that Il34 is a gene transcriptionally repressed by p53, and p53 loss resulted in IL-34 secretion by CSCs. IL-34 induced CD36-mediated elevations in fatty acid oxidative metabolism to drive M2-like polarization of foam-like tumor-associated macrophages (TAMs). These IL-34-orchestrated TAMs suppressed CD8+ T cell-mediated antitumor immunity to promote immune escape. Blockade of the IL-34-CD36 axis elicited antitumor immunity and synergized with anti-PD-1 immunotherapy, leading to a complete response. Our findings reveal the underlying mechanism of p53 modulation of the tumor immune microenvironment and provide a potential target for immunotherapy of cancer with p53 inactivation.

Keywords:  CD36; IL-34; cancer stem cell; foam-like macrophage; immune checkpoint inhibitor; liver cancer; p53; tumor immune escape; tumor immune microenvironment; tumor-associated macrophage

DOI:  https://doi.org/10.1016/j.immuni.2024.08.015
JCI Insight. 2024 Aug 13. pii: e178453. [Epub ahead of print]9(18):

Pyruvate metabolism dictates fibroblast sensitivity to GLS1 inhibition during fibrogenesis.

Greg Contento, Jo-Anne Am Wilson, Brintha Selvarajah, Manuela Platé, Delphine Guillotin, Valle Morales, Marcello Trevisani, Vanessa Pitozzi, Katiuscia Bianchi, Rachel C Chambers.

  Fibrosis is a chronic disease characterized by excessive extracellular matrix production, which leads to disruption of organ function. Fibroblasts are key effector cells of this process, responding chiefly to the pleiotropic cytokine transforming growth factor-β1 (TGF-β1), which promotes fibroblast to myofibroblast differentiation. We found that extracellular nutrient availability profoundly influenced the TGF-β1 transcriptome of primary human lung fibroblasts and that biosynthesis of amino acids emerged as a top enriched TGF-β1 transcriptional module. We subsequently uncovered a key role for pyruvate in influencing glutaminase (GLS1) inhibition during TGF-β1-induced fibrogenesis. In pyruvate-replete conditions, GLS1 inhibition was ineffective in blocking TGF-β1-induced fibrogenesis, as pyruvate can be used as the substrate for glutamate and alanine production via glutamate dehydrogenase (GDH) and glutamic-pyruvic transaminase 2 (GPT2), respectively. We further show that dual targeting of either GPT2 or GDH in combination with GLS1 inhibition was required to fully block TGF-β1-induced collagen synthesis. These findings embolden a therapeutic strategy aimed at additional targeting of mitochondrial pyruvate metabolism in the presence of a glutaminolysis inhibitor to interfere with the pathological deposition of collagen in the setting of pulmonary fibrosis and potentially other fibrotic conditions.

Keywords:  Cell biology; Collagens; Fibrosis; Glucose metabolism; Metabolism

DOI:  https://doi.org/10.1172/jci.insight.178453
Sci Adv. 2024 Sep 27. 10(39): eadj1252

Loss of synovial tissue macrophage homeostasis precedes rheumatoid arthritis clinical onset.

Megan M Hanlon, Conor M Smith, Mary Canavan, Nuno G B Neto, Qingxuan Song, Myles J Lewis, Aoife M O'Rourke, Orla Tynan, Brianne E Barker, Phil Gallagher, Ronan Mullan, Conor Hurson, Barry Moran, Michael G Monaghan, Costantino Pitzalis, Jean M Fletcher, Sunil Nagpal, Douglas J Veale, Ursula Fearon.

This study performed an in-depth investigation into the myeloid cellular landscape in the synovium of patients with rheumatoid arthritis (RA), "individuals at risk" of RA, and healthy controls (HC). Flow cytometric analysis demonstrated the presence of a CD40-expressing CD206+CD163+ macrophage population dominating the inflamed RA synovium, associated with disease activity and treatment response. In-depth RNA sequencing and metabolic analysis demonstrated that this macrophage population is transcriptionally distinct, displaying unique inflammatory and tissue-resident gene signatures, has a stable bioenergetic profile, and regulates stromal cell responses. Single-cell RNA sequencing profiling of 67,908 RA and HC synovial tissue cells identified nine transcriptionally distinct macrophage clusters. IL-1B+CCL20+ and SPP1+MT2A+ are the principal macrophage clusters in RA synovium, displaying heightened CD40 gene expression, capable of shaping stromal cell responses, and are importantly enriched before disease onset. Combined, these findings identify the presence of an early pathogenic myeloid signature that shapes the RA joint microenvironment and represents a unique opportunity for early diagnosis and therapeutic intervention.

DOI: https://doi.org/10.1126/sciadv.adj1252
Cell. 2024 Sep 17. pii: S0092-8674(24)00974-7. [Epub ahead of print]

A transmitochondrial sodium gradient controls membrane potential in mammalian mitochondria.

Pablo Hernansanz-Agustín, Carmen Morales-Vidal, Enrique Calvo, Paolo Natale, Yolanda Martí-Mateos, Sara Natalia Jaroszewicz, José Luis Cabrera-Alarcón, Rebeca Acín-Pérez, Iván López-Montero, Jesús Vázquez, José Antonio Enríquez.

  Eukaryotic cell function and survival rely on the use of a mitochondrial H+ electrochemical gradient (Δp), which is composed of an inner mitochondrial membrane (IMM) potential (ΔΨmt) and a pH gradient (ΔpH). So far, ΔΨmt has been assumed to be composed exclusively of H+. Here, using a rainbow of mitochondrial and nuclear genetic models, we have discovered that a Na+ gradient equates with the H+ gradient and controls half of ΔΨmt in coupled-respiring mammalian mitochondria. This parallelism is controlled by the activity of the long-sought Na+-specific Na+/H+ exchanger (mNHE), which we have identified as the P-module of complex I (CI). Deregulation of this mNHE function, without affecting the canonical enzymatic activity or the assembly of CI, occurs in Leber's hereditary optic neuropathy (LHON), which has profound consequences in ΔΨmt and mitochondrial Ca2+ homeostasis and explains the previously unknown molecular pathogenesis of this neurodegenerative disease.

Keywords:  LHON; Na(+) gradient; complex I; mitochondrial Na(+)/H(+) antiporter; ΔΨmt

DOI:  https://doi.org/10.1016/j.cell.2024.08.045
iScience. 2024 Sep 20. 27(9): 110853

Crosstalk between butyrate oxidation in colonocyte and butyrate-producing bacteria.

Bohye Park, Ji Yeon Kim, Olivia F Riffey, Triston J Walsh, Jeremiah Johnson, Dallas R Donohoe.

  The composition of gut microbiota, including butyrate-producing bacteria (BPB), is influenced by diet and physiological conditions. As such, given the importance of butyrate as an energetic substrate in colonocytes, it is unclear whether utilization of this substrate by the host would enhance BPB levels, thus defining a host-microbiome mutualistic relationship based on cellular metabolism. Here, it is shown through using a mouse model that lacks short-chain acyl dehydrogenase (SCAD), which is the first enzyme in the beta-oxidation pathway for short-chain fatty acids (SCFAs), that there is a significant diminishment in BPB at the phylum, class, species, and genus level compared to mice that have SCAD. Furthermore, SCAD-deficient mice do not show a prebiotic response from dietary fiber. Thus, oxidation of SCFAs by the host, which includes butyrate, is important in promoting BPB. These data help define the functional importance of diet-microbiome-host interactions toward microbiome composition, as it relates to function.

Keywords:  Biochemistry; Microbiology

DOI:  https://doi.org/10.1016/j.isci.2024.110853
JCI Insight. 2024 Sep 24. pii: e182589. [Epub ahead of print]

Extracellular vesicle transfer of miR-1 to adipose tissue modifies lipolytic pathways following resistance exercise.

Benjamin I Burke, Ahmed Ismaeel, Douglas E Long, Lauren A Depa, Peyton T Coburn, Jensen Goh, Tolulope P Saliu, Bonnie J Walton, Ivan J Vechetti, Bailey D Peck, Taylor R Valentino, C Brooks Mobley, Hasiyet Memetimin, Dandan Wang, Brian S Finlin, Philip A Kern, Charlotte A Peterson, John J McCarthy, Yuan Wen.

  Extracellular vesicles (EVs) have emerged as important mediators of inter-tissue signaling and exercise adaptations. In this human study (n = 32), we provide evidence that muscle-specific microRNA-1 (miR-1) was transferred to adipose tissue via EVs following an acute bout of resistance exercise. Using a multi-model machine learning automation tool, we discovered muscle primary miR-1 transcript and CD63+ EV count in circulation as top explanatory features for changes in adipose miR-1 levels in response to resistance exercise. RNA-sequencing (RNA-seq) and in-silico prediction of miR-1 target genes identified caveolin 2 (CAV2) and tripartite motif containing 6 (TRIM6) as miR-1 target genes downregulated in the adipose tissue of a subset of participants with the highest increases in miR-1 levels following resistance exercise (n = 6). Overexpression of miR-1 in differentiated human adipocyte-derived stem cells downregulated these miR-1 targets and enhanced catecholamine-induced lipolysis. These data identify a potential EV-mediated mechanism by which skeletal muscle communicates to adipose tissue and modulates lipolysis via miR-1.

Keywords:  Adipose tissue; Metabolism; Muscle biology; Skeletal muscle; Transport

DOI:  https://doi.org/10.1172/jci.insight.182589
Sci Transl Med. 2024 Sep 25. 16(766): eadn1285

Spermidine metabolism regulates leukemia stem and progenitor cell function through KAT7 expression in patient-derived mouse models.

Vincent Rondeau, Jacob M Berman, Tianyi Ling, Cristiana O'Brien, Rachel Culp-Hill, Julie A Reisz, Mark Wunderlich, Yun Chueh, Karina E Jiménez-Camacho, Christina Sexton, Katharine M Carter, Cody Stillwell, Jonathan St-Germain, Duhan Yendi, Aarushi Gupta, Mary Shi, Aleksandra Bourdine, Vikram R Paralkar, Soheil Jahangiri, Kristin J Hope, Anastasia N Tikhonova, Andrea Arruda, Mark D Minden, Brian Raught, Angelo D'Alessandro, Courtney L Jones.

Acute myeloid leukemia (AML) is a devastating disease initiated and maintained by a rare subset of cells called leukemia stem cells (LSCs). LSCs are responsible for driving disease relapse, making the development of new therapeutic strategies to target LSCs urgently needed. The use of mass spectrometry-based metabolomics profiling has enabled the discovery of unique and targetable metabolic properties in LSCs. However, we do not have a comprehensive understanding of metabolite differences between LSCs and their normal counterparts, hematopoietic stem and progenitor cells (HSPCs). In this study, we used an unbiased mass spectrometry-based metabolomics analysis to define differences in metabolites between primary human LSCs and HSPCs, which revealed that LSCs have a distinct metabolome. Spermidine was the most enriched metabolite in LSCs compared with HSPCs. Pharmacological reduction of spermidine concentrations decreased LSC function but spared normal HSPCs. Polyamine depletion also decreased leukemic burden in patient-derived xenografts. Mechanistically, spermidine depletion induced LSC myeloid differentiation by decreasing eIF5A-dependent protein synthesis, resulting in reduced expression of a select subset of proteins. KAT7, a histone acetyltransferase, was one of the top candidates identified to be down-regulated by spermidine depletion. Overexpression of KAT7 partially rescued polyamine depletion-induced decreased colony-forming ability, demonstrating that loss of KAT7 is an essential part of the mechanism by which spermidine depletion targets AML clonogenic potential. Together, we identified and mechanistically dissected a metabolic vulnerability of LSCs that has the potential to be rapidly translated into clinical trials to improve outcomes for patients with AML.

DOI: https://doi.org/10.1126/scitranslmed.adn1285
Nat Rev Cardiol. 2024 Sep 20.

Lysosomes in the immunometabolic reprogramming of immune cells in atherosclerosis.

Fabrizia Bonacina, Xiangyu Zhang, Nicolas Manel, Laurent Yvan-Charvet, Babak Razani, Giuseppe D Norata.

Lysosomes have a central role in the disposal of extracellular and intracellular cargo and also function as metabolic sensors and signalling platforms in the immunometabolic reprogramming of macrophages and other immune cells in atherosclerosis. Lysosomes can rapidly sense the presence of nutrients within immune cells, thereby switching from catabolism of extracellular material to the recycling of intracellular cargo. Such a fine-tuned degradative response supports the generation of metabolic building blocks through effectors such as mTORC1 or TFEB. By coupling nutrients to downstream signalling and metabolism, lysosomes serve as a crucial hub for cellular function in innate and adaptive immune cells. Lysosomal dysfunction is now recognized to be a hallmark of atherogenesis. Perturbations in nutrient-sensing and signalling have profound effects on the capacity of immune cells to handle cholesterol, perform phagocytosis and efferocytosis, and limit the activation of the inflammasome and other inflammatory pathways. Strategies to improve lysosomal function hold promise as novel modulators of the immunoinflammatory response associated with atherosclerosis. In this Review, we describe the crosstalk between lysosomal biology and immune cell function and polarization, with a particular focus on cellular immunometabolic reprogramming in the context of atherosclerosis.

DOI: https://doi.org/10.1038/s41569-024-01072-4
Redox Biol. 2024 Sep 19. pii: S2213-2317(24)00343-4. [Epub ahead of print]77 103365

Glutathione peroxidase 3 is essential for countering senescence in adipose remodelling by maintaining mitochondrial homeostasis.

Yijie Song, Mengjie Zhu, Md Ariful Islam, Wenyi Gu, Kavsar Alim, Chien-Shan Cheng, Jingxian Chen, Yu Xu, Hongxi Xu.

  Adipose tissue senescence is a precursor to organismal aging and understanding adipose remodelling contributes to discovering novel anti-aging targets. Glutathione peroxidase 3 (GPx3), a critical endogenous antioxidant enzyme, is diminished in the subcutaneous adipose tissue (sWAT) with white adipose expansion. Based on the active role of the antioxidant system in counteracting aging, we investigated the involvement of GPx3 in adipose senescence. We determined that knockdown of GPx3 in adipose tissue by adeno-associated viruses impaired mitochondrial function in mice, increased susceptibility to obesity, and exacerbated adipose tissue senescence. Impairment of GPx3 may cause mitochondrial dysfunction through inner mitochondrial membrane disruption. Adipose reshaping management (cold stimulation and intermittent diet) counteracted the aging of tissues, with an increase in GPx3 expression. Overall metabolic improvement induced by cold stimulation was partially attenuated when GPx3 was depleted. GPx3 may be involved in adipose browning by interacting with UCP1, and GPx3 may be a limiting factor for intracellular reactive oxygen species (ROS) accumulation during stem cell browning. Collectively, these findings emphasise the importance of restoring the imbalanced redox state in adipose tissue to counteract aging and that GPx3 may be a potential target for maintaining mitochondrial homeostasis and longevity.

Keywords:  Adipose tissue; Anti-Senescence; Glutathione peroxidase 3; Mitochondrial

DOI:  https://doi.org/10.1016/j.redox.2024.103365