bims-mepmim 2024-03-10 papers

bims-mepmim

Biomed News

on Metabolites in pathological microenvironments and immunometabolism

Issue of 2024–03–10
28 papers selected by
Erika Mariana Palmieri, NIH/NCI Laboratory of Cancer ImmunoMetabolism

Hepatic malonyl-CoA synthesis restrains gluconeogenesis by suppressing fat oxidation, pyruvate carboxylation, and amino acid availability.
Inhibition of mitochondrial folate metabolism drives differentiation through mTORC1 mediated purine sensing.
Fatty acid oxidation fuels natural killer cell responses against infection and cancer.
Immunometabolic Maladaptations to the Tumor Microenvironment.
Regulation of urea cycle by reversible high-stoichiometry lysine succinylation.
Hypothalamic astrocyte NAD+ salvage pathway mediates the coupling of dietary fat overconsumption in a mouse model of obesity.
CD8+ T cells sustain antitumor response by mediating crosstalk between adenosine A2A receptor and glutathione/GPX4.
Itaconate boosts malaria via induction of PD-L1.
NDUFS4 regulates cristae remodeling in diabetic kidney disease.
Metabolic flux analysis in adipose tissue reprogramming.
Not just sugar: Metabolic control of neutrophil development and effector functions.
ALKBH5-mediated m6A modification of IL-11 drives macrophage-to-myofibroblast transition and pathological cardiac fibrosis in mice.
Fatty Acids Play a Critical Role in Mitochondrial Oxidative Phosphorylation in Effector T Cells in Graft-versus-Host Disease.
Deficiency in SLC25A15, a hypoxia-responsive gene, promotes hepatocellular carcinoma by reprogramming glutamine metabolism.
Detection of nitric oxide-mediated metabolic effects using real-time extracellular flux analysis.
Carnosine facilitates lysosomal release of inhibitors of T cell surveillance.
Lactate dehydrogenase A regulates tumor-macrophage symbiosis to promote glioblastoma progression.
Leishmania braziliensis enhances monocyte responses to promote anti-tumor activity.
Cancer-on-a-chip model shows that the adenomatous polyposis coli mutation impairs T cell engagement and killing of cancer spheroids.
Vitamin A resolves lineage plasticity to orchestrate stem cell lineage choices.
Heme metabolism in non-erythroid cells.
Blood metabolomic and transcriptomic signatures stratify patient subgroups in multiple sclerosis according to disease severity.
The m6A reader IGF2BP2 regulates glycolytic metabolism and mediates histone lactylation to enhance hepatic stellate cell activation and liver fibrosis.
Futile lipid cycling: from biochemistry to physiology.
Integrated stress response signaling acts as a metabolic sensor in fat tissues to regulate oocyte maturation and ovulation.
Stem Leydig cells support macrophage immunological homeostasis through mitochondrial transfer in mice.
Age-related dysregulation of intestinal epithelium fucosylation is linked to an increased risk of colon cancer.
Activity-dependent compartmentalization of dendritic mitochondria morphology through local regulation of fusion-fission balance in neurons in vivo.

Cell Metab. 2024 Mar 01. pii: S1550-4131(24)00050-0. [Epub ahead of print]

Hepatic malonyl-CoA synthesis restrains gluconeogenesis by suppressing fat oxidation, pyruvate carboxylation, and amino acid availability.

Stanislaw Deja, Justin A Fletcher, Chai-Wan Kim, Blanka Kucejova, Xiaorong Fu, Monika Mizerska, Morgan Villegas, Natalia Pudelko-Malik, Nicholas Browder, Melissa Inigo-Vollmer, Cameron J Menezes, Prashant Mishra, Eric D Berglund, Jeffrey D Browning, John P Thyfault, Jamey D Young, Jay D Horton, Shawn C Burgess.

  Acetyl-CoA carboxylase (ACC) promotes prandial liver metabolism by producing malonyl-CoA, a substrate for de novo lipogenesis and an inhibitor of CPT-1-mediated fat oxidation. We report that inhibition of ACC also produces unexpected secondary effects on metabolism. Liver-specific double ACC1/2 knockout (LDKO) or pharmacologic inhibition of ACC increased anaplerosis, tricarboxylic acid (TCA) cycle intermediates, and gluconeogenesis by activating hepatic CPT-1 and pyruvate carboxylase flux in the fed state. Fasting should have marginalized the role of ACC, but LDKO mice maintained elevated TCA cycle intermediates and preserved glycemia during fasting. These effects were accompanied by a compensatory induction of proteolysis and increased amino acid supply for gluconeogenesis, which was offset by increased protein synthesis during feeding. Such adaptations may be related to Nrf2 activity, which was induced by ACC inhibition and correlated with fasting amino acids. The findings reveal unexpected roles for malonyl-CoA synthesis in liver and provide insight into the broader effects of pharmacologic ACC inhibition.

Keywords:  Nrf2; TCA cycle; acetyl-CoA carboxylase; anaplerosis; autophagy; gluconeogenesis; lipogenesis; malonyl-CoA; protein synthesis; proteolysis

DOI:  https://doi.org/10.1016/j.cmet.2024.02.004
Nat Commun. 2024 Mar 02. 15(1): 1931

Inhibition of mitochondrial folate metabolism drives differentiation through mTORC1 mediated purine sensing.

Martha M Zarou, Kevin M Rattigan, Daniele Sarnello, Engy Shokry, Amy Dawson, Angela Ianniciello, Karen Dunn, Mhairi Copland, David Sumpton, Alexei Vazquez, G Vignir Helgason.

Supporting cell proliferation through nucleotide biosynthesis is an essential requirement for cancer cells. Hence, inhibition of folate-mediated one carbon (1C) metabolism, which is required for nucleotide synthesis, has been successfully exploited in anti-cancer therapy. Here, we reveal that mitochondrial folate metabolism is upregulated in patient-derived leukaemic stem cells (LSCs). We demonstrate that inhibition of mitochondrial 1C metabolism through impairment of de novo purine synthesis has a cytostatic effect on chronic myeloid leukaemia (CML) cells. Consequently, changes in purine nucleotide levels lead to activation of AMPK signalling and suppression of mTORC1 activity. Notably, suppression of mitochondrial 1C metabolism increases expression of erythroid differentiation markers. Moreover, we find that increased differentiation occurs independently of AMPK signalling and can be reversed through reconstitution of purine levels and reactivation of mTORC1. Of clinical relevance, we identify that combination of 1C metabolism inhibition with imatinib, a frontline treatment for CML patients, decreases the number of therapy-resistant CML LSCs in a patient-derived xenograft model. Our results highlight a role for folate metabolism and purine sensing in stem cell fate decisions and leukaemogenesis.

DOI: https://doi.org/10.1038/s41467-024-46114-0
Proc Natl Acad Sci U S A. 2024 Mar 12. 121(11): e2319254121

Fatty acid oxidation fuels natural killer cell responses against infection and cancer.

Sam Sheppard, Katja Srpan, Wendy Lin, Mariah Lee, Rebecca B Delconte, Mark Owyong, Peter Carmeliet, Daniel M Davis, Joao B Xavier, Katharine C Hsu, Joseph C Sun.

  Natural killer (NK) cells are a vital part of the innate immune system capable of rapidly clearing mutated or infected cells from the body and promoting an immune response. Here, we find that NK cells activated by viral infection or tumor challenge increase uptake of fatty acids and their expression of carnitine palmitoyltransferase I (CPT1A), a critical enzyme for long-chain fatty acid oxidation. Using a mouse model with an NK cell-specific deletion of CPT1A, combined with stable 13C isotope tracing, we observe reduced mitochondrial function and fatty acid-derived aspartate production in CPT1A-deficient NK cells. Furthermore, CPT1A-deficient NK cells show reduced proliferation after viral infection and diminished protection against cancer due to impaired actin cytoskeleton rearrangement. Together, our findings highlight that fatty acid oxidation promotes NK cell metabolic resilience, processes that can be optimized in NK cell-based immunotherapies.

Keywords:  NK cells; T cells; cancer; metabolism; virus infection

DOI:  https://doi.org/10.1073/pnas.2319254121
Cold Spring Harb Perspect Med. 2024 Mar 04. pii: a041547. [Epub ahead of print]

Immunometabolic Maladaptations to the Tumor Microenvironment.

Emma S Hathaway, Erin Q Jennings, Jeffrey C Rathmell.

Tumors consist of cancer cells and a wide range of tissue resident and infiltrating cell types. Tumor metabolism, however, has largely been studied on whole tumors or cancer cells and the metabolism of infiltrating immune cells remains poorly understood. It is now clear from a range of analyses and metabolite rescue studies that metabolic adaptations to the tumor microenvironment (TME) directly impede T-cell and macrophage effector functions. The drivers of metabolic adaptation to the TME and metabolic immune suppression include depletion of essential nutrients, accumulation of waste products or immune suppression metabolites, and metabolic signaling through altered posttranslational modifications. Each infiltrating immune cell subset differs, however, with specific metabolic requirements and adaptations that can be maladaptive for antitumor immunity. Here, we review T-cell and macrophage adaptation and metabolic immune suppression in solid tumors. Ultimately, understanding and addressing these challenges will improve cancer immunotherapy and adoptive chimeric antigen receptor T-cell therapies.

DOI: https://doi.org/10.1101/cshperspect.a041547
Nat Metab. 2024 Mar 06.

Regulation of urea cycle by reversible high-stoichiometry lysine succinylation.

Ran Zhang, Jingqi Fang, Xueshu Xie, Chris Carrico, Jesse G Meyer, Lei Wei, Joanna Bons, Jacob Rose, Rebeccah Riley, Ryan Kwok, Prasanna Vadhana Ashok Kumaar, Yini Zhang, Wenjuan He, Yuya Nishida, Xiaojing Liu, Jason W Locasale, Birgit Schilling, Eric Verdin.

The post-translational modification lysine succinylation is implicated in the regulation of various metabolic pathways. However, its biological relevance remains uncertain due to methodological difficulties in determining high-impact succinylation sites. Here, using stable isotope labelling and data-independent acquisition mass spectrometry, we quantified lysine succinylation stoichiometries in mouse livers. Despite the low overall stoichiometry of lysine succinylation, several high-stoichiometry sites were identified, especially upon deletion of the desuccinylase SIRT5. In particular, multiple high-stoichiometry lysine sites identified in argininosuccinate synthase (ASS1), a key enzyme in the urea cycle, are regulated by SIRT5. Mutation of the high-stoichiometry lysine in ASS1 to succinyl-mimetic glutamic acid significantly decreased its enzymatic activity. Metabolomics profiling confirms that SIRT5 deficiency decreases urea cycle activity in liver. Importantly, SIRT5 deficiency compromises ammonia tolerance, which can be reversed by the overexpression of wild-type, but not succinyl-mimetic, ASS1. Therefore, lysine succinylation is functionally important in ammonia metabolism.

DOI: https://doi.org/10.1038/s42255-024-01005-y
Nat Commun. 2024 Mar 07. 15(1): 2102

Hypothalamic astrocyte NAD+ salvage pathway mediates the coupling of dietary fat overconsumption in a mouse model of obesity.

Jae Woo Park, Se Eun Park, Wuhyun Koh, Won Hee Jang, Jong Han Choi, Eun Roh, Gil Myoung Kang, Seong Jun Kim, Hyo Sun Lim, Chae Beom Park, So Yeon Jeong, Sang Yun Moon, Chan Hee Lee, Sang Yeob Kim, Hyung Jin Choi, Se Hee Min, C Justin Lee, Min-Seon Kim.

Nicotinamide adenine dinucleotide (NAD)+ serves as a crucial coenzyme in numerous essential biological reactions, and its cellular availability relies on the activity of the nicotinamide phosphoribosyltransferase (NAMPT)-catalyzed salvage pathway. Here we show that treatment with saturated fatty acids activates the NAD+ salvage pathway in hypothalamic astrocytes. Furthermore, inhibition of this pathway mitigates hypothalamic inflammation and attenuates the development of obesity in male mice fed a high-fat diet (HFD). Mechanistically, CD38 functions downstream of the NAD+ salvage pathway in hypothalamic astrocytes burdened with excess fat. The activation of the astrocytic NAMPT-NAD+-CD38 axis in response to fat overload induces proinflammatory responses in the hypothalamus. It also leads to aberrantly activated basal Ca2+ signals and compromised Ca2+ responses to metabolic hormones such as insulin, leptin, and glucagon-like peptide 1, ultimately resulting in dysfunctional hypothalamic astrocytes. Our findings highlight the significant contribution of the hypothalamic astrocytic NAD+ salvage pathway, along with its downstream CD38, to HFD-induced obesity.

DOI: https://doi.org/10.1038/s41467-024-46009-0
J Clin Invest. 2024 Mar 05. pii: e170071. [Epub ahead of print]

CD8+ T cells sustain antitumor response by mediating crosstalk between adenosine A2A receptor and glutathione/GPX4.

Siqi Chen, Jie Fan, Ping Xie, Jihae Ahn, Michelle Fernandez, Leah K Billingham, Jason Miska, Jennifer D Wu, Derek A Wainwright, Deyu Fang, Jeffrey A Sosman, Yong Wan, Yi Zhang, Navdeep S Chandel, Bin Zhang.

  Antitumor responses of CD8+ T cells are tightly regulated by distinct metabolic fitness. High levels of glutathione (GSH) are observed in the majority of tumors contributing to cancer progression and treatment resistance in part by preventing glutathione peroxidase 4 (GPX4) dependent ferroptosis. Here, we show the necessity of the adenosine A2A receptor (A2AR) signaling and the glutathione (GSH)-GPX4 axis in orchestrating metabolic fitness and survival of functionally competent CD8+ T cells. Activated CD8+ T cells treated ex vivo with simultaneous inhibition of A2AR and lipid peroxidation acquire a superior capacity to proliferate and persist in vivo, demonstrating a translatable means to prevent ferroptosis in adoptive cell therapy (ACT). Additionally, we identify a particular cluster of intratumoral CD8+ T cells expressing a putative gene signature of GSH metabolism (GMGS) in association with clinical response and survival across several human cancers. Our study addresses a key role of GSH-GPX4 and adenosinergic pathways in fine-tuning the metabolic fitness of antitumor CD8+ T cells.

Keywords:  Cancer immunotherapy; Immunology; Metabolism; T cells

DOI:  https://doi.org/10.1172/JCI170071
Cell Metab. 2024 Mar 05. pii: S1550-4131(24)00051-2. [Epub ahead of print]36(3): 457-458

Itaconate boosts malaria via induction of PD-L1.

Yukun Min, Luke A J O'Neill.

The Krebs-cycle-derived metabolite itaconate has been shown to be immunomodulatory, targeting multiple processes in macrophages. Ramalho et al. reveal an additional role for itaconate in malaria.1Plasmodium Chabaudi induces itaconate in dendritic cells (DCs), leading to programmed death-ligand 1 (PD-L1) induction. This suppresses CD8+ T cells, important for host defense against malaria, thereby promoting parasitemia.

DOI: https://doi.org/10.1016/j.cmet.2024.02.005
Nat Commun. 2024 Mar 04. 15(1): 1965

NDUFS4 regulates cristae remodeling in diabetic kidney disease.

Koki Mise, Jianyin Long, Daniel L Galvan, Zengchun Ye, Guizhen Fan, Rajesh Sharma, Irina I Serysheva, Travis I Moore, Collene R Jeter, M Anna Zal, Motoo Araki, Jun Wada, Paul T Schumacker, Benny H Chang, Farhad R Danesh.

The mitochondrial electron transport chain (ETC) is a highly adaptive process to meet metabolic demands of the cell, and its dysregulation has been associated with diverse clinical pathologies. However, the role and nature of impaired ETC in kidney diseases remains poorly understood. Here, we generate diabetic mice with podocyte-specific overexpression of Ndufs4, an accessory subunit of mitochondrial complex I, as a model investigate the role of ETC integrity in diabetic kidney disease (DKD). We find that conditional male mice with genetic overexpression of Ndufs4 exhibit significant improvements in cristae morphology, mitochondrial dynamics, and albuminuria. By coupling proximity labeling with super-resolution imaging, we also identify the role of cristae shaping protein STOML2 in linking NDUFS4 with improved cristae morphology. Together, we provide the evidence on the central role of NDUFS4 as a regulator of cristae remodeling and mitochondrial function in kidney podocytes. We propose that targeting NDUFS4 represents a promising approach to slow the progression of DKD.

DOI: https://doi.org/10.1038/s41467-024-46366-w
Immunometabolism (Cobham). 2024 Jan;6(1): e00039

Metabolic flux analysis in adipose tissue reprogramming.

Ashley Medina, Joanne Bruno, José O Alemán.

  Obesity is a growing epidemic in the United States and worldwide and is associated with insulin resistance and cardiovascular disease, among other comorbidities. Understanding of the pathology that links overnutrition to these disease processes is ongoing. Adipose tissue is a heterogeneous organ comprised of multiple different cell types and it is likely that dysregulated metabolism within these cell populations disrupts both inter- and intracellular interactions and is a key driver of human disease. In recent years, metabolic flux analysis, which offers a precise quantification of metabolic pathway fluxes in biological systems, has emerged as a candidate strategy for uncovering the metabolic changes that stoke these disease processes. In this mini review, we discuss metabolic flux analysis as an experimental tool, with a specific emphasis on mass spectrometry with isotope tracing as this is the technique most frequently used for metabolic flux analysis in adipocytes. Furthermore, we examine existing literature that uses metabolic flux analysis to further our understanding of adipose tissue biology. Our group has a specific interest in understanding the role of white adipose tissue inflammation in the progression of cardiometabolic disease, as we know that in obesity the accumulation of pro-inflammatory adipose tissue macrophages is associated with significant morbidity, so we use this as a paradigm throughout our review for framing the application of these experimental techniques. However, there are many other biological applications to which they can be applied to further understanding of not only adipose tissue biology but also systemic homeostasis.

Keywords:  adipose tissue macrophages; crown-like structures; diabetes; inflammation; metabolic disease; obesity

DOI:  https://doi.org/10.1097/IN9.0000000000000039
J Leukoc Biol. 2024 Mar 07. pii: qiae057. [Epub ahead of print]

Not just sugar: Metabolic control of neutrophil development and effector functions.

Paul Ettel, Thomas Weichhart.

  The mammalian immune system is constantly surveying our tissues to clear pathogens and maintain tissue homeostasis. In order to fulfill these tasks, immune cells take up nutrients to supply energy for survival and for directly regulating effector functions via their cellular metabolism; a process now known as immunometabolism. Neutrophilic granulocytes, the most abundant leukocytes in the human body, have a short half-life and are permanently needed in the defense against pathogens. According to a long-standing view, neutrophils were thought to primarily fuel their metabolic demands via glycolysis. Yet, this view has been challenged as other metabolic pathways recently emerged to contribute to neutrophil homeostasis and effector functions. In particular during neutrophilic development, the pentose phosphate pathway, glycogen synthesis, oxidative phosphorylation, and fatty acid oxidation crucially promote neutrophil maturation. At steady state, both glucose and lipid metabolism sustain neutrophil survival and maintain the intracellular redox balance. This review aims to comprehensively discuss how neutrophilic metabolism adapts during development, which metabolic pathways fuel their functionality and how these processes are reconfigured in case of various diseases. We provide several examples of hereditary diseases, where mutations in metabolic enzymes validate their critical role for neutrophil function.

Keywords:  immunometabolism; innate immunity; metabolism; neutrophil

DOI:  https://doi.org/10.1093/jleuko/qiae057
Nat Commun. 2024 Mar 05. 15(1): 1995

ALKBH5-mediated m6A modification of IL-11 drives macrophage-to-myofibroblast transition and pathological cardiac fibrosis in mice.

Tao Zhuang, Mei-Hua Chen, Ruo-Xi Wu, Jing Wang, Xi-De Hu, Ting Meng, Ai-Hua Wu, Yan Li, Yong-Feng Yang, Yu Lei, Dong-Hua Hu, Yan-Xiu Li, Li Zhang, Ai-Jun Sun, Wei Lu, Guan-Nan Zhang, Jun-Li Zuo, Cheng-Chao Ruan.

Cardiac macrophage contributes to the development of cardiac fibrosis, but factors that regulate cardiac macrophages transition and activation during this process remains elusive. Here we show, by single-cell transcriptomics, lineage tracing and parabiosis, that cardiac macrophages from circulating monocytes preferentially commit to macrophage-to-myofibroblast transition (MMT) under angiotensin II (Ang II)-induced hypertension, with accompanying increased expression of the RNA N6-methyladenosine demethylases, ALKBH5. Meanwhile, macrophage-specific knockout of ALKBH5 inhibits Ang II-induced MMT, and subsequently ameliorates cardiac fibrosis and dysfunction. Mechanistically, RNA immunoprecipitation sequencing identifies interlukin-11 (IL-11) mRNA as a target for ALKBH5-mediated m6A demethylation, leading to increased IL-11 mRNA stability and protein levels. By contrast, overexpression of IL11 in circulating macrophages reverses the phenotype in ALKBH5-deficient mice and macrophage. Lastly, targeted delivery of ALKBH5 or IL-11 receptor α (IL11RA1) siRNA to monocytes/macrophages attenuates MMT and cardiac fibrosis under hypertensive stress. Our results thus suggest that the ALKBH5/IL-11/IL11RA1/MMT axis alters cardiac macrophage and contributes to hypertensive cardiac fibrosis and dysfunction in mice, and thereby identify potential targets for cardiac fibrosis therapy in patients.

DOI: https://doi.org/10.1038/s41467-024-46357-x
Immunohorizons. 2024 Mar 01. 8(3): 228-241

Fatty Acids Play a Critical Role in Mitochondrial Oxidative Phosphorylation in Effector T Cells in Graft-versus-Host Disease.

Hirofumi Nakano, Kazuya Sato, Junko Izawa, Norihito Takayama, Hiroko Hayakawa, Takashi Ikeda, Shin-Ichiro Kawaguchi, Kiyomi Mashima, Kento Umino, Kaoru Morita, Ryoji Ito, Nobuhiko Ohno, Kaoru Tominaga, Hitoshi Endo, Yoshinobu Kanda.

Although the role of aerobic glycolysis in activated T cells has been well characterized, whether and how fatty acids (FAs) contribute to donor T cell function in allogeneic hematopoietic stem cell transplantation is unclear. Using xenogeneic graft-versus-host disease (GVHD) models, this study demonstrated that exogenous FAs serve as a crucial source of mitochondrial respiration in donor T cells in humans. By comparing human T cells isolated from wild-type NOD/Shi-scid-IL2rγnull (NOG) mice with those from MHC class I/II-deficient NOG mice, we found that donor T cells increased extracellular FA uptake, the extent of which correlates with their proliferation, and continued to increase FA uptake during effector differentiation. Gene expression analysis showed the upregulation of a wide range of lipid metabolism-related genes, including lipid hydrolysis, mitochondrial FA transport, and FA oxidation. Extracellular flux analysis demonstrated that mitochondrial FA transport was required to fully achieve the mitochondrial maximal respiration rate and spare respiratory capacity, whereas the substantial disruption of glucose supply by either glucose deprivation or mitochondrial pyruvate transport blockade did not impair oxidative phosphorylation. Taken together, FA-driven mitochondrial respiration is a hallmark that differentiates TCR-dependent T cell activation from TCR-independent immune response after hematopoietic stem cell transplant.

DOI: https://doi.org/10.4049/immunohorizons.2300115
J Hepatol. 2024 Feb;pii: S0168-8278(23)05224-8. [Epub ahead of print]80(2): 293-308

Deficiency in SLC25A15, a hypoxia-responsive gene, promotes hepatocellular carcinoma by reprogramming glutamine metabolism.

Qiangnu Zhang, Teng Wei, Wen Jin, Lesen Yan, Lulin Shi, Siqi Zhu, Yu Bai, Yuandi Zeng, Zexin Yin, Jilin Yang, Wenjian Zhang, Meilong Wu, Yusen Zhang, Gongze Peng, Stephanie Roessler, Liping Liu.

   BACKGROUND & AIMS: The role of solute carrier family 25 member 15 (SLC25A15), a critical component of the urea cycle, in hepatocellular carcinoma (HCC) progression remains poorly understood. This study investigated the impact of SLC25A15 on HCC progression and its mechanisms.
METHODS: We systematically investigated the function of SLC25A15 in HCC progression using large-scale data mining and cell, animal, and organoid models. Furthermore, we analyzed its involvement in reprogramming glutamine metabolism.
RESULTS: SLC25A15 expression was significantly decreased in HCC tissues, and patients with low SLC25A15 levels had a poorer prognosis. Hypoxia-exposed HCC cells or tissues had lower SLC25A15 expression. A positive correlation between HNF4A, a transcription factor suppressed by hypoxia, and SLC25A15 was observed in both HCC tissues and cells. Modulating HNF4A levels altered SLC25A15 mRNA levels. SLC25A15 upregulated SLC1A5, increasing glutamine uptake. The reactive metabolic pathway of glutamine was increased in SLC25A15-deficient HCC cells, providing energy for HCC progression through additional lipid synthesis. Ammonia accumulation due to low SLC25A15 levels suppressed the expression of OGDHL (oxoglutarate dehydrogenase L), a switch gene that mediates SLC25A15 deficiency-induced reprogramming of glutamine metabolism. SLC25A15-deficient HCC cells were more susceptible to glutamine deprivation and glutaminase inhibitors. Intervening in glutamine metabolism increased SLC25A15-deficient HCC cells' response to anti-PD-L1 treatment.
CONCLUSION: SLC25A15 is hypoxia-responsive in HCC, and low SLC25A15 levels result in glutamine reprogramming through SLC1A5 and OGDHL regulation, promoting HCC progression and regulating cell sensitivity to anti-PD-L1. Interrupting the glutamine-derived energy supply is a potential therapeutic strategy for treating SLC25A15-deficient HCC.
IMPACT AND IMPLICATIONS: We first demonstrated the tumor suppressor role of solute carrier family 25 member 15 (SLC25A15) in hepatocellular carcinoma (HCC) and showed that its deficiency leads to reprogramming of glutamine metabolism to promote HCC development. SLC25A15 can serve as a potential biomarker to guide the development of precision therapeutic strategies aimed at targeting glutamine deprivation. Furthermore, we highlight that the use of an inhibitor of glutamine utilization can enhance the sensitivity of low SLC25A15 HCC to anti-PD-L1 therapy.

Keywords:  Glutamine; Hypoxia; Liver cancer; SLC25A15; Urea cycle

DOI:  https://doi.org/10.1016/j.jhep.2023.10.024
PLoS One. 2024 ;19(3): e0299294

Detection of nitric oxide-mediated metabolic effects using real-time extracellular flux analysis.

Bay Vagher, Eyal Amiel.

Dendritic cell (DC) activation is marked by key events including: (I) rapid induction and shifting of metabolism favoring glycolysis for generation of biosynthetic metabolic intermediates and (II) large scale changes in gene expression including the upregulation of the antimicrobial enzyme inducible nitric oxide synthase (iNOS) which produces the toxic gas nitric oxide (NO). Historically, acute metabolic reprogramming and NO-mediated effects on cellular metabolism have been studied at specific timepoints during the DC activation process, namely at times before and after NO production. However, no formal method of real time detection of NO-mediated effects on DC metabolism have been fully described. Here, using Real-Time Extracellular Flux Analysis, we experimentally establish the phenomenon of an NO-dependent mitochondrial respiration threshold, which shows how titration of an activating stimulus is inextricably linked to suppression of mitochondrial respiration in an NO-dependent manner. As part of this work, we explore the efficacy of two different iNOS inhibitors in blocking the iNOS reaction kinetically in real time and explore/discuss parameters and considerations for application using Real Time Extracellular Flux Analysis technology. In addition, we show, the temporal relationship between acute metabolic reprogramming and NO-mediated sustained metabolic reprogramming kinetically in single real-time assay. These findings provide a method for detection of NO-mediated metabolic effects in DCs and offer novel insight into the timing of the DC activation process with its associated key metabolic events, revealing a better understanding of the nuances of immune cell biology.

DOI: https://doi.org/10.1371/journal.pone.0299294
Cell Metab. 2024 Mar 05. pii: S1550-4131(24)00049-4. [Epub ahead of print]36(3): 461-462

Carnosine facilitates lysosomal release of inhibitors of T cell surveillance.

Pawel Swietach, Marja Jäättelä, Shari Pillon-Thomas, Ebbe Boedtkjer.

Cancer metabolism produces large fluxes of lactate and H+, which are extruded by membrane transporters. However, H+ production and extrusion must be coupled by diffusion, facilitated by mobile buffers. Yan et al. propose that carnosine, generated by CARNS2, provides this mobile buffering and enables lysosomal functions that block T cell surveillance.

DOI: https://doi.org/10.1016/j.cmet.2024.02.003
Nat Commun. 2024 Mar 05. 15(1): 1987

Lactate dehydrogenase A regulates tumor-macrophage symbiosis to promote glioblastoma progression.

Fatima Khan, Yiyun Lin, Heba Ali, Lizhi Pang, Madeline Dunterman, Wen-Hao Hsu, Katie Frenis, R Grant Rowe, Derek A Wainwright, Kathleen McCortney, Leah K Billingham, Jason Miska, Craig Horbinski, Maciej S Lesniak, Peiwen Chen.

Abundant macrophage infiltration and altered tumor metabolism are two key hallmarks of glioblastoma. By screening a cluster of metabolic small-molecule compounds, we show that inhibiting glioblastoma cell glycolysis impairs macrophage migration and lactate dehydrogenase inhibitor stiripentol emerges as the top hit. Combined profiling and functional studies demonstrate that lactate dehydrogenase A (LDHA)-directed extracellular signal-regulated kinase (ERK) pathway activates yes-associated protein 1 (YAP1)/ signal transducer and activator of transcription 3 (STAT3) transcriptional co-activators in glioblastoma cells to upregulate C-C motif chemokine ligand 2 (CCL2) and CCL7, which recruit macrophages into the tumor microenvironment. Reciprocally, infiltrating macrophages produce LDHA-containing extracellular vesicles to promote glioblastoma cell glycolysis, proliferation, and survival. Genetic and pharmacological inhibition of LDHA-mediated tumor-macrophage symbiosis markedly suppresses tumor progression and macrophage infiltration in glioblastoma mouse models. Analysis of tumor and plasma samples of glioblastoma patients confirms that LDHA and its downstream signals are potential biomarkers correlating positively with macrophage density. Thus, LDHA-mediated tumor-macrophage symbiosis provides therapeutic targets for glioblastoma.

DOI: https://doi.org/10.1038/s41467-024-46193-z
Cell Rep. 2024 Mar 07. pii: S2211-1247(24)00260-2. [Epub ahead of print]43(3): 113932

Leishmania braziliensis enhances monocyte responses to promote anti-tumor activity.

Jéssica Cristina Dos Santos, María Moreno, Lisa U Teufel, Sofía Chilibroste, Samuel T Keating, Laszlo Groh, Jorge Domínguez-Andrés, David L Williams, Zuchao Ma, Douglas W Lowman, Harry E Ensley, Boris Novakovic, Fátima Ribeiro-Dias, Mihai G Netea, José A Chabalgoity, Leo A B Joosten.

  Innate immune cells can undergo long-term functional reprogramming after certain infections, a process called trained immunity (TI). Here, we focus on antigens of Leishmania braziliensis, which induced anti-tumor effects via trained immunity in human monocytes. We reveal that monocytes exposed to promastigote antigens of L. braziliensis develop an enhanced response to subsequent exposure to Toll-like receptor (TLR)2 or TLR4 ligands. Mechanistically, the induction of TI in monocytes by L. braziliensis is mediated by multiple pattern recognition receptors, changes in metabolism, and increased deposition of H3K4me3 at the promoter regions of immune genes. The administration of L. braziliensis exerts potent anti-tumor capabilities by delaying tumor growth and prolonging survival of mice with non-Hodgkin lymphoma. Our work reveals mechanisms of TI induced by L. braziliensis in vitro and identifies its potential for cancer immunotherapy.

Keywords:  CP: Cancer; CP: Immunology; Leishmania braziliensis; anti-tumor activities; enhanced cytokines responsiveness; human monocytes; non-Hodgkin lymphoma; trained immunity

DOI:  https://doi.org/10.1016/j.celrep.2024.113932
Proc Natl Acad Sci U S A. 2024 Mar 12. 121(11): e2316500121

Cancer-on-a-chip model shows that the adenomatous polyposis coli mutation impairs T cell engagement and killing of cancer spheroids.

Valentin Bonnet, Erik Maikranz, Marianne Madec, Nadia Vertti-Quintero, Céline Cuche, Marta Mastrogiovanni, Andrés Alcover, Vincenzo Di Bartolo, Charles N Baroud.

  Evaluating the ability of cytotoxic T lymphocytes (CTLs) to eliminate tumor cells is crucial, for instance, to predict the efficiency of cell therapy in personalized medicine. However, the destruction of a tumor by CTLs involves CTL migration in the extra-tumoral environment, accumulation on the tumor, antigen recognition, and cooperation in killing the cancer cells. Therefore, identifying the limiting steps in this complex process requires spatio-temporal measurements of different cellular events over long periods. Here, we use a cancer-on-a-chip platform to evaluate the impact of adenomatous polyposis coli (APC) mutation on CTL migration and cytotoxicity against 3D tumor spheroids. The APC mutated CTLs are found to have a reduced ability to destroy tumor spheroids compared with control cells, even though APC mutants migrate in the extra-tumoral space and accumulate on the spheroids as efficiently as control cells. Once in contact with the tumor however, mutated CTLs display reduced engagement with the cancer cells, as measured by a metric that distinguishes different modes of CTL migration. Realigning the CTL trajectories around localized killing cascades reveals that all CTLs transition to high engagement in the 2 h preceding the cascades, which confirms that the low engagement is the cause of reduced cytotoxicity. Beyond the study of APC mutations, this platform offers a robust way to compare cytotoxic cell efficiency of even closely related cell types, by relying on a multiscale cytometry approach to disentangle complex interactions and to identify the steps that limit the tumor destruction.

Keywords:  3D cell culture; immuno-oncology; microfluidics; quantitative biology

DOI:  https://doi.org/10.1073/pnas.2316500121
Science. 2024 Mar 08. 383(6687): eadi7342

Vitamin A resolves lineage plasticity to orchestrate stem cell lineage choices.

Matthew T Tierney, Lisa Polak, Yihao Yang, Merve Deniz Abdusselamoglu, Inwha Baek, Katherine S Stewart, Elaine Fuchs.

Lineage plasticity-a state of dual fate expression-is required to release stem cells from their niche constraints and redirect them to tissue compartments where they are most needed. In this work, we found that without resolving lineage plasticity, skin stem cells cannot effectively generate each lineage in vitro nor regrow hair and repair wounded epidermis in vivo. A small-molecule screen unearthed retinoic acid as a critical regulator. Combining high-throughput approaches, cell culture, and in vivo mouse genetics, we dissected its roles in tissue regeneration. We found that retinoic acid is made locally in hair follicle stem cell niches, where its levels determine identity and usage. Our findings have therapeutic implications for hair growth as well as chronic wounds and cancers, where lineage plasticity is unresolved.

DOI: https://doi.org/10.1126/science.adi7342
J Biol Chem. 2024 Mar 01. pii: S0021-9258(24)01627-2. [Epub ahead of print] 107132

Heme metabolism in non-erythroid cells.

Luke S Dunaway, Skylar A Loeb, Sara Petrillo, Emanuela Tolosano, Brant E Isakson.

  Heme is an iron-containing prosthetic group necessary for the function of several proteins termed "hemoproteins". Erythrocytes contain most of the body's heme in the form of hemoglobin and contain high concentrations of free heme. In non-erythroid cells, where cytosolic heme concentrations are 2-3 orders of magnitude lower, heme plays an essential and often overlooked role in a variety of cellular processes. Indeed, hemoproteins are found in almost every subcellular compartment and are integral in cellular operations such as oxidative phosphorylation, amino acid metabolism, xenobiotic metabolism, and transcriptional regulation. Growing evidence reveals the participation of heme in dynamic processes such as circadian rhythms, NO signaling, and the modulation of enzyme activity. This dynamic view of heme biology uncovers exciting possibilities as to how hemoproteins may participate in a range of physiologic systems. Here we discuss how heme is regulated at the level of its synthesis, availability, redox state, transport, and degradation and highlight the implications for cellular function and whole organism physiology.

Keywords:  Heme; Heme oxygenase; Iron; Metalloprotein; Oxidation-reduction (redox)

DOI:  https://doi.org/10.1016/j.jbc.2024.107132
iScience. 2024 Mar 15. 27(3): 109225

Blood metabolomic and transcriptomic signatures stratify patient subgroups in multiple sclerosis according to disease severity.

Alexandra E Oppong, Leda Coelewij, Georgia Robertson, Lucia Martin-Gutierrez, Kirsty E Waddington, Pierre Dönnes, Petra Nytrova, Rachel Farrell, Inés Pineda-Torra, Elizabeth C Jury.

  There are no blood-based biomarkers distinguishing patients with relapsing-remitting (RRMS) from secondary progressive multiple sclerosis (SPMS) although evidence supports metabolomic changes according to MS disease severity. Here machine learning analysis of serum metabolomic data stratified patients with RRMS from SPMS with high accuracy and a putative score was developed that stratified MS patient subsets. The top differentially expressed metabolites between SPMS versus patients with RRMS included lipids and fatty acids, metabolites enriched in pathways related to cellular respiration, notably, elevated lactate and glutamine (gluconeogenesis-related) and acetoacetate and bOHbutyrate (ketone bodies), and reduced alanine and pyruvate (glycolysis-related). Serum metabolomic changes were recapitulated in the whole blood transcriptome, whereby differentially expressed genes were also enriched in cellular respiration pathways in patients with SPMS. The final gene-metabolite interaction network demonstrated a potential metabolic shift from glycolysis toward increased gluconeogenesis and ketogenesis in SPMS, indicating metabolic stress which may trigger stress response pathways and subsequent neurodegeneration.

Keywords:  Classification Description; Machine learning; Metabolomics; Molecular network; Transcriptomics

DOI:  https://doi.org/10.1016/j.isci.2024.109225
Cell Death Dis. 2024 Mar 05. 15(3): 189

The m6A reader IGF2BP2 regulates glycolytic metabolism and mediates histone lactylation to enhance hepatic stellate cell activation and liver fibrosis.

Yongqiang Zhou, Jiexi Yan, He Huang, Lu Liu, Longfei Ren, Jinjing Hu, Xiaoxu Jiang, Yan Zheng, Lingcong Xu, Fupeng Zhong, Xun Li.

Evidence for the involvement of N6-Methyladenosine (m6A) modification in the etiology and progression of liver fibrosis has emerged and holds promise as a therapeutic target. Insulin-like growth factor 2 (IGF2) mRNA-binding protein 2 (IGF2BP2) is a newly identified m6A-binding protein that functions to enhance mRNA stability and translation. However, its role as an m6A-binding protein in liver fibrosis remains elusive. Here, we observed that IGF2BP2 is highly expressed in liver fibrosis and activated hepatic stellate cells (HSCs), and inhibition of IGF2BP2 protects against HSCs activation and liver fibrogenesis. Mechanistically, as an m6A-binding protein, IGF2BP2 regulates the expression of Aldolase A (ALDOA), a key target in the glycolytic metabolic pathway, which in turn regulates HSCs activation. Furthermore, we observed that active glycolytic metabolism in activated HSCs generates large amounts of lactate as a substrate for histone lactylation. Importantly, histone lactylation transforms the activation phenotype of HSCs. In conclusion, our findings reveal the essential role of IGF2BP2 in liver fibrosis by regulating glycolytic metabolism and highlight the potential of targeting IGF2BP2 as a therapeutic for liver fibrosis.

DOI: https://doi.org/10.1038/s41419-024-06509-9
Nat Metab. 2024 Mar 08.

Futile lipid cycling: from biochemistry to physiology.

Anand Kumar Sharma, Radhika Khandelwal, Christian Wolfrum.

In the healthy state, the fat stored in our body isn't just inert. Rather, it is dynamically mobilized to maintain an adequate concentration of fatty acids (FAs) in our bloodstream. Our body tends to produce excess FAs to ensure that the FA availability is not limiting. The surplus FAs are actively re-esterified into glycerides, initiating a cycle of breakdown and resynthesis of glycerides. This cycle consumes energy without generating a new product and is commonly referred to as the 'futile lipid cycle' or the glyceride/FA cycle. Contrary to the notion that it's a wasteful process, it turns out this cycle is crucial for systemic metabolic homeostasis. It acts as a control point in intra-adipocyte and inter-organ cross-talk, a metabolic rheostat, an energy sensor and a lipid diversifying mechanism. In this Review, we discuss the metabolic regulation and physiological implications of the glyceride/FA cycle and its mechanistic underpinnings.

DOI: https://doi.org/10.1038/s42255-024-01003-0
Cell Rep. 2024 Mar 06. pii: S2211-1247(24)00191-8. [Epub ahead of print]43(3): 113863

Integrated stress response signaling acts as a metabolic sensor in fat tissues to regulate oocyte maturation and ovulation.

Lydia Grmai, Manuel Michaca, Emily Lackner, Narayanan Nampoothiri V P, Deepika Vasudevan.

  Reproduction is an energy-intensive process requiring systemic coordination. However, the inter-organ signaling mechanisms that relay nutrient status to modulate reproductive output are poorly understood. Here, we use Drosophila melanogaster as a model to establish the integrated stress response (ISR) transcription factor, Atf4, as a fat tissue metabolic sensor that instructs oogenesis. We demonstrate that Atf4 regulates lipase activity to mediate yolk lipoprotein synthesis in the fat body. Depletion of Atf4 in the fat body also blunts oogenesis recovery after amino acid deprivation and re-feeding, suggestive of a nutrient-sensing role for Atf4. We also discovered that Atf4 promotes secretion of a fat-body-derived neuropeptide, CNMamide, which modulates neural circuits that promote egg-laying behavior (ovulation). Thus, we posit that ISR signaling in fat tissue acts as a "metabolic sensor" that instructs female reproduction-directly by impacting yolk lipoprotein production and follicle maturation and systemically by regulating ovulation.

Keywords:  Atf4; CNMa; CP: Cell biology; CP: Developmental biology; adipocyte; bmm; egg retention; integrated stress response; oogenesis; ovulation; yolk protein

DOI:  https://doi.org/10.1016/j.celrep.2024.113863
Nat Commun. 2024 Mar 08. 15(1): 2120

Stem Leydig cells support macrophage immunological homeostasis through mitochondrial transfer in mice.

Ani Chi, Bicheng Yang, Hao Dai, Xinyu Li, Jiahui Mo, Yong Gao, Zhihong Chen, Xin Feng, Menghui Ma, Yanqing Li, Chao Yang, Jie Liu, Hanchao Liu, Zhenqing Wang, Feng Gao, Yan Liao, Xuetao Shi, Chunhua Deng, Min Zhang.

As testicular mesenchymal stromal cells, stem Leydig cells (SLCs) show great promise in the treatment of male hypogonadism. The therapeutic functions of mesenchymal stromal cells are largely determined by their reciprocal regulation by immune responses. However, the immunoregulatory properties of SLCs remain unclear. Here, we observe that SLCs transplantation restore male fertility and testosterone production in an ischemia‒reperfusion injury mouse model. SLCs prevent inflammatory cascades through mitochondrial transfer to macrophages. Reactive oxygen species (ROS) released from activated macrophages inducing mitochondrial transfer from SLCs to macrophages in a transient receptor potential cation channel subfamily member 7 (TRPM7)-mediated manner. Notably, knockdown of TRPM7 in transplanted SLCs compromised therapeutic outcomes in both testicular ischemia‒reperfusion and testicular aging mouse models. These findings reveal a new mechanism of SLCs transplantation that may contribute to preserve testis function in male patients with hypogonadism related to immune disorders.

DOI: https://doi.org/10.1038/s41467-024-46190-2
JCI Insight. 2024 Mar 08. pii: e167676. [Epub ahead of print]9(5):

Age-related dysregulation of intestinal epithelium fucosylation is linked to an increased risk of colon cancer.

Zhihan Wang, Pan Gao, Kai Guo, Grace Schirrick, Jappreet Singh Gill, Jett Weis, Abby Lund Da Costa, Mansib Rahman, Het Mehta, Julia Fleecs, Shilpi Jain, Trishna Debnath, Junguk Hur, Nadeem Khan, Robert Sticca, Holly M Brown-Borg, Donald A Jurivich, Ramkumar Mathur.

  Colon cancer affects people of all ages. However, its frequency, as well as the related morbidity and mortality, are high among older adults. The complex physiological changes in the aging gut substantially limit the development of cancer therapies. Here, we identify a potentially unique intestinal microenvironment that is linked with an increased risk of colon cancer in older adults. Our findings show that aging markedly influenced persistent fucosylation of the apical surfaces of intestinal epithelial cells, which resulted in a favorable environment for tumor growth. Furthermore, our findings shed light on the importance of the host-commensal interaction, which facilitates the dysregulation of fucosylation and promotes tumor growth as people get older. We analyzed colonic microbial populations at the species level to find changes associated with aging that could contribute to the development of colon cancer. Analysis of single-cell RNA-sequencing data from previous publications identified distinct epithelial cell subtypes involved in dysregulated fucosylation in older adults. Overall, our study provides compelling evidence that excessive fucosylation is associated with the development of colon cancer, that age-related changes increase vulnerability to colon cancer, and that a dysbiosis in microbial diversity and metabolic changes in the homeostasis of older mice dysregulate fucosylation levels with age.

Keywords:  Aging; Cellular senescence; Colorectal cancer; Drug therapy; Microbiology

DOI:  https://doi.org/10.1172/jci.insight.167676
Nat Commun. 2024 Mar 08. 15(1): 2142

Activity-dependent compartmentalization of dendritic mitochondria morphology through local regulation of fusion-fission balance in neurons in vivo.

Daniel M Virga, Stevie Hamilton, Bertha Osei, Abigail Morgan, Parker Kneis, Emiliano Zamponi, Natalie J Park, Victoria L Hewitt, David Zhang, Kevin C Gonzalez, Fiona M Russell, D Grahame Hardie, Julien Prudent, Erik Bloss, Attila Losonczy, Franck Polleux, Tommy L Lewis.

Neuronal mitochondria play important roles beyond ATP generation, including Ca2+ uptake, and therefore have instructive roles in synaptic function and neuronal response properties. Mitochondrial morphology differs significantly between the axon and dendrites of a given neuronal subtype, but in CA1 pyramidal neurons (PNs) of the hippocampus, mitochondria within the dendritic arbor also display a remarkable degree of subcellular, layer-specific compartmentalization. In the dendrites of these neurons, mitochondria morphology ranges from highly fused and elongated in the apical tuft, to more fragmented in the apical oblique and basal dendritic compartments, and thus occupy a smaller fraction of dendritic volume than in the apical tuft. However, the molecular mechanisms underlying this striking degree of subcellular compartmentalization of mitochondria morphology are unknown, precluding the assessment of its impact on neuronal function. Here, we demonstrate that this compartment-specific morphology of dendritic mitochondria requires activity-dependent, Ca2+ and Camkk2-dependent activation of AMPK and its ability to phosphorylate two direct effectors: the pro-fission Drp1 receptor Mff and the recently identified anti-fusion, Opa1-inhibiting protein, Mtfr1l. Our study uncovers a signaling pathway underlying the subcellular compartmentalization of mitochondrial morphology in dendrites of neurons in vivo through spatially precise and activity-dependent regulation of mitochondria fission/fusion balance.

DOI: https://doi.org/10.1038/s41467-024-46463-w