bims-mepmim 2022-06-05 papers

bims-mepmim

Biomed News

on Metabolites in pathological microenvironments and immunometabolism

Issue of 2022–06–05
28 papers selected by
Erika Mariana Palmieri, NIH/NCI Laboratory of Cancer ImmunoMetabolism

Tumor-Derived Lactate Creates a Favorable Niche for Tumor via Supplying Energy Source for Tumor and Modulating the Tumor Microenvironment.
Mesaconate is synthesized from itaconate and exerts immunomodulatory effects in macrophages.
Intracellular acetyl CoA potentiates the therapeutic efficacy of anti-tumor CD8+ T cells.
A Metabolic Paradigm for H2S Signaling via ETC Plasticity.
Fatty acid metabolism of Mycobacterium tuberculosis: A double-edged sword.
The Mitochondrial Pyruvate Carrier at the Crossroads of Intermediary Metabolism.
Citraconate inhibits ACOD1 (IRG1) catalysis, reduces interferon responses and oxidative stress, and modulates inflammation and cell metabolism.
Metabolic Reprogramming by Dual-targeting Biomimetic Nanoparticles for Enhanced Tumor Chemo-Immunotherapy.
Metabolic Reprogramming in Adipose Tissue During Cancer Cachexia.
Fe-Based Theranostic Agents Respond to the Tumor Microenvironment for MRI-Guided Ferroptosis-/Apoptosis-Inducing Anticancer Therapy.
Human Macrophages Exhibit GM-CSF Dependent Restriction of Mycobacterium tuberculosis Infection via Regulating Their Self-Survival, Differentiation and Metabolism.
Purine nucleoside phosphorylase enables dual metabolic checkpoints that prevent T cell immunodeficiency and TLR7-dependent autoimmunity.
Sex-Biased Control of Inflammation and Metabolism by a Mitochondrial Nod-Like Receptor.
Nutritional and Metabolic Control of Ferroptosis.
Ferrochelatase: Mapping the Intersection of Iron and Porphyrin Metabolism in the Mitochondria.
The prognostic role of M2 tumor-associated macrophages in non-small-cell lung cancer.
Integrative understanding of immune-metabolic interaction.
Macrophage circadian rhythms are differentially affected based on stimuli.
Metabolic Reprogramming and Lipophagy Mediates Survival of Ascites Derived Metastatic Ovarian Cancer Cells.
METALIC reveals interorganelle lipid flux in live cells by enzymatic mass tagging.
A Cobalamin-Dependent Radical SAM Enzyme Catalyzes the Unique Cα-Methylation of Glutamine in Methyl-Coenzyme M Reductase.
M2-Macrophage-Derived Exosomes Promote Meningioma Progression through TGF-β Signaling Pathway.
PRODH2-Mediated Proline Metabolism Boosts CAR T-cell Effector Function.
Analysis of Metabolic Pathways by 13C-Labeled Molecular Probes and HRMAS Nuclear Magnetic Resonance Spectroscopy: Isotopologue Identification and Quantification Methods for Medical Applications.
Endothelial extracellular vesicles promote tumour growth by tumour-associated macrophage reprogramming.
Deciphering Innate Immune Cell-Tumor Microenvironment Crosstalk at a Single-Cell Level.
PFKP alleviates glucose starvation-induced metabolic stress in lung cancer cells via AMPK-ACC2 dependent fatty acid oxidation.
Excessive branched-chain amino acid accumulation restricts mesenchymal stem cell-based therapy efficacy in myocardial infarction.

Front Cell Dev Biol. 2022 ;10 808859

Tumor-Derived Lactate Creates a Favorable Niche for Tumor via Supplying Energy Source for Tumor and Modulating the Tumor Microenvironment.

Mengyao Jin, Wei Cao, Bo Chen, Maoming Xiong, Guodong Cao.

  Tumor evolution is influenced by events involving tumor cells and the environment in which they live, known as the tumor microenvironment (TME). TME is a functional and structural niche composed of tumor cells, endothelial cells (ECs), cancer-associated fibroblasts (CAFs), mesenchymal stromal cells (MSCs), and a subset of immune cells (macrophages, dendritic cells, natural killer cells, T cells, B cells). Otto Warburg revealed the Warburg effect in 1923, a characteristic metabolic mechanism of tumor cells that performs high glucose uptake and excessive lactate formation even in abundant oxygen. Tumor tissues excrete a large amount of lactate into the extracellular microenvironment in response to TME's hypoxic or semi-hypoxic state. High lactate concentrations in tumor biopsies have been linked to metastasis and poor clinical outcome. This indicates that the metabolite may play a role in carcinogenesis and lead to immune escape in TME. Lactate is now recognized as an essential carbon source for cellular metabolism and as a signaling molecule in TME, forming an active niche that influences tumor progression. This review summarized the advanced literature demonstrating the functional role of lactate in TME remodeling, elucidating how lactate shapes the behavior and the phenotype of both tumor cells and tumor-associated cells. We also concluded the intriguing interactions of multiple immune cells in TME. Additionally, we demonstrated how lactate functioned as a novel function factor by being used in a new histone modification, histone lysine lactylation, and to regulate gene expression in TME. Ultimately, because lactate created a favorable niche for tumor progression, we summarized potential anti-tumor strategies targeting lactate metabolism and signaling to investigate better cancer treatment.

Keywords:  energy source; immune response; lactate; lactylation; tumor micoenvironment

DOI:  https://doi.org/10.3389/fcell.2022.808859
Nat Metab. 2022 Jun 02.

Mesaconate is synthesized from itaconate and exerts immunomodulatory effects in macrophages.

Wei He, Antonia Henne, Mario Lauterbach, Eike Geißmar, Fabian Nikolka, Celia Kho, Alexander Heinz, Catherine Dostert, Melanie Grusdat, Thekla Cordes, Janika Härm, Oliver Goldmann, Anouk Ewen, Charlène Verschueren, Julia Blay-Cadanet, Robert Geffers, Hendrikus Garritsen, Manfred Kneiling, Christian K Holm, Christian M Metallo, Eva Medina, Zeinab Abdullah, Eicke Latz, Dirk Brenner, Karsten Hiller.

Since its discovery in inflammatory macrophages, itaconate has attracted much attention due to its antimicrobial and immunomodulatory activity1-3. However, instead of investigating itaconate itself, most studies used derivatized forms of itaconate and thus the role of non-derivatized itaconate needs to be scrutinized. Mesaconate, a metabolite structurally very close to itaconate, has never been implicated in mammalian cells. Here we show that mesaconate is synthesized in inflammatory macrophages from itaconate. We find that both, non-derivatized itaconate and mesaconate dampen the glycolytic activity to a similar extent, whereas only itaconate is able to repress tricarboxylic acid cycle activity and cellular respiration. In contrast to itaconate, mesaconate does not inhibit succinate dehydrogenase. Despite their distinct impact on metabolism, both metabolites exert similar immunomodulatory effects in pro-inflammatory macrophages, specifically a reduction of interleukin (IL)-6 and IL-12 secretion and an increase of CXCL10 production in a manner that is independent of NRF2 and ATF3. We show that a treatment with neither mesaconate nor itaconate impairs IL-1β secretion and inflammasome activation. In summary, our results identify mesaconate as an immunomodulatory metabolite in macrophages, which interferes to a lesser extent with cellular metabolism than itaconate.

DOI: https://doi.org/10.1038/s42255-022-00565-1
Cancer Res. 2022 May 31. pii: canres.4052.2021. [Epub ahead of print]

Intracellular acetyl CoA potentiates the therapeutic efficacy of anti-tumor CD8+ T cells.

Snehanshu Chowdhury, Anwesha Kar, Debaleena Bhowmik, Anupam Gautam, Debashree Basak, Ishita Sarkar, Puspendu Ghosh, Deborpita Sarkar, Alvina Deka, Paramita Chakraborty, Asima Mukhopadhyay, Shikhar Mehrotra, Soumen Basak, Sandip Paul, Shilpak Chatterjee.

Effector CD8+ T cells rely primarily on glucose metabolism to meet their biosynthetic and functional needs. However, nutritional limitations in the tumor microenvironment can cause T cell hyporesponsiveness. Therefore, T cells must acquire metabolic traits enabling sustained effector function at the tumor site to elicit a robust anti-tumor immune response. Here, we report that IL-12-stimulated CD8+ T cells have elevated intracellular acetyl CoA levels and can maintain IFNγ levels in nutrient-deprived, tumour-conditioned media (TCM). Pharmacological and metabolic analyses demonstrated an active glucose-citrate-acetyl CoA circuit in IL-12-stimulated CD8+ T cells supporting an intracellular pool of acetyl CoA in an ATP-citrate lyase (ACLY)-dependent manner. Intracellular acetyl CoA levels enhanced histone acetylation, lipid synthesis, and IFNγ production, improving the metabolic and functional fitness of CD8+ T cells in tumors. Pharmacological inhibition or genetic knockdown of ACLY severely impaired IFNγ production and viability of CD8+ T cells in nutrient-restricted conditions. Furthermore, CD8+ T cells cultured in high pyruvate-containing media in vitro acquired critical metabolic features of IL-12-stimulated CD8+ T cells and displayed improved anti-tumor potential upon adoptive transfer in murine lymphoma and melanoma models. Overall, this study delineates the metabolic configuration of CD8+ T cells required for stable effector function in tumors and presents an affordable approach to promote the efficacy of CD8+ T cells for adoptive T cell therapy.

DOI: https://doi.org/10.1158/0008-5472.CAN-21-4052
Antioxid Redox Signal. 2022 Jun 01.

A Metabolic Paradigm for H2S Signaling via ETC Plasticity.

David Hanna, Roshan Kumar, Ruma Banerjee.

SIGNIFICANCE: A burgeoning literature has attributed varied physiological effects to H2S, which is a product of eukaryotic sulfur amino acid metabolism. Protein persulfidation represents a major focus of studies elucidating the mechanism underlying H2S signaling. On the other hand, the capacity of H2S to induce reductive stress by targeting the electron transport chain (ETC), and signal by reprogramming redox metabolism have only recently begun to be elucidated.
RECENT ADVANCES: In contrast to the nonspecific reaction of H2S with oxidized cysteines to form protein persulfides, its inhibition of complex IV represents a specific mechanism of action. Studies on the dual impact of H2S as an ETC substrate and an inhibitor have led to the exciting discovery of ETC plasticity and the use of fumarate as a terminal electron acceptor. H2S oxidation combined with complex IV targeting generate mitochondrial reductive stress, which is signaled through the metabolic network, leading to increased aerobic glycolysis, glutamine-dependent reductive carboxylation and lipogenesis.
CRITICAL ISSUES: Insights into H2S-induced metabolic reprogramming are ushering in a paradigm shift for understanding the mechanism of its cellular action. It will be critical to reevaluate the physiological effects of H2S e.g., cytoprotection against ischemia-reperfusion injury, through the framework of metabolic reprogramming and ETC remodeling by H2S.
FUTURE DIRECTIONS: The metabolic ramifications of H2S in other cellular compartments, e.g., the endoplasmic reticulum and the nucleus, as well as the intersections between hypoxia and H2S signaling are important future directions that merit elucidation.

DOI: https://doi.org/10.1089/ars.2022.0067
Microb Cell. 2022 May 02. 9(5): 123-125

Fatty acid metabolism of Mycobacterium tuberculosis: A double-edged sword.

Camila G Quinonez, Jae Jin Lee, Juhyeon Lim, Mark Odell, Christopher P Lawson, Amarachukwu Anyogu, Saki Raheem, Hyungjin Eoh.

  Unlike other heterotrophic bacteria, Mycobacterium tuberculosis (Mtb) can co-catabolize a range of carbon sources simultaneously. Evolution of Mtb within host nutrient environment allows Mtb to consume the host's fatty acids as a main carbon source during infection. The fatty acid-induced metabolic advantage greatly contributes to Mtb's pathogenicity and virulence. Thus, the identification of key enzymes involved in Mtb's fatty acid metabolism is urgently needed to aid new drug development. Two fatty acid metabolism enzymes, phosphoenolpyruvate carboxykinase (PEPCK) and isocitrate lyase (ICL) have been intensively studied as promising drug targets, but recently, Quinonez et al. (mBio, doi: 10.1128/mbio.03559-21) highlighted a link between the fatty acid-induced dormancy-like state and drug tolerance. Using metabolomics profiling of a PEPCK-deficient mutant, Quinonez et al. identified that over-accumulation of methylcitrate cycle (MCC) intermediates are phenotypically associated with enhanced drug tolerance against first- and second- line TB antibiotics. This finding was further corroborated by metabolomics and phenotypic characterization of Mtb mutants lacking either ICL or 2-methylcitrate dehydratase. Fatty acid metabolism induced drug-tolerance was also recapitulated in wildtype Mtb after treatment with authentic 2-methylisocitrate, an MCC intermediate. Together, the fatty acid-induced dormancy-like state and drug tolerance are attributed to dysregulated MCC activity.

Keywords:  drug tolerance; fatty acids; metabolomics; methylcitrate cycle; tuberculosis

DOI:  https://doi.org/10.15698/mic2022.05.777
Am J Physiol Endocrinol Metab. 2022 May 30.

The Mitochondrial Pyruvate Carrier at the Crossroads of Intermediary Metabolism.

Nicole K H Yiew, Brian N Finck.

  Pyruvate metabolism, a central nexus of carbon homeostasis, is an evolutionarily-conserved process and aberrant pyruvate metabolism is associated with and contributes to numerous human metabolic disorders including diabetes, cancer, and heart disease. As a product of glycolysis, pyruvate is primarily generated in the cytosol before being transported into the mitochondrion for further metabolism. Pyruvate entry into the mitochondrial matrix is a critical step for efficient generation of reducing equivalents and ATP and for the biosynthesis of glucose, fatty acids, and amino acids from pyruvate. However, for many years the identity of the carrier protein(s) that transported pyruvate into the mitochondrial matrix remained a mystery. In 2012, the molecular-genetic identification of the mitochondrial pyruvate carrier (MPC), a heterodimeric complex composed of protein subunits MPC1 and MPC2, enabled studies that shed light on the many metabolic and physiologic processes regulated by pyruvate metabolism. A better understanding of the mechanisms regulating pyruvate transport and the processes affected by pyruvate metabolism may enable novel therapeutics to modulate mitochondrial pyruvate flux to treat a variety disorders. Herein, we review our current knowledge of the MPC, discuss recent advances in the understanding of mitochondrial pyruvate metabolism in various tissue and cell types, and address some of the outstanding questions relevant to this field.

Keywords:  adipose tissue; heart; liver; mitochondrion; pyruvate

DOI:  https://doi.org/10.1152/ajpendo.00074.2022
Nat Metab. 2022 Jun 02.

Citraconate inhibits ACOD1 (IRG1) catalysis, reduces interferon responses and oxidative stress, and modulates inflammation and cell metabolism.

F Chen, W A M Elgaher, M Winterhoff, K Büssow, F H Waqas, E Graner, Y Pires-Afonso, L Casares Perez, L de la Vega, N Sahini, L Czichon, W Zobl, T Zillinger, M Shehata, S Pleschka, H Bähre, C Falk, A Michelucci, S Schuchardt, W Blankenfeldt, A K H Hirsch, F Pessler.

Although the immunomodulatory and cytoprotective properties of itaconate have been studied extensively, it is not known whether its naturally occurring isomers mesaconate and citraconate have similar properties. Here, we show that itaconate is partially converted to mesaconate intracellularly and that mesaconate accumulation in macrophage activation depends on prior itaconate synthesis. When added to human cells in supraphysiological concentrations, all three isomers reduce lactate levels, whereas itaconate is the strongest succinate dehydrogenase (SDH) inhibitor. In cells infected with influenza A virus (IAV), all three isomers profoundly alter amino acid metabolism, modulate cytokine/chemokine release and reduce interferon signalling, oxidative stress and the release of viral particles. Of the three isomers, citraconate is the strongest electrophile and nuclear factor-erythroid 2-related factor 2 (NRF2) agonist. Only citraconate inhibits catalysis of itaconate by cis-aconitate decarboxylase (ACOD1), probably by competitive binding to the substrate-binding site. These results reveal mesaconate and citraconate as immunomodulatory, anti-oxidative and antiviral compounds, and citraconate as the first naturally occurring ACOD1 inhibitor.

DOI: https://doi.org/10.1038/s42255-022-00577-x
Acta Biomater. 2022 May 29. pii: S1742-7061(22)00321-X. [Epub ahead of print]

Metabolic Reprogramming by Dual-targeting Biomimetic Nanoparticles for Enhanced Tumor Chemo-Immunotherapy.

Shuya Zang, Kexin Huang, Jiaxin Li, Kebai Ren, Ting Li, Xuan He, Yuan Tao, Jiao He, Ziyan Dong, Man Li, Qin He.

  Cancer-associated fibroblasts (CAFs)-mediated metabolic support plays a vital role in tumorigenesis. The metabolic network between cancer cells and CAFs may serve as promising targets for cancer therapy. Here, aiming at targeted blockade of the metabolic support of CAFs to cancer cells, a biomimetic nanocarrier is designed by coating solid lipid nanoparticles containing chemotherapeutic paclitaxel (PTX) and glycolysis inhibitor PFK15 with hybrid membranes of cancer cells and activated fibroblasts. The nanoparticles possess outstanding dual-targeting ability which can simultaneously target cancer cells and CAFs. The encapsulated glycolysis inhibitor PFK15 can prevent the glycolysis of cancer cells and CAFs at the same time, thus increasing the chemosensitivity of cancer cells and blocking the metabolic support of CAFs to cancer cells. The results showed that the combination of PTX and PFK15 exhibited synergistic effects and inhibited tumor growth effectively. Moreover, the biomimetic nanoparticles obviously reduced the lactate production in the tumor microenvironment, leading to activated immune responses and enhanced tumor suppression. This work presents a facile strategy to destroy the metabolic network between cancer cells and CAFs, and proves the potential to elevate chemo-immunotherapy by glycolysis inhibition. STATEMENT OF SIGNIFICANCE: : In many solid tumors, most cancer cells produce energy and carry out biosynthesis through glycolysis, even in aerobic conditions. As the main tumor stromal cells, cancer-associated fibroblasts (CAFs) usually turn oxidative phosphorylation into aerobic glycolysis with metabolic reprogramming and provide high-energy glycolytic metabolites for cancer cells. The metabolic network between cancer cells and CAFs is regarded as the vulnerability among cancer cells. Moreover, lactate produced by cancer cells and CAFs through glycolysis often leads to the immunosuppressive tumor microenvironment. The present study provides an effective approach to destroy the metabolic network between cancer cells and CAFs and greatly improves the antitumor immune response by reducing lactate production, which serves as a promising strategy for combined chemo-immunotherapy mediated by glycolysis.

Keywords:  biomimetic nanoparticles; chemo-immunotherapy; dual-target; glycolysis; metabolic support

DOI:  https://doi.org/10.1016/j.actbio.2022.05.045
Front Oncol. 2022 ;12 848394

Metabolic Reprogramming in Adipose Tissue During Cancer Cachexia.

Bahar Zehra Camurdanoglu Weber, Dilsad H Arabaci, Serkan Kir.

  Cancer cachexia is a disorder of energy balance characterized by the wasting of adipose tissue and skeletal muscle resulting in severe weight loss with profound influence on morbidity and mortality. Treatment options for cancer cachexia are still limited. This multifactorial syndrome is associated with changes in several metabolic pathways in adipose tissue which is affected early in the course of cachexia. Adipose depots are involved in energy storage and consumption as well as endocrine functions. In this mini review, we discuss the metabolic reprogramming in all three types of adipose tissues - white, brown, and beige - under the influence of the tumor macro-environment. Alterations in adipose tissue lipolysis, lipogenesis, inflammation and adaptive thermogenesis of beige/brown adipocytes are highlighted. Energy-wasting circuits in adipose tissue impacts whole-body metabolism and particularly skeletal muscle. Targeting of key molecular players involved in the metabolic reprogramming may aid in the development of new treatment strategies for cancer cachexia.

Keywords:  adipokines; adipose tissue; adipose tissue browning; cancer cachexia; inflammation; lipogenesis; lipolysis; non-shivering thermogenesis

DOI:  https://doi.org/10.3389/fonc.2022.848394
ACS Biomater Sci Eng. 2022 Jun 02.

Fe-Based Theranostic Agents Respond to the Tumor Microenvironment for MRI-Guided Ferroptosis-/Apoptosis-Inducing Anticancer Therapy.

Caiju Zhang, Kai Deng, Dan Xu, Huan Wang, Yue Liu, Xiao Chen, Li Ze, Xinyan Zong, Bo Wu, Haibo Xu.

  Tumor microenvironment-specific magnetic resonance imaging (MRI) contrast agents are conducive to accurate diagnoses by visualization of biochemical and pathological changes for suitable treatment. Herein, we reported a pH-responsive contrast agent DFeZd NP with MRI diagnosis and tumor treatment capabilities. DFeZd NPs can map the pH change by modulating the MR signal in different acid-base environments. Moreover, T1 signals are stronger in the tumor site, which proves efficient in distinguishing malignant tumors from normal tissues, as well as demarcating the tumor boundary. Subsequently, sustained supply of Fe through the Fe-based contrast agent leads to Fe redox cycling and lipid peroxides, inducing ferroptosis in tumor cells. Furthermore, under an acidic tumor microenvironment, in the presence of ascorbic acid, increased Fe2+ is generated, which serves as a stronger inducer of ferroptosis. Moreover, due to the different relaxivity of Fe3+ and Fe2+, redox cycling and ferroptosis in tumors can be monitored by MRI. Therefore, we propose DFeZd NPs as accessible and promising Fe-based dopamine-derived contrast agents for specific MRI imaging and ferroptosis induction for anticancer therapy.

Keywords:  MR imaging; ferroptosis; pH-responsive; theranostic agent

DOI:  https://doi.org/10.1021/acsbiomaterials.1c01626
Front Immunol. 2022 ;13 859116

Human Macrophages Exhibit GM-CSF Dependent Restriction of Mycobacterium tuberculosis Infection via Regulating Their Self-Survival, Differentiation and Metabolism.

Abhishek Mishra, Vipul K Singh, Chinnaswamy Jagannath, Selvakumar Subbian, Blanca I Restrepo, Marie-Claire Gauduin, Arshad Khan.

  GM-CSF is an important cytokine that regulates the proliferation of monocytes/macrophages and its various functions during health and disease. Although growing evidences support the notion that GM-CSF could play a major role in immunity against tuberculosis (TB) infection, the mechanism of GM-CSF mediated protective effect against TB remains largely unknown. Here in this study we examined the secreted levels of GM-CSF by human macrophages from different donors along with the GM-CSF dependent cellular processes that are critical for control of M. tuberculosis infection. While macrophage of different donors varied in their ability to produce GM-CSF, a significant correlation was observed between secreted levels of GM-CSF, survial of macrophages and intra-macrophage control of Mycobacterium tuberculosis bacilli. GM-CSF levels secreted by macrophages negatively correlated with the intra-macrophage M. tuberculosis burden, survival of infected host macrophages positively correlated with their GM-CSF levels. GM-CSF-dependent prolonged survival of human macrophages also correlated with significantly decreased bacterial burden and increased expression of self-renewal/cell-survival associated genes such as BCL-2 and HSP27. Antibody-mediated depletion of GM-CSF in macrophages resulted in induction of significantly elevated levels of apoptotic/necrotic cell death and a simultaneous decrease in autophagic flux. Additionally, protective macrophages against M. tuberculosis that produced more GM-CSF, induced a stronger granulomatous response and produced significantly increased levels of IL-1β, IL-12 and IL-10 and decreased levels of TNF-α and IL-6. In parallel, macrophages isolated from the peripheral blood of active TB patients exhibited reduced capacity to control the intracellular growth of M. tuberculosis and produced significantly lower levels of GM-CSF. Remarkably, as compared to healthy controls, macrophages of active TB patients exhibited significantly altered metabolic state correlating with their GM-CSF secretion levels. Altogether, these results suggest that relative levels of GM-CSF produced by human macrophages plays a critical role in preventing cell death and maintaining a protective differentiation and metabolic state of the host cell against M. tuberculosis infection.

Keywords:  Mycobacterium tuberculosis; antigen presentation; autophagy; cell death; cellular metabolism; granulocyte macrophage colony-stimulating factor; macrophages; tuberculosis

DOI:  https://doi.org/10.3389/fimmu.2022.859116
J Clin Invest. 2022 Jun 02. pii: e160852. [Epub ahead of print]

Purine nucleoside phosphorylase enables dual metabolic checkpoints that prevent T cell immunodeficiency and TLR7-dependent autoimmunity.

Evan R Abt, Khalid Rashid, Thuc M Le, Suwen Li, Hailey R Lee, Vincent Lok, Luyi Li, Amanda L Creech, Amanda N Labora, Hanna K Mandl, Alex K Lam, Arthur Cho, Valerie Rezek, Nanping Wu, Gabriel Abril-Rodriguez, Ethan W Rosser, Steven D Mittelman, Willy Hugo, Thomas Mehrling, Shanta Bantia, Antoni Ribas, Timothy R Donahue, Gay M Crooks, Ting-Ting Wu, Caius G Radu.

  Purine nucleoside phosphorylase (PNP) enables the breakdown and recycling of guanine nucleosides. PNP insufficiency in humans is paradoxically associated with both immunodeficiency and autoimmunity, but the mechanistic basis for these outcomes is incompletely understood. Here we identify two immune lineage-dependent consequences of PNP inactivation dictated by distinct gene interactions. During T cell development, PNP inactivation is synthetically lethal with down-regulation of the dNTP triphosphohydrolase SAMHD1. This interaction requires deoxycytidine kinase activity and is antagonized by microenvironmental deoxycytidine. In B lymphocytes and macrophages, PNP regulates Toll like receptor 7 signaling by controlling the levels of its (deoxy)guanosine nucleoside ligands. Overriding this regulatory mechanism promotes germinal center formation in the absence of exogenous antigen and accelerates disease in a mouse model of autoimmunity. This work reveals that one purine metabolism gene protects against immunodeficiency and autoimmunity via independent mechanisms operating in distinct immune lineages and identifies PNP as a novel metabolic immune checkpoint.

Keywords:  Autoimmune diseases; Immunology; Immunotherapy; Metabolism; T cell development

DOI:  https://doi.org/10.1172/JCI160852
Front Immunol. 2022 ;13 882867

Sex-Biased Control of Inflammation and Metabolism by a Mitochondrial Nod-Like Receptor.

Tiia Snäkä, Amel Bekkar, Chantal Desponds, Florence Prével, Stéphanie Claudinot, Nathalie Isorce, Filipa Teixeira, Coline Grasset, Ioannis Xenarios, Isabel C Lopez-Mejia, Lluis Fajas, Nicolas Fasel.

  Mitochondria regulate steroid hormone synthesis, and in turn sex hormones regulate mitochondrial function for maintaining cellular homeostasis and controlling inflammation. This crosstalk can explain sex differences observed in several pathologies such as in metabolic or inflammatory disorders. Nod-like receptor X1 (NLRX1) is a mitochondria-associated innate receptor that could modulate metabolic functions and attenuates inflammatory responses. Here, we showed that in an infectious model with the human protozoan parasite, Leishmania guyanensis, NLRX1 attenuated inflammation in females but not in male mice. Analysis of infected female and male bone marrow derived macrophages showed both sex- and genotype-specific differences in both inflammatory and metabolic profiles with increased type I interferon production, mitochondrial respiration, and glycolytic rate in Nlrx1-deficient female BMDMs in comparison to wild-type cells, while no differences were observed between males. Transcriptomics of female and male BMDMs revealed an altered steroid hormone signaling in Nlrx1-deficient cells, and a "masculinization" of Nlrx1-deficient female BMDMs. Thus, our findings suggest that NLRX1 prevents uncontrolled inflammation and metabolism in females and therefore may contribute to the sex differences observed in infectious and inflammatory diseases.

Keywords:  inflammation; innate immunity; metabolism; nod-like receptor X1; sex

DOI:  https://doi.org/10.3389/fimmu.2022.882867
Annu Rev Nutr. 2022 Jun 01.

Nutritional and Metabolic Control of Ferroptosis.

Eikan Mishima, Marcus Conrad.

Ferroptosis is a type of regulated cell death characterized by an excessive lipid peroxidation of cellular membranes caused by the disruption of the antioxidant defense system and/or an imbalanced cellular metabolism. Ferroptosis differentiates from other forms of regulated cell death in that several metabolic pathways and nutritional aspects, including endogenous antioxidants (such as coenzyme Q10, vitamin E, and di/tetrahydrobiopterin), iron handling, energy sensing, selenium utilization, amino acids, and fatty acids, directly regulate the cells' sensitivity to lipid peroxidation and ferroptosis. As hallmarks of ferroptosis have been documented in a variety of diseases, including neurodegeneration, acute organ injury, and therapy-resistant tumors, the modulation of ferroptosis using pharmacological tools or by metabolic reprogramming holds great potential for the treatment of ferroptosis-associated diseases and cancer therapy. Hence, this review focuses on the regulation of ferroptosis by metabolic and nutritional cues and discusses the potential of nutritional interventions for therapy by targeting ferroptosis. Expected final online publication date for the Annual Review of Nutrition, Volume 42 is August 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

DOI: https://doi.org/10.1146/annurev-nutr-062320-114541
Front Cell Dev Biol. 2022 ;10 894591

Ferrochelatase: Mapping the Intersection of Iron and Porphyrin Metabolism in the Mitochondria.

Chibuike David Obi, Tawhid Bhuiyan, Harry A Dailey, Amy E Medlock.

  Porphyrin and iron are ubiquitous and essential for sustaining life in virtually all living organisms. Unlike iron, which exists in many forms, porphyrin macrocycles are mostly functional as metal complexes. The iron-containing porphyrin, heme, serves as a prosthetic group in a wide array of metabolic pathways; including respiratory cytochromes, hemoglobin, cytochrome P450s, catalases, and other hemoproteins. Despite playing crucial roles in many biological processes, heme, iron, and porphyrin intermediates are potentially cytotoxic. Thus, the intersection of porphyrin and iron metabolism at heme synthesis, and intracellular trafficking of heme and its porphyrin precursors are tightly regulated processes. In this review, we discuss recent advances in understanding the physiological dynamics of eukaryotic ferrochelatase, a mitochondrially localized metalloenzyme. Ferrochelatase catalyzes the terminal step of heme biosynthesis, the insertion of ferrous iron into protoporphyrin IX to produce heme. In most eukaryotes, except plants, ferrochelatase is localized to the mitochondrial matrix, where substrates are delivered and heme is synthesized for trafficking to multiple cellular locales. Herein, we delve into the structural and functional features of ferrochelatase, as well as its metabolic regulation in the mitochondria. We discuss the regulation of ferrochelatase via post-translational modifications, transportation of substrates and product across the mitochondrial membrane, protein-protein interactions, inhibition by small-molecule inhibitors, and ferrochelatase in protozoal parasites. Overall, this review presents insight on mitochondrial heme homeostasis from the perspective of ferrochelatase.

Keywords:  ferrochelatase; heme; iron; metabolon; porphyria; porphyrin

DOI:  https://doi.org/10.3389/fcell.2022.894591
Histol Histopathol. 2022 May 31. 18474

The prognostic role of M2 tumor-associated macrophages in non-small-cell lung cancer.

Zhuo Li, Yun-Jie Wang, Jian Zhou, Michinobu Umakoshi, Akiteru Goto.

Lung cancer is a high-risk tumor and is a main cause of death worldwide. The tumor aggressiveness and degree of malignancy depend not only on the tumor itself, but also on the microenvironment. The inflammatory microenvironment is one of the key factors in promoting the progression of lung cancer. It has been found that macrophages are the most abundant immune cells in the tumor microenvironment, with strong plasticity and heterogeneity. Tumor-Associated Macrophages (TAMs) are important components of the tumor immune microenvironment. TAMs are thought to be polarized into two main phenotypes: inflammatory or classically activated (M1) and antiinflammatory or alternatively activated (M2) macrophages. Their phenotype and function change according to environment and the appearance of tumor cells. M2 macrophages have been reported to be protumorigenic, because they can promote the formation of blood vessels in the tumor microenvironment, helping tumor cells escape the body's immune defense and promote their growth, by releasing a variety of cytokines, including chemokines, inflammatory factors and growth factor. However, the prognostic impact of TAMs and their phenotypes in non-small-cell lung cancer (NSCLC) remains to be fully elucidated. Some reports of the association between the characteristics of macrophages in lung tumor and patients' survival outcomes show contradicting results. In order to explore the prognostic role of TAMs in NSCLS, the association between the phenotype, density and distribution of macrophages and the prognosis of human NSCLC, as well as the potential mechanisms of M2 macrophages leading to poor prognosis in NSCLC, are reviewed in this study.

DOI: https://doi.org/10.14670/HH-18-474
BMB Rep. 2022 Jun 02. pii: 5619. [Epub ahead of print]

Integrative understanding of immune-metabolic interaction.

Seonyoung Lim, Hawon Kim, Myunghyun Jeong, Hyeon Yang, Jun Young Hong.

Recent studies have revealed that the immune system plays a critical role in various physiological processes beyond its classical pathogen control activity. Even under a sterile condition, various cells and tissues can utilize the immune system to meet a specific demand for proper physiological functions. Particularly, a strong link between immunity and metabolism has been identified. Studies have identified the reciprocal regulation between these two systems. For example, immune signals can regulate metabolism, and metabolism (cellular or systemic) can regulate immunity. In this review, we will summarize recent findings on this reciprocal regulation between immunity and metabolism, and discuss potential biological rules behind this interaction with integrative perspectives.
Integr Biol (Camb). 2022 Jun 01. pii: zyac007. [Epub ahead of print]

Macrophage circadian rhythms are differentially affected based on stimuli.

Sujeewa S Lellupitiyage Don, Javier A Mas-Rosario, Hui-Hsien Lin, Evelyn M Nguyen, Stephanie R Taylor, Michelle E Farkas.

  Macrophages are white blood cells that play disparate roles in homeostasis and immune responses. They can reprogram their phenotypes to pro-inflammatory (M1) or anti-inflammatory (M2) states in response to their environment. About 8-15% of the macrophage transcriptome has circadian oscillations, including genes closely related to their functioning. As circadian rhythms are associated with cellular phenotypes, we hypothesized that polarization of macrophages to opposing subtypes might differently affect their circadian rhythms. We tracked circadian rhythms in RAW 264.7 macrophages using luminescent reporters. Cells were stably transfected with Bmal1:luc and Per2:luc reporters, representing positive and negative components of the molecular clock. Strength of rhythmicity, periods and amplitudes of time series were assessed using multiple approaches. M1 polarization decreased amplitudes and rhythmicities of Bmal1:luc and Per2:luc, but did not significantly affect periods, while M2 polarization increased periods but caused no substantial alterations to amplitudes or rhythmicity. As macrophage phenotypes are also altered in the presence of cancer cells, we tested circadian effects of conditioned media from mouse breast cancer cells. Media from highly aggressive 4T1 cells caused loss of rhythmicity, while media from less aggressive EMT6 cells yielded no changes. As macrophages play roles in tumors, and oncogenic features are associated with circadian rhythms, we tested whether conditioned media from macrophages could alter circadian rhythms of cancer cells. Conditioned media from RAW 264.7 cells resulted in lower rhythmicities and periods, but higher amplitudes in human osteosarcoma, U2OS-Per2:luc cells. We show that phenotypic changes in macrophages result in altered circadian characteristics and suggest that there is an association between circadian rhythms and macrophage polarization state. Additionally, our data demonstrate that macrophages treated with breast cancer-conditioned media have circadian phenotypes similar to those of the M1 subtype, and cancer cells treated with macrophage-conditioned media have circadian alterations, providing insight to another level of cross-talk between macrophages and cancer.

Keywords:  cancer; circadian rhythms; macrophages; rhythmicity

DOI:  https://doi.org/10.1093/intbio/zyac007
Asian Pac J Cancer Prev. 2022 May 01. pii: 90121. [Epub ahead of print]23(5): 1699-1709

Metabolic Reprogramming and Lipophagy Mediates Survival of Ascites Derived Metastatic Ovarian Cancer Cells.

Sandeep Kumar S, Shalini N Swamya, Varadahally Rangaiah Devaraj, Chennagiri S Premalathac, V Rd Pallavi, Bk Chandrashekar Sagar, Dhananjay D Shinde, Ramesh Gawari.

   OBJECTIVE: The study was aimed at understanding the survival of metastatic ovarian cancer spheroids in the malignant ascites microenvironment.
METHODS: All the assays were performed using aseptically collected patient samples. The cells were characterized for the expression of ovarian and cancer stem cell markers using immunocytochemistry. The presence of lipid in the primary metastatic cancer spheroids were confirmed by neutral fat staining using Oil Red-O and transmission electron microscopy. The mRNA expression of autophagy and lipid metabolism genes was analyzed using RT-PCR. The lipid content was analyzed using lipidomics analysis. Etomoxir and chloroquine were used to study the effect of inhibition of autophagy in the metastatic cells. The data were analyzed using appropriate statistical tools and a p-value <0.05 was considered to be statistically significant.
RESULTS: Metastatic ovarian cancer spheroids exhibit cancer stem like properties and undergo a metabolic reprogramming when they disseminate from the primary tumor. We report here the accumulation of numerous cytoplasmic lipid droplets and lipophagic vesicles in the metastatic cells in contrast to their primary tumors. In addition we also report that these cells depend on lipophagy for the utilization of lipids rather than the conventional lipolytic pathway. The lipidomics analysis data reveals that the metastatic cells possess high levels of unsaturated fatty acids. We have also reported the occurrence of distinct accumulation of multiple nuclei in the patient derived metastatic cells. Inhibition of beta-oxidation and autophagic machinery using etomoxir and chloroquine resulted in cell death suggesting a potential mode to suppress metastatic cancer cells.
CONCLUSION: Metabolic reprogramming is a characteristic feature of the metastatic ovarian cancer cells that are persisting in the malignant ascites. Targeting of the metastatic by gaining an insight into the various metabolic and molecular changes that occur in the metastatic niche provides a promising therapeutic approach in management of the disease.

Keywords:  Autophagy; CPT-1a; Multinucleated cancer cells; Unsaturated fatty acids; lipid droplets

DOI:  https://doi.org/10.31557/APJCP.2022.23.5.1699
Nat Cell Biol. 2022 Jun 02.

METALIC reveals interorganelle lipid flux in live cells by enzymatic mass tagging.

Arun T John Peter, Carmelina Petrungaro, Matthias Peter, Benoît Kornmann.

The distinct activities of organelles depend on the proper function of their membranes. Coordinated membrane biogenesis of different organelles necessitates lipid transport from their site of synthesis to their destination. Several factors have been proposed to participate in lipid distribution, but despite its basic importance, in vivo evidence linking the absence of putative transport pathways to specific transport defects remains scarce. A reason for this scarcity is the near absence of in vivo lipid trafficking assays. Here we introduce a versatile method named METALIC (Mass tagging-Enabled TrAcking of Lipids In Cells) to track interorganelle lipid flux inside cells. In this strategy, two enzymes, one directed to a 'donor' and the other to an 'acceptor' organelle, add two distinct mass tags to lipids. Mass-spectrometry-based detection of lipids bearing the two mass tags is then used to quantify exchange between the two organelles. By applying this approach, we show that the ERMES and Vps13-Mcp1 complexes have transport activity in vivo, and unravel their relative contributions to endoplasmic reticulum-mitochondria lipid exchange.

DOI: https://doi.org/10.1038/s41556-022-00917-9
Angew Chem Int Ed Engl. 2022 May 30.

A Cobalamin-Dependent Radical SAM Enzyme Catalyzes the Unique Cα-Methylation of Glutamine in Methyl-Coenzyme M Reductase.

Jana Gagsteiger, Sören Jahn, Lorenz Heidinger, Lukas Gericke, Jennifer N Andexer, Thorsten Friedrich, Christoph Loenarz, Gunhild Layer.

  Methyl-coenzyme M reductase, which is responsible for the production of the greenhouse gas methane during biological methane formation, carries several unique posttranslational amino acid modifications, inter alia a 2-(S)-methylglutamine. The enzyme responsible for the Cα-methylation of this glutamine is not known. Here, we identify and characterize a cobalamin-dependent Radical SAM enzyme as the glutamine C-methyltransferase. The recombinant protein from Methanoculleus thermophilus binds cobalamin in a base-off, His-off conformation and contains a single [4Fe-4S] cluster. The cobalamin cofactor cycles between the methyl-cob(III)alamin, cob(II)alamin and cob(I)alamin states during catalysis and produces methylated substrate, 5'-deoxyadenosine and S-adenosyl-L-homocysteine in a 1:1:1 ratio. The newly identified glutamine C-methyltransferase belongs to the class B of Radical SAM methyltransferases known to catalyze challenging methylation reactions of sp3-hybridized carbon atoms.

Keywords:  MCR modification; Methanogenesis; Radical S-adenosylmethionine; Radical reactions; metalloproteins

DOI:  https://doi.org/10.1002/anie.202204198
J Immunol Res. 2022 ;2022 8326591

M2-Macrophage-Derived Exosomes Promote Meningioma Progression through TGF-β Signaling Pathway.

Xiao-Hong Fu, Jian-Ping Li, Xue-Ying Li, Yan Tan, Min Zhao, Shao-Fu Zhang, Xue-Dong Wu, Jian-Guo Xu.

Tumor-associated macrophages (TAMs) have been shown to be an essential component of the tumor microenvironment and facilitate the proliferation and invasion of a variety of malignancies. However, the contribution of TAMs to meningioma progression has not been characterized in detail. In this study, we aimed to discover a novel regulatory pathway by which exosome-mediated M2-polarized macrophages participate in meningioma tumorigenesis and progression. Methods. First, the distribution and functional phenotype of macrophages in meningioma tissues were assessed by immunohistochemistry. Macrophage-derived exosomes (MDEs) were characterized, and further cell coculture experiments were performed to explore the effects of M2-MDEs on the proliferation, migration, and invasion of meningioma cells. RNA sequencing was used to analyze the transcriptomic signatures in meningioma cells treated with M2-MDEs. Three-dimensional tumorspheres and xenograft tumor models were used to evaluate the effects of M2-MDEs on meningioma tumorigenesis and development. Results. We found that M2 macrophages were enriched in meningioma tissue. Coculture with meningioma cells induced the M2 polarization of macrophages. We also found that M2-MDEs were able to significantly promote cell proliferation, cell migration, cell invasion, and tumorigenesis in meningiomas. Bioinformatic analysis suggested that the TGF-β pathway was activated in meningioma cells treated with M2-MDEs. Functional experiments demonstrated that blocking the TGF-β signaling pathway could effectively reverse the tumor-promotive effects mediated by M2-MDEs. Conclusions. Overall, our study showed that M2-MDEs promoted meningioma development and invasion by activating the TGF-β signaling pathway. Targeting exosome-mediated intercellular communication in the tumor microenvironment may be a novel therapeutic strategy for meningioma patients.

DOI: https://doi.org/10.1155/2022/8326591
Cancer Discov. 2022 Jun 02. 12(6): 1405

PRODH2-Mediated Proline Metabolism Boosts CAR T-cell Effector Function.

Overexpression of PRODH2 augments CAR T-cell proliferation, effector function, and memory phenotype.

DOI: https://doi.org/10.1158/2159-8290.CD-RW2022-054
Anal Chem. 2022 Jun 03.

Analysis of Metabolic Pathways by 13C-Labeled Molecular Probes and HRMAS Nuclear Magnetic Resonance Spectroscopy: Isotopologue Identification and Quantification Methods for Medical Applications.

Hassiba Outilaft, Caroline Bund, Martial Piotto, Izzie J Namer.

The use of 13C-labeled molecular probes is essential to explore altered metabolic pathways in human pathologies. The analysis of the different 13C isotopologues resulting from these changes in metabolic pathways is essential to understand the different biological processes involved. We propose an NMR methodology consisting of eight different NMR experiments performed under HRMAS conditions to explore metabolic pathways in unprocessed pathological cells and tissues. This methodology has the potential to study human pathologies in the medical field and to enable the analysis of the mode of action of therapeutic treatments.

DOI: https://doi.org/10.1021/acs.analchem.2c00214
J Extracell Vesicles. 2022 Jun;11(6): e12228

Endothelial extracellular vesicles promote tumour growth by tumour-associated macrophage reprogramming.

Makon-Sébastien Njock, Tina O'Grady, Olivier Nivelles, Michelle Lion, Sophie Jacques, Maureen Cambier, Stephanie Herkenne, Florian Muller, Aurélie Christian, Claire Remacle, Julien Guiot, Souad Rahmouni, Franck Dequiedt, Ingrid Struman.

  Tumour-derived extracellular vesicles (EVs) participate in tumour progression by deregulating various physiological processes including angiogenesis and inflammation. Here we report that EVs released by endothelial cells in a mammary tumour environment participate in the recruitment of macrophages within the tumour, leading to an immunomodulatory phenotype permissive for tumour growth. Using RNA-Seq approaches, we identified several microRNAs (miRNAs) found in endothelial EVs sharing common targets involved in the regulation of the immune system. To further study the impact of these miRNAs in a mouse tumour model, we focused on three miRNAs that are conserved between humans and mouse, that is, miR-142-5p, miR-183-5p and miR-222-3p. These miRNAs are released from endothelial cells in a tumour microenvironment and are transferred via EVs to macrophages. In mouse mammary tumour models, treatment with EVs enriched in these miRNAs leads to a polarization of macrophages toward an M2-like phenotype, which in turn promotes tumour growth.

Keywords:  TAM; breast cancer; extracellular vesicles; macrophages; microRNA

DOI:  https://doi.org/10.1002/jev2.12228
Front Cell Dev Biol. 2022 ;10 803947

Deciphering Innate Immune Cell-Tumor Microenvironment Crosstalk at a Single-Cell Level.

Ryohichi Sugimura, Yiming Chao.

  The tumor microenvironment encompasses various innate immune cells which regulate tumor progression. Exploiting innate immune cells is a new frontier of cancer immunotherapy. However, the classical surface markers for cell-type classification cannot always well-conclude the phenotype, which will further hinge our understanding. The innate immune cells include dendritic cells, monocytes/macrophages, natural killer cells, and innate lymphoid cells. They play important roles in tumor growth and survival, in some cases promoting cancer, in other cases negating cancer. The precise characterization of innate immune cells at the single-cell level will boost the potential of cancer immunotherapy. With the development of single-cell RNA sequencing technology, the transcriptome of each cell in the tumor microenvironment can be dissected at a single-cell level, which paves a way for a better understanding of the cell type and its functions. Here, we summarize the subtypes and functions of innate immune cells in the tumor microenvironment based on recent literature on single-cell technology. We provide updates on recent achievements and prospects for how to exploit novel functions of tumor-associated innate immune cells and target them for cancer immunotherapy.

Keywords:  ScRNA-seq; coding; data mining; innate immune cell; tumor microenvironment

DOI:  https://doi.org/10.3389/fcell.2022.803947
Cell Discov. 2022 May 31. 8(1): 52

PFKP alleviates glucose starvation-induced metabolic stress in lung cancer cells via AMPK-ACC2 dependent fatty acid oxidation.

Jiaqing Chen, Li Zou, Guang Lu, Oleg Grinchuk, Lei Fang, Derrick Sek Tong Ong, Reshma Taneja, Choon-Nam Ong, Han-Ming Shen.

Cancer cells adopt metabolic reprogramming to promote cell survival under metabolic stress. A key regulator of cell metabolism is AMP-activated protein kinase (AMPK) which promotes catabolism while suppresses anabolism. However, the underlying mechanism of AMPK in handling metabolic stress in cancer remains to be fully understood. In this study, by performing a proteomics screening of AMPK-interacting proteins in non-small-cell lung cancer (NSCLC) cells, we discovered the platelet isoform of phosphofructokinase 1 (PFKP), a rate-limiting enzyme in glycolysis. Moreover, PFKP was found to be highly expressed in NSCLC patients associated with poor survival. We demonstrated that the interaction of PFKP and AMPK was greatly enhanced upon glucose starvation, a process regulated by PFKP-associated metabolites. Notably, the PFKP-AMPK interaction promoted mitochondrial recruitment of AMPK which subsequently phosphorylated acetyl-CoA carboxylase 2 (ACC2) to enhance long-chain fatty acid oxidation, a process helping maintenance of the energy and redox homeostasis and eventually promoting cancer cell survival under glucose starvation. Collectively, we revealed a critical non-glycolysis-related function of PFKP in regulating long-chain fatty acid oxidation via AMPK to alleviate glucose starvation-induced metabolic stress in NSCLC cells.

DOI: https://doi.org/10.1038/s41421-022-00406-1
Signal Transduct Target Ther. 2022 Jun 03. 7(1): 171

Excessive branched-chain amino acid accumulation restricts mesenchymal stem cell-based therapy efficacy in myocardial infarction.

Fuyang Zhang, Guangyu Hu, Xiyao Chen, Ling Zhang, Lanyan Guo, Congye Li, Hang Zhao, Zhe Cui, Xiong Guo, Fangfang Sun, Dandan Song, Wenjun Yan, Yunlong Xia, Shan Wang, Miaomiao Fan, Ling Tao.

Mesenchymal stem cells (MSCs) delivered into the post-ischemic heart milieu have a low survival and retention rate, thus restricting the cardioreparative efficacy of MSC-based therapy. Chronic ischemia results in metabolic reprogramming in the heart, but little is known about how these metabolic changes influence implanted MSCs. Here, we found that excessive branched-chain amino acid (BCAA) accumulation, a metabolic signature seen in the post-ischemic heart, was disadvantageous to the retention and cardioprotection of intramyocardially injected MSCs. Discovery-driven experiments revealed that BCAA at pathological levels sensitized MSCs to stress-induced cell death and premature senescence via accelerating the loss of histone 3 lysine 9 trimethylation (H3K9me3). A novel mTORC1/DUX4/KDM4E axis was identified as the cause of BCAA-induced H3K9me3 loss and adverse phenotype acquisition. Enhancing BCAA catabolic capability in MSCs via genetic/pharmacological approaches greatly improved their adaptation to the high BCAA milieu and strengthened their cardioprotective efficacy. We conclude that aberrant BCAA accumulation is detrimental to implanted MSCs via a previously unknown metabolite-signaling-epigenetic mechanism, emphasizing that the metabolic changes of the post-ischemic heart crucially influence the fate of implanted MSCs and their therapeutic benefits.

DOI: https://doi.org/10.1038/s41392-022-00971-7