bims-mepmim 2022-04-10 papers

bims-mepmim

Biomed News

on Metabolites in pathological microenvironments and immunometabolism

Issue of 2022–04–10
thirty-six papers selected by
Erika Mariana Palmieri, NIH/NCI Laboratory of Cancer ImmunoMetabolism

Supramolecular nanotherapeutics enable metabolic reprogramming of tumor-associated macrophages to inhibit tumor growth.
Compartmentalized metabolism supports midgestation mammalian development.
Intercellular communications and metabolic reprogramming as new predictive markers for immunotherapy responses in gastric cancer.
Regulation of Glucose, Fatty Acid and Amino Acid Metabolism by Ubiquitination and SUMOylation for Cancer Progression.
Bioenergetic and Metabolic Adaptation in Tumor Progression and Metastasis.
Proximal Tubular Oxidative Metabolism in Acute Kidney Injury and the Transition to CKD.
Pancreatic Stellate Cells and Metabolic Alteration: Physiology and Pathophysiology.
Effects of PD-1 Signaling on Immunometabolic Reprogramming.
Fluxomics - New Metabolomics Approaches to Monitor Metabolic Pathways.
Immune Metabolism-An Opportunity to Better Understand Allergic Pathology and Improve Treatment of Allergic Diseases?
Pharmacologically Inferred Glycolysis and Glutaminolysis Requirement of B Cells in Lupus-Prone Mice.
Glycolytic metabolism supports microglia training during age-related neurodegeneration.
Glutathione-dependent redox balance characterizes the distinct metabolic properties of follicular and marginal zone B cells.
Pkd1 Mutation Has No Apparent Effects on Peroxisome Structure or Lipid Metabolism.
Sugar addiction: An Achilles' heel of auto-immune diseases?
Metaboloepigenetics in cancer, immunity and cardiovascular disease.
Biomimetic Nanocarriers Guide Extracellular ATP Homeostasis to Remodel Energy Metabolism for Activating Innate and Adaptive Immunity System.
NADPH metabolism determines the leukemogenic capacity and drug resistance of AML cells.
Prolonged exposure to simulated microgravity promotes stemness impairing morphological, metabolic and migratory profile of pancreatic cancer cells: a comprehensive proteomic, lipidomic and transcriptomic analysis.
Ferroptosis at the intersection of lipid metabolism and cellular signaling.
Microbial Metabolism Activates Immune-Suppressive Tumor Macrophages.
A mitochondrial long-chain fatty acid oxidation defect leads to tRNA uncharging and activation of the integrated stress response in the mouse heart.
Cholesterol and HIF-1α: Dangerous Liaisons in Atherosclerosis.
Specificity of ABCA7-mediated cell lipid efflux.
Filamentous GLS1 promotes ROS-induced apoptosis upon glutamine deprivation via insufficient asparagine synthesis.
Bone marrow adipose tissue in metabolic health.
Vitamin D activates FBP1 to block the Warburg effect and modulate blast metabolism in acute myeloid leukemia.
Podocyte Lipotoxicity in CKD.
Prognostic significance of three endothelial nitric oxide synthase (eNOS) polymorphisms and metabolic syndrome (MetS) in patients with colorectal cancer.
Gut microbiota severely hampers the efficacy of NAD-lowering therapy in leukemia.
Microbial metabolite as icebreaker for immunotherapy.
Metabolism drives macrophage heterogeneity in the tumor microenvironment.
Urine Xanthine Crystals in Hematologic Malignancies with Tumor Lysis Syndrome.
Osteoblast lineage Sod2 deficiency leads to an osteoporosis-like phenotype in mice.
Membrane potential-dependent regulation of mitochondrial complex II by oxaloacetate in interscapular brown adipose tissue.
The Mitochondria-Targeting Agent MitoQ Improves Muscle Atrophy, Weakness and Oxidative Metabolism in C26 Tumor-Bearing Mice.

J Biomed Mater Res A. 2022 Apr 07.

Supramolecular nanotherapeutics enable metabolic reprogramming of tumor-associated macrophages to inhibit tumor growth.

Anujan Ramesh, Vaishali Malik, Anthony Brouillard, Ashish Kulkarni.

  Tumor-associated macrophages (TAMs) exist in multiple phenotypes across the spectrum, defined by an M1 antitumorigenic phenotype and an M2 pro-tumorigenic phenotype on two ends of the spectrum. A largely immunosuppressive tumor-microenvironment aids the polarization of the infiltrating macrophages to a pro-tumorigenic M2 phenotype that promotes tumor progression and metastasis. Recent developments in macrophage immunotherapy have focused on strategies to re-educate TAMs from an M2 to M1 phenotype. Recent findings in the realm of immuno-metabolism have indicated that distinct metabolic signatures accompany macrophages based on their polarization states (M1-Glycolysis and M2-TCA cycle). These metabolites are important drivers of cellular signaling responsible for acquiring these polarization states, with evidence showing that metabolism is essential to facilitate the energy requirements of immune cells and regulate immune cell response. We hypothesized that TAMs could be reprogrammed metabolically by co-delivery of drugs using a supramolecular nanoparticle system that could effectively rewire macrophage metabolism by simultaneous inhibition of the TCA cycle and upregulation of the glycolytic metabolic pathway. TLR7/8 agonist and Fatty Acid Oxidation (FAO) inhibitor loaded metabolic supramolecular nanoparticles (MSNPs) were synthesized. In vitro assays showed macrophages treated with MSNPs were reprogrammed from an M2 phenotype to an M1 phenotype while significantly upregulating phagocytosis. When injected in 4T1 tumor-bearing mice, MSNPs treatment reduced tumor growth progression more than other treatments. Hence, the delivery of TLR7/8 agonist combined with an FAO inhibitor can enhance antitumor efficacy through metabolic reprogramming of tumor-associated macrophages.

Keywords:  cancer; combination; immunotherapy; macrophage; metabolic reprogramming

DOI:  https://doi.org/10.1002/jbm.a.37391
Nature. 2022 Apr 06.

Compartmentalized metabolism supports midgestation mammalian development.

Ashley Solmonson, Brandon Faubert, Wen Gu, Aparna Rao, Mitzy A Cowdin, Ivan Menendez-Montes, Sherwin Kelekar, Thomas J Rogers, Chunxiao Pan, Gerardo Guevara, Amy Tarangelo, Lauren G Zacharias, Misty S Martin-Sandoval, Duyen Do, Panayotis Pachnis, Dennis Dumesnil, Thomas P Mathews, Alpaslan Tasdogan, An Pham, Ling Cai, Zhiyu Zhao, Min Ni, Ondine Cleaver, Hesham A Sadek, Sean J Morrison, Ralph J DeBerardinis.

Mammalian embryogenesis requires rapid growth and proper metabolic regulation1. Midgestation features increasing oxygen and nutrient availability concomitant with fetal organ development2,3. Understanding how metabolism supports development requires approaches to observe metabolism directly in model organisms in utero. Here we used isotope tracing and metabolomics to identify evolving metabolic programmes in the placenta and embryo during midgestation in mice. These tissues differ metabolically throughout midgestation, but we pinpointed gestational days (GD) 10.5-11.5 as a transition period for both placenta and embryo. Isotope tracing revealed differences in carbohydrate metabolism between the tissues and rapid glucose-dependent purine synthesis, especially in the embryo. Glucose's contribution to the tricarboxylic acid (TCA) cycle rises throughout midgestation in the embryo but not in the placenta. By GD12.5, compartmentalized metabolic programmes are apparent within the embryo, including different nutrient contributions to the TCA cycle in different organs. To contextualize developmental anomalies associated with Mendelian metabolic defects, we analysed mice deficient in LIPT1, the enzyme that activates 2-ketoacid dehydrogenases related to the TCA cycle4,5. LIPT1 deficiency suppresses TCA cycle metabolism during the GD10.5-GD11.5 transition, perturbs brain, heart and erythrocyte development and leads to embryonic demise by GD11.5. These data document individualized metabolic programmes in developing organs in utero.

DOI: https://doi.org/10.1038/s41586-022-04557-9
Cancer Commun (Lond). 2022 Apr 09.

Intercellular communications and metabolic reprogramming as new predictive markers for immunotherapy responses in gastric cancer.

Ji-Yong Sung, Jae-Ho Cheong.

DOI: https://doi.org/10.1002/cac2.12285
Front Cell Dev Biol. 2022 ;10 849625

Regulation of Glucose, Fatty Acid and Amino Acid Metabolism by Ubiquitination and SUMOylation for Cancer Progression.

Shunqin Zhu, Hongyu Gu, Cheng Peng, Fanwei Xia, Huan Cao, Hongjuan Cui.

  Ubiquitination and SUMOylation, which are posttranslational modifications, play prominent roles in regulating both protein expression and function in cells, as well as various cellular signal transduction pathways. Metabolic reprogramming often occurs in various diseases, especially cancer, which has become a new entry point for understanding cancer mechanisms and developing treatment methods. Ubiquitination or SUMOylation of protein substrates determines the fate of modified proteins. Through accurate and timely degradation and stabilization of the substrate, ubiquitination and SUMOylation widely control various crucial pathways and different proteins involved in cancer metabolic reprogramming. An understanding of the regulatory mechanisms of ubiquitination and SUMOylation of cell proteins may help us elucidate the molecular mechanism underlying cancer development and provide an important theory for new treatments. In this review, we summarize the processes of ubiquitination and SUMOylation and discuss how ubiquitination and SUMOylation affect cancer metabolism by regulating the key enzymes in the metabolic pathway, including glucose, lipid and amino acid metabolism, to finally reshape cancer metabolism.

Keywords:  SUMOylation; cancer; glucose metabolism; lipid metabolism; metabolic reprogramming; ubiquitination

DOI:  https://doi.org/10.3389/fcell.2022.849625
Front Oncol. 2022 ;12 857686

Bioenergetic and Metabolic Adaptation in Tumor Progression and Metastasis.

Patries M Herst, Georgia M Carson, David A Eccles, Michael V Berridge.

  The ability of cancer cells to adjust their metabolism in response to environmental changes is a well-recognized hallmark of cancer. Diverse cancer and non-cancer cells within tumors compete for metabolic resources. Metabolic demands change frequently during tumor initiation, progression and metastasis, challenging our quest to better understand tumor biology and develop novel therapeutics. Vascularization, physical constraints, immune responses and genetic instability promote tumor evolution resulting in immune evasion, opportunities to breach basement membrane barriers and spread through the circulation and lymphatics. In addition, the unfolded protein response linked to the ubiquitin proteasome system is a key player in addressing stoichiometric imbalances between nuclear and mitochondrially-encoded protein subunits of respiratory complexes, and nuclear-encoded mitochondrial ribosomal protein subunits. While progressive genetic changes, some of which affect metabolic adaptability, contribute to tumorigenesis and metastasis through clonal expansion, epigenetic changes are also important and more dynamic in nature. Understanding the role of stromal and immune cells in the tumor microenvironment in remodeling cancer cell energy metabolism has become an increasingly important area of research. In this perspective, we discuss the adaptations made by cancer cells to balance mitochondrial and glycolytic energy metabolism. We discuss how hypoxia and nutrient limitations affect reductive and oxidative stress through changes in mitochondrial electron transport activity. We propose that integrated responses to cellular stress in cancer cells are central to metabolic flexibility in general and bioenergetic adaptability in particular and are paramount in tumor progression and metastasis.

Keywords:  bioenergetic flexibility; glycolysis-OXPHOS continuum; mito-nuclear gene expression; tumor microenvironment (TME); tumor progression and metastasis

DOI:  https://doi.org/10.3389/fonc.2022.857686
Kidney360. 2021 Feb 25. 2(2): 355-364

Proximal Tubular Oxidative Metabolism in Acute Kidney Injury and the Transition to CKD.

Jennifer A Schaub, Manjeri A Venkatachalam, Joel M Weinberg.

  The proximal tubule relies on oxidative mitochondrial metabolism to meet its energy needs and has limited capacity for glycolysis, which makes it uniquely susceptible to damage during AKI, especially after ischemia and anoxia. Under these conditions, mitochondrial ATP production is initially decreased by several mechanisms, including fatty acid-induced uncoupling and inhibition of respiration related to changes in the shape and volume of mitochondria. Glycolysis is initially insufficient as a source of ATP to protect the cells and mitochondrial function, but supplementation of tricarboxylic acid cycle intermediates augments anaerobic ATP production, and improves recovery of mitochondrial oxidative metabolism. Incomplete recovery is characterized by defects of respiratory enzymes and lipid metabolism. During the transition to CKD, tubular cells atrophy but maintain high expression of glycolytic enzymes, and there is decreased fatty acid oxidation. These metabolic changes may be amenable to a number of therapeutic interventions.

Keywords:  AKI; CKD; aTP; acute kidney injury and ICU nephrology; basic science; glycolysis; metabolism; mitochondria; tricarboxylic acid cycle

DOI:  https://doi.org/10.34067/KID.0004772020
Front Physiol. 2022 ;13 865105

Pancreatic Stellate Cells and Metabolic Alteration: Physiology and Pathophysiology.

Shin Hamada, Ryotaro Matsumoto, Atsushi Masamune.

  Pancreatic stellate cells play a pivotal role in the development of pancreatic fibrosis. A wide variety of external stimuli can cause PSC activation accompanied by metabolic changes, which alters the tissue microenvironment by producing extracellular matrix proteins, cytokines, growth factors, and other mediators. Several metabolites aggravate fibrosis and inflammation by acting as key activating factors for PSCs. In other words, PSCs sense systemic metabolic changes. The detrimental effects of PSC activation on normal pancreatic cells, especially islet cells, further complicate metabolic imbalance through the dysregulation of glucose metabolism. PSC activation promotes cancer by altering the metabolism in pancreatic cancer cells, which collaborate with PSCs to efficiently adapt to environmental changes, promoting their growth and survival. This collaboration also contributes to the acquisition of chemoresistance. PSCs sequester chemotherapeutic agents and produce competing molecules as additional resistance mechanisms. The application of these metabolic targets for novel therapeutic strategies is currently being explored. This mini-review summarizes the role of PSCs in metabolic regulation of normal and cancerous cells.

Keywords:  PSC activation; fibrosis; metabolism; pancreatic cancer; pancreatic stellate cells

DOI:  https://doi.org/10.3389/fphys.2022.865105
Immunometabolism. 2022 ;pii: e220007. [Epub ahead of print]4(2):

Effects of PD-1 Signaling on Immunometabolic Reprogramming.

Vassiliki A Boussiotis, Nikolaos Patsoukis.

  Programmed Death-1 (PD-1; CD279) is an inhibitory receptor induced in several activated immune cells and, after engagement with its ligands PD-L1 and PD-L2, serves as a key mediator of peripheral tolerance. However, PD-1 signaling also has detrimental effects on T cell function by posing breaks on antitumor and antiviral immunity. PD-1 blocking immunotherapy either alone or in combination with other therapeutic modalities has shown great promise in cancer treatment. However, it is unclear why only a small fraction of patients responds to this type of therapy. For this reason, efforts to better understand the mechanisms of PD-1 function have recently been intensified, with the goal to reveal new strategies to overcome current limitations. The signaling pathways that are inhibited by PD-1 impact key regulators of metabolism. Here, we provide an overview of the current knowledge about the effects of PD-1 on metabolic reprogramming of immune cells and their consequences on systemic metabolism.

Keywords:  PD-1; T cell exhaustion; T cells; adaptive and innate immunity; immunometabolism; metabolic reprogramming

DOI:  https://doi.org/10.20900/immunometab20220007
Front Pharmacol. 2022 ;13 805782

Fluxomics - New Metabolomics Approaches to Monitor Metabolic Pathways.

Abdul-Hamid Emwas, Kacper Szczepski, Inas Al-Younis, Joanna Izabela Lachowicz, Mariusz Jaremko.

  Fluxomics is an innovative -omics research field that measures the rates of all intracellular fluxes in the central metabolism of biological systems. Fluxomics gathers data from multiple different -omics fields, portraying the whole picture of molecular interactions. Recently, fluxomics has become one of the most relevant approaches to investigate metabolic phenotypes. Metabolic flux using 13C-labeled molecules is increasingly used to monitor metabolic pathways, to probe the corresponding gene-RNA and protein-metabolite interaction networks in actual time. Thus, fluxomics reveals the functioning of multi-molecular metabolic pathways and is increasingly applied in biotechnology and pharmacology. Here, we describe the main fluxomics approaches and experimental platforms. Moreover, we summarize recent fluxomic results in different biological systems.

Keywords:  flux; fluxomics; mass spectrometry (MS); metabolomics; nuclear magnetic resonance (NMR); pharmacometabolomics

DOI:  https://doi.org/10.3389/fphar.2022.805782
Front Allergy. 2022 ;3 825931

Immune Metabolism-An Opportunity to Better Understand Allergic Pathology and Improve Treatment of Allergic Diseases?

Alexandra Goretzki, Jennifer Zimmermann, Yen-Ju Lin, Stefan Schülke.



Keywords:  Warburg; allergy; immune effector molecules; immune metabolism; metabolic state

DOI:  https://doi.org/10.3389/falgy.2022.825931
J Immunol. 2022 Apr 06. pii: ji2100356. [Epub ahead of print]

Pharmacologically Inferred Glycolysis and Glutaminolysis Requirement of B Cells in Lupus-Prone Mice.

Seung-Chul Choi, Wei Li, Xiaojuan Zhang, Nathalie Kanda, Leilani Zeumer-Spataro, Xiangyu Teng, Laurence Morel.

Several studies have shown an enhanced metabolism in the CD4+ T cells of lupus patients and lupus-prone mice. Little is known about the metabolism of B cells in lupus. In this study, we compared the metabolism of B cells between lupus-prone B6.Sle1.Sle2.Sle3 triple-congenic mice and C57BL/6 controls at steady state relative to autoantibody production, as well as during T cell-dependent (TD) and T cell-independent (TI) immunizations. Starting before the onset of autoimmunity, B cells from triple-congenic mice showed an elevated glycolysis and mitochondrial respiration, which were normalized in vivo by inhibiting glycolysis with a 2-deoxy-d-glucose (2DG) treatment. 2DG greatly reduced the production of TI-Ag-specific Abs, but showed minimal effect with TD-Ags. In contrast, the inhibition of glutaminolysis with 6-diazo-5-oxo-l-norleucine had a greater effect on TD than TI-Ag-specific Abs in both strains. Analysis of the TI and TD responses in purified B cells in vitro suggests, however, that the glutaminolysis requirement is not B cell-intrinsic. Thus, B cells have a greater requirement for glycolysis in TI than TD responses, as inferred from pharmacological interventions. B cells from lupus-prone and control mice have different intrinsic metabolic requirements or different responses toward 2DG and 6-diazo-5-oxo-l-norleucine, which mirrors our previous results obtained with follicular Th cells. Overall, these results predict that targeting glucose metabolism may provide an effective therapeutic approach for systemic autoimmunity by eliminating both autoreactive follicular Th and B cells, although it may also impair TI responses.

DOI: https://doi.org/10.4049/jimmunol.2100356
Pharmacol Rep. 2022 Apr 03.

Glycolytic metabolism supports microglia training during age-related neurodegeneration.

Alberto Camacho-Morales.

  Glucose is a major energy source for the brain, necessary to preserve proper neurophysiological functions; aberrant glucose metabolism in the brain has been documented in chronic neurodegenerative pathologies. In addition, glucose-dependent metabolic pathways, including substrates of the Krebs cycle, are involved in peripheral and central innate immune activation through a molecular program known as trained immunity. Notably, it seems that defective glucose metabolism favors trained immunity in the brain, leading to neuronal damage and neurodegeneration. In addition, defective glucose metabolism in the brain correlates with a positive proinflammatory profile and microglia activation, as was found in postmortem samples of neurodegenerative pathologies. We hypothesized that fluctuations in glucose supply or metabolism in the brain during aging may alter microglial training, turning these cells to unresponsive or overresponsive to a challenge during age-related neurodegeneration. This review will cover the most significant advances in glucose-dependent metabolic pathways that favor innate trained immunity of microglia and their contribution to neurodegeneration.

Keywords:  Glucose; Immunometabolism; Microglia; Neurodegeneration; Trained immunity

DOI:  https://doi.org/10.1007/s43440-022-00363-2
Nat Commun. 2022 Apr 04. 13(1): 1789

Glutathione-dependent redox balance characterizes the distinct metabolic properties of follicular and marginal zone B cells.

Davide G Franchina, Henry Kurniawan, Melanie Grusdat, Carole Binsfeld, Luana Guerra, Lynn Bonetti, Leticia Soriano-Baguet, Anouk Ewen, Takumi Kobayashi, Sophie Farinelle, Anna Rita Minafra, Niels Vandamme, Anaïs Carpentier, Felix K Borgmann, Christian Jäger, Ying Chen, Markus Kleinewietfeld, Vasilis Vasiliou, Michel Mittelbronn, Karsten Hiller, Philipp A Lang, Dirk Brenner.

The metabolic principles underlying the differences between follicular and marginal zone B cells (FoB and MZB, respectively) are not well understood. Here we show, by studying mice with B cell-specific ablation of the catalytic subunit of glutamate cysteine ligase (Gclc), that glutathione synthesis affects homeostasis and differentiation of MZB to a larger extent than FoB, while glutathione-dependent redox control contributes to the metabolic dependencies of FoB. Specifically, Gclc ablation in FoB induces metabolic features of wild-type MZB such as increased ATP levels, glucose metabolism, mTOR activation, and protein synthesis. Furthermore, Gclc-deficient FoB have a block in the mitochondrial electron transport chain (ETC) due to diminished complex I and II activity and thereby accumulate the tricarboxylic acid cycle metabolite succinate. Finally, Gclc deficiency hampers FoB activation and antibody responses in vitro and in vivo, and induces susceptibility to viral infections. Our results thus suggest that Gclc is required to ensure the development of MZB, the mitochondrial ETC integrity in FoB, and the efficacy of antiviral humoral immunity.

DOI: https://doi.org/10.1038/s41467-022-29426-x
Kidney360. 2021 Oct 28. 2(10): 1576-1591

Pkd1 Mutation Has No Apparent Effects on Peroxisome Structure or Lipid Metabolism.

Takeshi Terabayashi, Luis F Menezes, Fang Zhou, Hongyi Cai, Peter J Walter, Hugo M Garraffo, Gregory G Germino.

   Background: Multiple studies of tissue and cell samples from patients and preclinical models of autosomal dominant polycystic kidney disease report abnormal mitochondrial function and morphology and suggest metabolic reprogramming is an intrinsic feature of this disease. Peroxisomes interact with mitochondria physically and functionally, and congenital peroxisome biogenesis disorders can cause various phenotypes, including mitochondrial defects, metabolic abnormalities, and renal cysts. We hypothesized that a peroxisomal defect might contribute to the metabolic and mitochondrial impairments observed in autosomal dominant polycystic kidney disease.
Methods: Using control and Pkd1-/- kidney epithelial cells, we investigated peroxisome abundance, biogenesis, and morphology by immunoblotting, immunofluorescence, and live cell imaging of peroxisome-related proteins and assayed peroxisomal specific β-oxidation. We further analyzed fatty acid composition by mass spectrometry in kidneys of Pkd1fl/fl;Ksp-Cre mice. We also evaluated peroxisome lipid metabolism in published metabolomics datasets of Pkd1 mutant cells and kidneys. Lastly, we investigated if the C terminus or full-length polycystin-1 colocalize with peroxisome markers by imaging studies.
Results: Peroxisome abundance, morphology, and peroxisome-related protein expression in Pkd1-/- cells were normal, suggesting preserved peroxisome biogenesis. Peroxisomal β-oxidation was not impaired in Pkd1-/- cells, and there was no obvious accumulation of very-long-chain fatty acids in kidneys of mutant mice. Reanalysis of published datasets provide little evidence of peroxisomal abnormalities in independent sets of Pkd1 mutant cells and cystic kidneys, and provide further evidence of mitochondrial fatty acid oxidation defects. Imaging studies with either full-length polycystin-1 or its C terminus, a fragment previously shown to go to the mitochondria, showed minimal colocalization with peroxisome markers restricted to putative mitochondrion-peroxisome contact sites.
Conclusions: Our studies showed that loss of Pkd1 does not disrupt peroxisome biogenesis nor peroxisome-dependent fatty acid metabolism.

Keywords:  ADPKD; basic science; cystic kidney disease; fatty acids; genetic diseases; metabolism; peroxisomes

DOI:  https://doi.org/10.34067/KID.0000962021
Cell Metab. 2022 Apr 05. pii: S1550-4131(22)00095-X. [Epub ahead of print]34(4): 503-505

Sugar addiction: An Achilles' heel of auto-immune diseases?

Dietmar M W Zaiss, Paul J Coffer.

In this issue of Cell Metabolism, Hochrein et al. identify a metabolic checkpoint controlling the transcriptional programming of effector CD4+ T cells. The authors show that GLUT3-mediated glucose import and ACLY-dependent acetyl-CoA generation control histone acetylation and, hence, the epigenetic imprinting of effector gene expression in differentiated effector CD4+ T cells. These findings suggest a novel therapeutic target for inflammation-associated diseases.

DOI: https://doi.org/10.1016/j.cmet.2022.03.007
Cardiovasc Res. 2022 Apr 07. pii: cvac058. [Epub ahead of print]

Metaboloepigenetics in cancer, immunity and cardiovascular disease.

Samuel T Keating, Assam El-Osta.

  The influence of cellular metabolism on epigenetic pathways are well documented but misunderstood. Scientists have long known of the metabolic impact on epigenetic determinants. More often than not, that title role for DNA methylation was portrayed by the metabolite SAM or S-adenosylmethionine. Technically speaking there are many other metabolites that drive epigenetic processes that instruct seemingly distant - yet highly connect pathways - and none more so than our understanding of the cancer epigenome. Recent studies have shown that available energy link the extracellular environment to influence cellular responses. This focused review examines the recent interest in epigenomics and casts cancer, metabolism and immunity in unfamiliar roles - cooperating. There are not only language lessons from cancer research, we have come round to appreciate that reaching into areas previously thought of as too distinct are also object lessons in understanding health and disease. The Warburg effect is one such signature of how glycolysis influences metabolic shift during oncogenesis. That shift in metabolism - now recognised as central to proliferation in cancer biology - influence core enzymes that not only control gene expression but are also central to replication, condensation and the repair of nucleic acid. These nuclear processes rely on metabolism and with glucose at center stage the role of respiration and oxidative metabolism are now synonymous with the mitochondria as the powerhouses of metaboloepigenetics. The emerging evidence for metaboloepigenetics in trained innate immunity has revealed recognisable signalling pathways with antecedent extracellular stimulation. With due consideration to immunometabolism we discuss the striking signalling similarities influencing these core pathways. The immunometabolic-epigenetic axis in cardiovascular disease has deeply etched connections with inflammation and we examine the chromatin template as a carrier of epigenetic indices that determine the expression of genes influencing atherosclerosis and vascular complications of diabetes.

Keywords:  Metabolism; cardiovascular disease; diabetes; epigenetics; glycolysis; metaboloepigenetics; trained immunity

DOI:  https://doi.org/10.1093/cvr/cvac058
Adv Sci (Weinh). 2022 Apr 09. e2105376

Biomimetic Nanocarriers Guide Extracellular ATP Homeostasis to Remodel Energy Metabolism for Activating Innate and Adaptive Immunity System.

Long Wu, Wei Xie, Yang Li, Qiankun Ni, Peter Timashev, Meng Lyu, Ligang Xia, Yuan Zhang, Lingrong Liu, Yufeng Yuan, Xing-Jie Liang, Qiqing Zhang.

  Metabolic interventions via targeting intratumoral dysregulated metabolism pathways have shown promise in reinvigorating antitumor immunity. However, approved small molecule immunomodulators often suffer from ineffective response rates and severe off-target toxicity. ATP occupies a crucial role in energy metabolism of components that form the tumor microenvironment (TME) and influences cancer immunosurveillance. Here, a nanocarrier-assisted immunometabolic therapy strategy that targets the ATP-adenosine axis for metabolic reprogramming of TME is reported. An ecto-enzyme (CD39) antagonist POM1 and AMP-activated protein kinase (AMPK) agonist metformin are both encapsulated into cancer cell-derived exosomes and used as nanocarriers for tumor targeting delivery. This method increases the level of pro-inflammatory extracellular ATP (eATP) while preventing the accumulation of immunosuppressive adenosine and alleviating hypoxia. Elevated eATP triggers the activation of P2X7-NLRP3-inflammasome to drive macrophage pyroptosis, potentiates the maturation and antigen capacity of dendritic cells (DCs) to enhance the cytotoxic function of T cells and natural killer (NK) cells. As a result, synergistic antitumor immune responses are initiated to suppress tumor progress, inhibit tumor distant metastases, provide long-term immune memory that offers protection against tumor recurrence and overcome anti-PD1 resistance. Overall, this study provides an innovative strategy to advance eATP-driven antitumor immunity in cancer therapy.

Keywords:  AMPK activation; ATP-adenosine pathway; CD39 inhibition; exosome; immunnometabolic therapy

DOI:  https://doi.org/10.1002/advs.202105376
Cell Rep. 2022 Apr 05. pii: S2211-1247(22)00355-2. [Epub ahead of print]39(1): 110607

NADPH metabolism determines the leukemogenic capacity and drug resistance of AML cells.

Chiqi Chen, Xiaoyun Lai, Yaping Zhang, Li Xie, Zhuo Yu, Sijia Dan, Yu Jiang, Weicai Chen, Ligen Liu, Yi Yang, Dan Huang, Yuzheng Zhao, Junke Zheng.

  The mechanism by which redox metabolism regulates the fates of acute myeloid leukemia (AML) cells remains largely unknown. Using a highly sensitive, genetically encoded fluorescent sensor of nicotinamide adenine dinucleotide phosphate (NADPH), iNap1, we find three heterogeneous subpopulations of AML cells with different cytosolic NADPH levels in an MLL-AF9-induced murine AML model. The iNap1-high AML cells have enhanced proliferation capacities both in vitro and in vivo and are enriched for more functional leukemia-initiating cells than iNap1-low counterparts. The iNap1-high AML cells prefer localizing in the bone marrow endosteal niche and are resistant to methotrexate treatment. Furthermore, iNap1-high human primary AML cells have enhanced proliferation abilities both in vitro and in vivo. Mechanistically, the MTHFD1-mediated folate cycle regulates NADPH homeostasis to promote leukemogenesis and methotrexate resistance. These results provide important clues for understanding mechanisms by which redox metabolism regulates cancer cell fates and a potential metabolic target for AML treatments.

Keywords:  CP: Cancer; NADPH metabolism; acute myeloid leukemia; endosteal niche; folate cycle; leukemia-initiating cells; metabolic sensor; methotrexate resistance; methylenetetrahydrofolate dehydrogenase; tetrahydrofolic acid; vascular niche

DOI:  https://doi.org/10.1016/j.celrep.2022.110607
Cell Mol Life Sci. 2022 Apr 07. 79(5): 226

Prolonged exposure to simulated microgravity promotes stemness impairing morphological, metabolic and migratory profile of pancreatic cancer cells: a comprehensive proteomic, lipidomic and transcriptomic analysis.

Maria Angela Masini, Valentina Bonetto, Marcello Manfredi, Anna Pastò, Elettra Barberis, Sara Timo, Virginia Vita Vanella, Elisa Robotti, Francesca Masetto, Francesca Andreoli, Alessandra Fiore, Sara Tavella, Antonio Sica, Massimo Donadelli, Emilio Marengo.

   BACKGROUND: The impact of the absence of gravity on cancer cells is of great interest, especially today that space is more accessible than ever. Despite advances, few and contradictory data are available mainly due to different setup, experimental design and time point analyzed.
METHODS: Exploiting a Random Positioning Machine, we dissected the effects of long-term exposure to simulated microgravity (SMG) on pancreatic cancer cells performing proteomic, lipidomic and transcriptomic analysis at 1, 7 and 9 days.
RESULTS: Our results indicated that SMG affects cellular morphology through a time-dependent activation of Actin-based motility via Rho and Cdc42 pathways leading to actin rearrangement, formation of 3D spheroids and enhancement of epithelial-to-mesenchymal transition. Bioinformatic analysis reveals that SMG may activates ERK5/NF-κB/IL-8 axis that triggers the expansion of cancer stem cells with an increased migratory capability. These cells, to remediate energy stress and apoptosis activation, undergo a metabolic reprogramming orchestrated by HIF-1α and PI3K/Akt pathways that upregulate glycolysis and impair β-oxidation, suggesting a de novo synthesis of triglycerides for the membrane lipid bilayer formation.
CONCLUSIONS: SMG revolutionizes tumor cell behavior and metabolism leading to the acquisition of an aggressive and metastatic stem cell-like phenotype. These results dissect the time-dependent cellular alterations induced by SMG and pave the base for altered gravity conditions as new anti-cancer technology.

Keywords:  Cancer stem cells; Lipidomic; Metabolism; Microgravity; Proteomic

DOI:  https://doi.org/10.1007/s00018-022-04243-z
Mol Cell. 2022 Mar 30. pii: S1097-2765(22)00260-X. [Epub ahead of print]

Ferroptosis at the intersection of lipid metabolism and cellular signaling.

Deguang Liang, Alexander M Minikes, Xuejun Jiang.

  Ferroptosis, a newly emerged form of regulated necrotic cell death, has been demonstrated to play an important role in multiple diseases including cancer, neurodegeneration, and ischemic organ injury. Mounting evidence also suggests its potential physiological function in tumor suppression and immunity. The execution of ferroptosis is driven by iron-dependent phospholipid peroxidation. As such, the metabolism of biological lipids regulates ferroptosis via controlling phospholipid peroxidation, as well as various other cellular processes relevant to phospholipid peroxidation. In this review, we provide a comprehensive analysis by focusing on how lipid metabolism impacts the initiation, propagation, and termination of phospholipid peroxidation; how multiple signal transduction pathways communicate with ferroptosis via modulating lipid metabolism; and how such intimate cross talk of ferroptosis with lipid metabolism and related signaling pathways can be exploited for the development of rational therapeutic strategies.

Keywords:  cancer therapy; ferroptosis; lipid metabolism

DOI:  https://doi.org/10.1016/j.molcel.2022.03.022
Cancer Discov. 2022 Apr 01. 12(4): 883

Microbial Metabolism Activates Immune-Suppressive Tumor Macrophages.

Microbial metabolites promote pancreatic tumor growth through effects on macrophage polarization.

DOI: https://doi.org/10.1158/2159-8290.CD-RW2022-028
Cardiovasc Res. 2022 Apr 07. pii: cvac050. [Epub ahead of print]

A mitochondrial long-chain fatty acid oxidation defect leads to tRNA uncharging and activation of the integrated stress response in the mouse heart.

Pablo Ranea-Robles, Natalya N Pavlova, Aaron Bender, Andrea S Pereyra, Jessica M Ellis, Brandon Stauffer, Chunli Yu, Craig B Thompson, Carmen Argmann, Michelle Puchowicz, Sander M Houten.

   AIMS: Cardiomyopathy and arrhythmias can be severe presentations in patients with inherited defects of mitochondrial long-chain fatty acid β-oxidation (FAO). The pathophysiological mechanisms that underlie these cardiac abnormalities remain largely unknown. We investigated the molecular adaptations to a FAO deficiency in the heart using the long-chain acyl-CoA dehydrogenase (LCAD) knockout (KO) mouse model.
METHODS AND RESULTS: We observed enrichment of amino acid metabolic pathways and of ATF4 target genes among the upregulated genes in the LCAD KO heart transcriptome. We also found a prominent activation of the eIF2α/ATF4 axis at the protein level that was independent of the feeding status, in addition to a reduction of cardiac protein synthesis during a short period of food withdrawal. These findings are consistent with an activation of the integrated stress response (ISR) in the LCAD KO mouse heart. Notably, charging of several tRNAs, such as tRNAGln was decreased in LCAD KO hearts, reflecting a reduced availability of cardiac amino acids, in particular, glutamine. We replicated the activation of the ISR in hearts of mice with a muscle-specific deletion of carnitine palmitoyltransferase 2.
CONCLUSIONS: Our results show that perturbations in amino acid metabolism caused by long-chain FAO deficiency impact on cardiac metabolic signaling, in particular the ISR. These results may serve as a foundation for investigating the role of the ISR in the cardiac pathology associated with long-chain FAO defects.Translational Perspective: The heart relies mainly on mitochondrial fatty acid β-oxidation (FAO) for its high energy requirements. The heart disease observed in patients with a genetic defect in this pathway highlights the importance of FAO for cardiac health. We show that the consequences of a FAO defect extend beyond cardiac energy homeostasis and include amino acid metabolism and associated signaling pathways such as the integrated stress response.

Keywords:  LCAD; amino acids; fatty acid oxidation; hypertrophy; tRNA

DOI:  https://doi.org/10.1093/cvr/cvac050
Front Immunol. 2022 ;13 868958

Cholesterol and HIF-1α: Dangerous Liaisons in Atherosclerosis.

Charles Thomas, Damien Leleu, David Masson.

  HIF-1α exerts both detrimental and beneficial actions in atherosclerosis. While there is evidence that HIF-1α could be pro-atherogenic within the atheromatous plaque, experimental models of atherosclerosis suggest a more complex role that depends on the cell type expressing HIF-1α. In atheroma plaques, HIF-1α is stabilized by local hypoxic conditions and by the lipid microenvironment. Macrophage exposure to oxidized LDLs (oxLDLs) or to necrotic plaque debris enriched with oxysterols induces HIF-1α -dependent pathways. Moreover, HIF-1α is involved in many oxLDL-induced effects in macrophages including inflammatory response, angiogenesis and metabolic reprogramming. OxLDLs activate toll-like receptor signaling pathways to promote HIF-1α stabilization. OxLDLs and oxysterols also induce NADPH oxidases and reactive oxygen species production, which subsequently leads to HIF-1α stabilization. Finally, recent investigations revealed that the activation of liver X receptor, an oxysterol nuclear receptor, results in an increase in HIF-1α transcriptional activity. Reciprocally, HIF-1α signaling promotes triglycerides and cholesterol accumulation in macrophages. Hypoxia and HIF-1α increase the uptake of oxLDLs, promote cholesterol and triglyceride synthesis and decrease cholesterol efflux. In conclusion, the impact of HIF-1α on cholesterol homeostasis within macrophages and the feedback activation of the inflammatory response by oxysterols via HIF-1α could play a deleterious role in atherosclerosis. In this context, studies aimed at understanding the specific mechanisms leading to HIF-1α activation within the plaque represents a promising field for research investigations and a path toward development of novel therapies.

Keywords:  atherosclerosis; cholesterol; hypoxia inducible factor (HIF); liver X receptor; macrophage; oxysterol

DOI:  https://doi.org/10.3389/fimmu.2022.868958
Biochim Biophys Acta Mol Cell Biol Lipids. 2022 Apr 02. pii: S1388-1981(22)00047-6. [Epub ahead of print] 159157

Specificity of ABCA7-mediated cell lipid efflux.

Antonino Picataggi, Amrith Rodrigues, Debra A Cromley, Hu Wang, Joel P Wiener, Viktor Garliyev, Jeffrey T Billheimer, Brian C Grabiner, Jessica A Hurt, Allen C Chen, Xianlin Han, Daniel J Rader, Domenico Praticò, Nicholas N Lyssenko.

  Adenosine triphosphate-binding cassette transporter subfamily A member 7 (ABCA7) performs incompletely understood biochemical functions that affect pathogenesis of Alzheimer's disease. ABCA7 is most similar in primary structure to ABCA1, the protein that mediates cell lipid efflux and formation of high-density lipoprotein (HDL). Lipid metabolic labeling/tracer efflux assays were employed to investigate lipid efflux in BHK-ABCA7(low expression), BHK-ABCA7(high expression) and BHK-ABCA1 cells. Shotgun lipid mass spectrometry was used to determine lipid composition of HDL synthesized by BHK-ABCA7 and BHK-ABCA1 cells. BHK-ABCA7(low) cells exhibited significant efflux only of choline-phospholipid and phosphatidylinositol. BHK-ABCA7(high) cells had significant cholesterol and choline-phospholipid efflux to apolipoprotein (apo) A-I, apo E, the 18A peptide, HDL, plasma and cerebrospinal fluid and significant efflux of sphingosine-lipid, serine-lipid (which is composed of phosphatidylserine and phosphatidylethanolamine in BHK cells) and phosphatidylinositol to apo A-I. In efflux assays to apo A-I, after adjustment to choline-phospholipid, ABCA7-mediated efflux removed ~4 times more serine-lipid and phosphatidylinositol than ABCA1-mediated efflux, while ABCA1-mediated efflux removed ~3 times more cholesterol than ABCA7-mediated efflux. Shotgun lipidomic analysis revealed that ABCA7-HDL had ~20 mol% less phosphatidylcholine and 3-5 times more serine-lipid and phosphatidylinositol than ABCA1-HDL, while ABCA1-HDL contained only ~6 mol% (or ~1.1 times) more cholesterol than ABCA7-HDL. The discrepancy between the tracer efflux assays and shotgun lipidomics with respect to cholesterol may be explained by an underestimate of ABCA7-mediated cholesterol efflux in the former approach. Overall, these results suggest that ABCA7 lacks specificity for phosphatidylcholine and releases significantly but not dramatically less cholesterol in comparison with ABCA1.

Keywords:  ABC transporters; Apolipoprotein; Cholesterol metabolism; HDL formation; Lipid efflux; Phospholipid metabolism

DOI:  https://doi.org/10.1016/j.bbalip.2022.159157
Mol Cell. 2022 Mar 25. pii: S1097-2765(22)00254-4. [Epub ahead of print]

Filamentous GLS1 promotes ROS-induced apoptosis upon glutamine deprivation via insufficient asparagine synthesis.

Bin Jiang, Jia Zhang, Guohui Zhao, Mengjue Liu, Jielu Hu, Furong Lin, Jinyang Wang, Wentao Zhao, Huanhuan Ma, Cixiong Zhang, Caiming Wu, Luming Yao, Qingfeng Liu, Xin Chen, Yating Cao, Yi Zheng, Chensong Zhang, Aidong Han, Donghai Lin, Qinxi Li.

  GLS1 orchestrates glutaminolysis and promotes cell proliferation when glutamine is abundant by regenerating TCA cycle intermediates and supporting redox homeostasis. CB-839, an inhibitor of GLS1, is currently under clinical investigation for a variety of cancer types. Here, we show that GLS1 facilitates apoptosis when glutamine is deprived. Mechanistically, the absence of exogenous glutamine sufficiently reduces glutamate levels to convert dimeric GLS1 to a self-assembled, extremely low-Km filamentous polymer. GLS1 filaments possess an enhanced catalytic activity, which further depletes intracellular glutamine. Functionally, filamentous GLS1-dependent glutamine scarcity leads to inadequate synthesis of asparagine and mitogenome-encoded proteins, resulting in ROS-induced apoptosis that can be rescued by asparagine supplementation. Physiologically, we observed GLS1 filaments in solid tumors and validated the tumor-suppressive role of constitutively active, filamentous GLS1 mutants K320A and S482C in xenograft models. Our results change our understanding of GLS1 in cancer metabolism and suggest the therapeutic potential of promoting GLS1 filament formation.

Keywords:  apoptosis; glutaminase; glutamine metabolism

DOI:  https://doi.org/10.1016/j.molcel.2022.03.016
Trends Endocrinol Metab. 2022 Apr 05. pii: S1043-2760(22)00055-8. [Epub ahead of print]

Bone marrow adipose tissue in metabolic health.

Gisela Pachón-Peña, Miriam A Bredella.

  Recent studies have highlighted the role of bone marrow adipose tissue (BMAT) as a regulator of skeletal homeostasis and energy metabolism. While long considered an inert filler, occupying empty spaces from bone loss and reduced hematopoiesis, BMAT is now considered a secretory and metabolic organ that responds to nutritional challenges and secretes cytokines, which indirectly impact energy and bone metabolism. The recent advances in our understanding of the function of BMAT have been enabled by novel noninvasive imaging techniques, which allow longitudinal assessment of BMAT in vivo following interventions. This review will focus on the latest advances in our understanding of BMAT and its role in metabolic health. Imaging techniques to quantify the content and composition of BMAT will be discussed.

Keywords:  aging; bone marrow adipose tissue (BMAT); bone metabolism; caloric restriction; energy metabolism; proton magnetic resonance spectroscopy (1H-MRS)

DOI:  https://doi.org/10.1016/j.tem.2022.03.003
Biomark Res. 2022 Apr 02. 10(1): 16

Vitamin D activates FBP1 to block the Warburg effect and modulate blast metabolism in acute myeloid leukemia.

Yi Xu, Christopher Hino, David J Baylink, Jeffrey Xiao, Mark E Reeves, Jiang F Zhong, Saied Mirshahidi, Huynh Cao.

  Acute myeloid leukemia (AML) has the lowest survival rate among the leukemias. Targeting intracellular metabolism and energy production in leukemic cells can be a promising therapeutic strategy for AML. Recently, we presented the successful use of vitamin D (1,25VD3) gene therapy to treat AML mouse models in vivo. In this study, recognizing the importance of 1,25VD3 as one of only 2 molecules (along with glucose) photosynthesized for energy during the beginning stage of life on this planet, we explored the functional role of 1,25VD3 in AML metabolism.Transcriptome database (RNA-seq) of four different AML cell lines revealed 17,757 genes responding to 1,25VD3-treatment. Moreover, we discovered that fructose-bisphosphatase 1 (FBP1) noticeably stands out as the only gene (out of 17,757 genes) with a 250-fold increase in gene expression, which is known to encode the key rate-limiting gluconeogenic enzyme fructose-1,6-bisphosphatase. The significant increased expression of FBP1 gene and proteins induced by 1,25VD3 was confirmed by qPCR, western blot, flow cytometry, immunocytochemistry and functional lactate assay. Additionally, 1,25VD3 was found to regulate different AML metabolic processes including gluconeogenesis, glycolysis, TCA, de novo nucleotide synthesis, etc. In summary, we provided the first evidence that 1,25 VD3-induced FBP1 overexpression might be a novel therapeutic target to block the "Warburg Effect" to reduce energy production in AML blasts.

Keywords:  AML; FBP1; Glycolysis; Metabolism; Vitamin D; Warburg effect

DOI:  https://doi.org/10.1186/s40364-022-00367-3
Kidney360. 2021 Apr 29. 2(4): 755-762

Podocyte Lipotoxicity in CKD.

Jin-Ju Kim, Sydney S Wilbon, Alessia Fornoni.

  CKD represents the ninth most common cause of death in the United States but, despite this large health burden, treatment options for affected patients remain limited. To remedy this, several relevant pathways have been identified that may lead to novel therapeutic options. Among them, altered renal lipid metabolism, first described in 1982, has been recognized as a common pathway in clinical and experimental CKD of both metabolic and nonmetabolic origin. This observation has led many researchers to investigate the cause of this renal parenchyma lipid accumulation and its downstream effect on renal structure and function. Among key cellular components of the kidney parenchyma, podocytes are terminally differentiated cells that cannot be easily replaced when lost. Clinical and experimental evidence supports a role of reduced podocyte number in the progression of CKD. Given the importance of the podocytes in the maintenance of the glomerular filtration barrier and the accumulation of TG and cholesterol-rich lipid droplets in the podocyte and glomerulus in kidney diseases that cause CKD, understanding the upstream cause and downstream consequences of lipid accumulation in podocytes may lead to novel therapeutic opportunities. In this review, we hope to consolidate our understanding of the causes and consequences of dysregulated renal lipid metabolism in CKD development and progression, with a major focus on podocytes.

Keywords:  basic science; chronic kidney disease; lipid accumulation; podocyte lipotoxicity

DOI:  https://doi.org/10.34067/KID.0006152020
Genes Genomics. 2022 Apr 04.

Prognostic significance of three endothelial nitric oxide synthase (eNOS) polymorphisms and metabolic syndrome (MetS) in patients with colorectal cancer.

Eun Ju Ko, Eo Jin Kim, Hye Jung Cho, Jisu Oh, Han Sung Park, Chang Soo Ryu, Jung Oh Kim, Hak Hoon Jun, So Young Chong, Jong Woo Kim, Nam Keun Kim.

   BACKGROUND: Polymorphisms of endothelial nitric oxide synthases (eNOS) have been associated with cancer susceptibility. Also, metabolic syndrome is associated with cancer malignancy. However, the effect of eNOS polymorphisms and metabolic syndrome on colorectal cancer (CRC) prognosis remains unclear.
OBJECTIVE: To investigated whether three genetic polymorphisms (- 786 T > C rs2070744, 4a4b rs869109213, and 894G > T rs1799983) in the eNOS and metabolic syndrome (MetS) were associated with CRC patient survival.
METHODS: We genotyped three polymorphisms of eNOS (- 786 T > C, 4a4b, and 894G > T) in 312 CRC cases from the Korean population by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis.
RESULTS: Although the three eNOS polymorphisms were not causative of MetS, the TT genotype of the 894G > T polymorphism was associated with a worse survival rate compared with the GG genotype in the CRC group with MetS than in the CRC group without MetS (5-years survival; adjusted HR = 54.777; 95% CI 5.073-591.487 and RFS; adjusted HR = 14.909; 95% CI 1.571-141.528).
CONCLUSIONS: The eNOS polymorphisms were not associated with metabolic syndrome prevalence in CRC patients. However, our findings suggest that the eNOS 894G > T polymorphism with MetS was associated with poor clinical outcomes.

Keywords:  Colorectal cancer; Metabolic syndrome; Nitric oxide; Polymorphism; Susceptibility; eNOS

DOI:  https://doi.org/10.1007/s13258-022-01246-9
Cell Death Dis. 2022 Apr 08. 13(4): 320

Gut microbiota severely hampers the efficacy of NAD-lowering therapy in leukemia.

Oussama ElMokh, Saki Matsumoto, Paulina Biniecka, Axel Bellotti, Karin Schaeuble, Francesco Piacente, Hector Gallart-Ayala, Julijana Ivanisevic, Ivan Stamenkovic, Alessio Nencioni, Aimable Nahimana, Michel A Duchosal.

Most cancer cells have high need for nicotinamide adenine dinucleotide (NAD+) to sustain their survival. This led to the development of inhibitors of nicotinamide (NAM) phosphoribosyltransferase (NAMPT), the rate-limiting NAD+ biosynthesis enzyme from NAM. Such inhibitors kill cancer cells in preclinical studies but failed in clinical ones. To identify parameters that could negatively affect the therapeutic efficacy of NAMPT inhibitors and propose therapeutic strategies to circumvent such failure, we performed metabolomics analyses in tumor environment and explored the effect of the interaction between microbiota and cancer cells. Here we show that tumor environment enriched in vitamin B3 (NAM) or nicotinic acid (NA) significantly lowers the anti-tumor efficacy of APO866, a prototypic NAMPT inhibitor. Additionally, bacteria (from the gut, or in the medium) can convert NAM into NA and thus fuel an alternative NAD synthesis pathway through NA. This leads to the rescue from NAD depletion, prevents reactive oxygen species production, preserves mitochondrial integrity, blunts ATP depletion, and protects cancer cells from death.Our data in an in vivo preclinical model reveal that antibiotic therapy down-modulating gut microbiota can restore the anti-cancer efficacy of APO866. Alternatively, NAphosphoribosyltransferase inhibition may restore anti-cancer activity of NAMPT inhibitors in the presence of gut microbiota and of NAM in the diet.

DOI: https://doi.org/10.1038/s41419-022-04763-3
Cell Metab. 2022 Apr 05. pii: S1550-4131(22)00091-2. [Epub ahead of print]34(4): 506-507

Microbial metabolite as icebreaker for immunotherapy.

Yong Tang, Yibin Kang.

Immunotherapy has limited success in triple-negative breast cancer (TNBC). In this issue of Cell Metabolism, Wang et al. found that microbial metabolite TMAO boosts CD8+ T cell-mediated antitumor immunity by inducing pyroptosis in tumor cells, enhancing the efficacy of immunotherapy in TNBC (Wang et al., 2022).

DOI: https://doi.org/10.1016/j.cmet.2022.03.003
Cell Rep. 2022 Apr 05. pii: S2211-1247(22)00357-6. [Epub ahead of print]39(1): 110609

Metabolism drives macrophage heterogeneity in the tumor microenvironment.

Shasha Li, Jiali Yu, Amanda Huber, Ilona Kryczek, Zhuwen Wang, Long Jiang, Xiong Li, Wan Du, Gaopeng Li, Shuang Wei, Linda Vatan, Wojciech Szeliga, Arul M Chinnaiyan, Michael D Green, Marcin Cieslik, Weiping Zou.

  Tumor-associated macrophages (TAMs) are a major cellular component in the tumor microenvironment (TME). However, the relationship between the phenotype and metabolic pattern of TAMs remains poorly understood. We performed single-cell transcriptome profiling on hepatic TAMs from mice bearing liver metastatic tumors. We find that TAMs manifest high heterogeneity at the levels of transcription, development, metabolism, and function. Integrative analyses and validation experiments indicate that increased purine metabolism is a feature of TAMs with pro-tumor and terminal differentiation phenotypes. Like mouse TAMs, human TAMs are highly heterogeneous. Human TAMs with increased purine metabolism exhibit a pro-tumor phenotype and correlate with poor therapeutic efficacy to immune checkpoint blockade. Altogether, our work demonstrates that TAMs are developmentally, metabolically, and functionally heterogeneous and purine metabolism may be a key metabolic feature of a pro-tumor macrophage population.

Keywords:  CP: Cancer; CP: Metabolism; cancer; checkpoint; immunosuppression; immunotherapy; liver; macrophage; metabolism; purine; single-cell RNA sequencing; tumor microenvironment

DOI:  https://doi.org/10.1016/j.celrep.2022.110609
Intern Med. 2022 Apr 02.

Urine Xanthine Crystals in Hematologic Malignancies with Tumor Lysis Syndrome.

Shoko Ito, Shin-Ichiro Fujiwara, Tomoaki Yoshizawa, Kaori Hayatsu, Kaoru Sekiguchi, Rui Murahashi, Hirotomo Nakashima, Sae Matsuoka, Takashi Ikeda, Yumiko Toda, Shinichiro Kawaguchi, Takashi Nagayama, Kento Umino, Daisuke Minakata, Hirofumi Nakano, Kaoru Morita, Ryoko Yamasaki, Masahiro Ashizawa, Chihiro Yamamoto, Kaoru Hatano, Kazuya Sato, Ken Ohmine, Yoshinobu Kanda.

  Tumor lysis syndrome (TLS) is a metabolic disorder caused by massive tumor lysis. Hypouricemic agents are administered to prevent TLS-related hyperuricemia and renal failure. We experienced three cases of urine xanthine crystals during TLS in patients with hematologic malignancies who received prophylactic febuxostat. Yellowish and pinkish deposits were observed in urinary tract catheters and urinary bags. Urine microscopy revealed that the deposits were xanthine crystals. In rapid tumor lysis, inhibition of xanthine oxidase can cause xanthine accumulation and urine xanthine crystallization. During TLS, urine xanthine crystals may be overlooked, so careful observation and management are required to avoid xanthine nephropathy.

Keywords:  allopurinol; febuxostat; rasburicase; tumor lysis syndrome; xanthine crystals

DOI:  https://doi.org/10.2169/internalmedicine.9332-22
Dis Model Mech. 2022 Apr 08. pii: dmm.049392. [Epub ahead of print]

Osteoblast lineage Sod2 deficiency leads to an osteoporosis-like phenotype in mice.

Astrid M Schoppa, Xiangxu Chen, Jan-Moritz Ramge, Anna Vikman, Verena Fischer, Melanie Haffner-Luntzer, Jana Riegger, Jan Tuckermann, Karin Scharffetter-Kochanek, Anita Ignatius.

  Osteoporosis is a systemic metabolic skeletal disease characterized by low bone mass and strength associated with fragility fractures. Oxidative stress, which results from elevated intracellular reactive oxygen species (ROS) and arises in the aging organism, is considered one of the critical factors contributing to osteoporosis. Mitochondrial (mt)ROS, as the superoxide anion (O2.-) generated during mitochondrial respiration, are eliminated in the young organism by antioxidant defense mechanisms, including superoxide dismutase (SOD) 2, whose expression and activity are decreased in aging mesenchymal progenitor cells, accompanied by increased mtROS production. Using a mouse model of osteoblast lineage Sod2 deficiency, we observed significant bone loss in trabecular and cortical bone accompanied by decreased osteoblast activity, increased adipocyte accumulation in the bone marrow, and augmented osteoclast activity, suggestive of altered mesenchymal progenitor cell differentiation and osteoclastogenesis. Furthermore, osteoblast senescence was increased. To date, there are so far only a few studies suggesting a causal association between mtROS and cellular senescence in tissue in vivo. Targeting SOD2 to improve redox homeostasis may represent a potential therapeutic strategy for maintaining bone health during aging.

Keywords:  Mitochondrial dysfunction; Osteoporosis; Reactive oxygen species; Senescence; Skeletal aging

DOI:  https://doi.org/10.1242/dmm.049392
FASEB Bioadv. 2022 Mar;4(3): 197-210

Membrane potential-dependent regulation of mitochondrial complex II by oxaloacetate in interscapular brown adipose tissue.

Brian D Fink, Adam J Rauckhorst, Eric B Taylor, Liping Yu, William I Sivitz.

  Classically, mitochondrial respiration responds to decreased membrane potential (ΔΨ) by increasing respiration. However, we found that for succinate-energized complex II respiration in skeletal muscle mitochondria (unencumbered by rotenone), low ΔΨ impairs respiration by a mechanism culminating in oxaloacetate (OAA) inhibition of succinate dehydrogenase (SDH). Here, we investigated whether this phenomenon extends to far different mitochondria of a tissue wherein ΔΨ is intrinsically low, i.e., interscapular brown adipose tissue (IBAT). Also, to advance our knowledge of the mechanism, we performed isotopomer studies of metabolite flux not done in our previous muscle studies. In additional novel work, we addressed possible ways ADP might affect the mechanism in IBAT mitochondria. UCP1 activity, and consequently ΔΨ, were perturbed both by GDP, a well-recognized potent inhibitor of UCP1 and by the chemical uncoupler carbonyl cyanide m-chlorophenyl hydrazone (FCCP). In succinate-energized mitochondria, GDP increased ΔΨ but also increased rather than decreased (as classically predicted under low ΔΨ) O2 flux. In GDP-treated mitochondria, FCCP reduced potential but also decreased respiration. Metabolite studies by NMR and flux analyses by LC-MS support a mechanism, wherein ΔΨ effects on the production of reactive oxygen alters the NADH/NAD+ ratio affecting OAA accumulation and, hence, OAA inhibition of SDH. We also found that ADP-altered complex II respiration in complex fashion probably involving decreased ΔΨ due to ATP synthesis, a GDP-like nucleotide inhibition of UCP1, and allosteric enzyme action. In summary, complex II respiration in IBAT mitochondria is regulated by UCP1-dependent ΔΨ altering substrate flow through OAA and OAA inhibition of SDH.

Keywords:  bioenergetics; brown adipose tissue; metabolism; metabolomics; mitochondria; mitochondrial metabolism; reactive oxygen species (ROS); uncoupling protein

DOI:  https://doi.org/10.1096/fba.2021-00137
Front Cell Dev Biol. 2022 ;10 861622

The Mitochondria-Targeting Agent MitoQ Improves Muscle Atrophy, Weakness and Oxidative Metabolism in C26 Tumor-Bearing Mice.

Fabrizio Pin, Joshua R Huot, Andrea Bonetto.

  Cancer cachexia is a debilitating syndrome characterized by skeletal muscle wasting, weakness and fatigue. Several pathogenetic mechanisms can contribute to these muscle derangements. Mitochondrial alterations, altered metabolism and increased oxidative stress are known to promote muscle weakness and muscle catabolism. To the extent of improving cachexia, several drugs have been tested to stimulate mitochondrial function and normalize the redox balance. The aim of this study was to test the potential beneficial anti-cachectic effects of Mitoquinone Q (MitoQ), one of the most widely-used mitochondria-targeting antioxidant. Here we show that MitoQ administration (25 mg/kg in drinking water, daily) in vivo was able to improve body weight loss in Colon-26 (C26) bearers, without affecting tumor size. Consistently, the C26 hosts displayed ameliorated skeletal muscle and strength upon treatment with MitoQ. In line with improved skeletal muscle mass, the treatment with MitoQ was able to partially correct the expression of the E3 ubiquitin ligases Atrogin-1 and Murf1. Contrarily, the anabolic signaling was not improved by the treatment, as showed by unchanged AKT, mTOR and 4EBP1 phosphorylation. Assessment of gene expression showed altered levels of markers of mitochondrial biogenesis and homeostasis in the tumor hosts, although only Mitofusin-2 levels were significantly affected by the treatment. Interestingly, the levels of Pdk4 and CytB, genes involved in the regulation of mitochondrial function and metabolism, were also partially increased by MitoQ, in line with the modulation of hexokinase (HK), pyruvate dehydrogenase (PDH) and succinate dehydrogenase (SDH) enzymatic activities. The improvement of the oxidative metabolism was associated with reduced myosteatosis (i.e., intramuscular fat infiltration) in the C26 bearers receiving MitoQ, despite unchanged muscle LDL receptor expression, therefore suggesting that MitoQ could boost β-oxidation in the muscle tissue and promote a glycolytic-to-oxidative shift in muscle metabolism and fiber composition. Overall, our data identify MitoQ as an effective treatment to improve skeletal muscle mass and function in tumor hosts and further support studies aimed at testing the anti-cachectic properties of mitochondria-targeting antioxidants also in combination with routinely administered chemotherapy agents.

Keywords:  MitoQ; cachexia; cancer; metabolism; mitochondria; muscle

DOI:  https://doi.org/10.3389/fcell.2022.861622