bims-mepmim Biomed News
on Metabolites in pathological microenvironments and immunometabolism
Issue of 2023‒03‒26
twenty papers selected by
Erika Mariana Palmieri
NIH/NCI Laboratory of Cancer ImmunoMetabolism
  1. Macrophage metabolic rewiring improves heme-suppressed efferocytosis and tissue damage in sickle cell disease.
  2. Accumulated cholesterol protects tumours from elevated lipid peroxidation in the microenvironment.
  3. Inhibition of nucleotide biosynthesis disrupts lipid accumulation and adipogenesis.
  4. Nitric oxide regulates metabolism in murine stress erythroid progenitors to promote recovery during inflammatory anemia.
  5. Stromal and therapy-induced macrophage proliferation promotes PDAC progression and susceptibility to innate immunotherapy.
  6. Nrf2 regulates glucose uptake and metabolism in neurons and astrocytes.
  7. Oxoglutarate dehydrogenase complex controls glutamate-mediated neuronal death.
  8. 1H-NMR protocol for rapid diagnosis of purine and pyrimidine metabolic disorders in urine.
  9. The lactate dehydrogenase (LDH) isoenzyme spectrum enables optimally controlling T cell glycolysis and differentiation.
  10. Molecular and metabolic heterogeneity of astrocytes and microglia.
  11. ATG7 and ATG14 restrict cytosolic and phagosomal Mycobacterium tuberculosis replication in human macrophages.
  12. Saturated fatty acids dampen the immunogenicity of cancer by suppressing STING.
  13. H2O2 transit through the mitochondrial intermembrane space promotes tumor cell growth in vitro and in vivo.
  14. Identification of bile acid-CoA:amino acid N-acyltransferase as the hepatic N-acyl taurine synthase for polyunsaturated fatty acids.
  15. Defects in lipid homeostasis reflect the function of TANGO2 in phospholipid and neutral lipid metabolism.
  16. Loss of fatty acid degradation by astrocytic mitochondria triggers neuroinflammation and neurodegeneration.
  17. Lipid hydroperoxides promote sarcopenia through carbonyl stress.
  18. SLC25A46 promotes mitochondrial fission and mediates resistance to lipotoxic stress in INS-1E insulin secreting cells.
  19. Systematic analysis of the aberrances and functional implications of cuproptosis in cancer.
  20. Single-cell RNA sequencing reveals maturation trajectory in human pluripotent stem cell-derived cardiomyocytes in engineered tissues.
  1. Blood. 2023 Mar 23. pii: blood.2022018026. [Epub ahead of print]
    Macrophage metabolic rewiring improves heme-suppressed efferocytosis and tissue damage in sickle cell disease.
    Richa Sharma, Ada Antypiuk, S Zebulon Vance, Deepa Manwani, Quentinn Pearce, James Eric Cox, Xiuli An, Karina Yazdanbakhsh, Francesca Vinchi.
      Sickle cell disease (SCD) is hallmarked by an underlying chronic inflammatory condition, which is contributed by heme-activated pro-inflammatory macrophages. While previous studies addressed heme ability to stimulate macrophage inflammatory skewing through TLR4/ROS signaling, how heme alters cell functional properties remains unexplored. Macrophage-mediated immune cell recruitment and apoptotic cell (AC) clearance are relevant in the context of SCD, where tissue damage, cell apoptosis and inflammation occur due to vasoocclusive episodes, hypoxia and ischemic injury. Here we show that heme strongly alters macrophage functional response to AC damage by exacerbating immune cell recruitment and impairing cell efferocytic capacity. In SCD, heme-driven excessive leukocyte influx and defective efferocytosis contribute to exacerbated tissue damage and sustained inflammation. Mechanistically, these events depend on heme-mediated activation of TLR4 signaling and suppression of the transcription factor PPARg and its coactivator PGC1a. These changes reduce efferocytic receptor expression and promote mitochondrial remodeling, resulting in a coordinated functional and metabolic reprogramming of macrophages. Overall, this results in limited AC engulfment, impaired metabolic shift to mitochondrial fatty acid b-oxidation and ultimately reduced secretion of the anti-inflammatory cytokines IL-4 and IL-10, with consequent inhibition of continual efferocytosis, resolution of inflammation and tissue repair. We further demonstrate that impaired phagocytic capacity is recapitulated by macrophage exposure to sickle patients'plasma and improved by hemopexin-mediated heme scavenging, PPARg agonists or IL-4 exposure through functional and metabolic macrophage rewiring. Our data indicate that therapeutic improvement of heme-altered macrophage functional properties via heme scavenging or PGC1a/PPARg modulation significantly ameliorate tissue damage associated with SCD pathophysiology.
    DOI:  https://doi.org/10.1182/blood.2022018026
  2. Redox Biol. 2023 Mar 15. pii: S2213-2317(23)00079-4. [Epub ahead of print]62 102678
    Accumulated cholesterol protects tumours from elevated lipid peroxidation in the microenvironment.
    Xi Zhao, Xinyu Lian, Jianlan Xie, Guoquan Liu.
      Elevated lipid peroxidation (LPO), usually present in the tumour microenvironment (TME), is profoundly implicated in antitumour immunity and may be targeted for the development of new antitumour therapies. However, tumour cells may also rewire their metabolism to survive elevated LPO. Here, we report a novel and nonantioxidant mechanism by which tumour cells benefit from accumulated cholesterol to restrain LPO and ferroptosis, a nonapoptotic form of cell death characterized by accumulated LPO. Modulating cholesterol metabolism, especially LDLR-mediated cholesterol uptake, shifted the susceptibility of tumour cells to ferroptosis. Elevation of cellular cholesterol content specifically restrained LPO triggered by GSH-GPX4 inhibition or oxidizing factors in the TME. Furthermore, depletion of TME cholesterol by MβCD efficiently enhanced the antitumour efficacy of ferroptosis in a mouse xenograft model. Distinct from the antioxidant effect of its metabolic intermediates, the protective role of cholesterol was ascribed to its ability to decrease membrane fluidity and promote lipid raft formation, which affects the diffusion of LPO substrates. A correlation between LPO and lipid rafts was also found in tumour tissues from renal cancer patients. Together, our findings have identified a general and nonsacrificial mechanism by which cholesterol suppresses LPO, which can be exploited to enhance the efficacy of ferroptosis-based antitumour strategies.
    Keywords:  Cholesterol; Ferroptosis; LDLR; Lipid peroxidation; Lipid raft; Tumour microenvironment
    DOI:  https://doi.org/10.1016/j.redox.2023.102678
  3. J Biol Chem. 2023 Mar 22. pii: S0021-9258(23)00277-6. [Epub ahead of print] 104635
    Inhibition of nucleotide biosynthesis disrupts lipid accumulation and adipogenesis.
    Abhijit B Shinde, Elizabeth R Nunn, Genesis A Wilson, Mathew T Chvasta, Julia A Pinette, Jacob W Myers, Sun H Peck, Jessica B Spinelli, Elma Zaganjor.
      Energy balance and nutrient availability are key determinants of cellular decisions to remain quiescent, proliferate or differentiate into a mature cell. After assessing its environmental state, the cell must rewire its metabolism to support distinct cellular outcomes. Mechanistically, how metabolites regulate cell fate decisions is poorly understood. We used adipogenesis as our model system to ascertain the role of metabolism in differentiation. We isolated adipose tissue stromal vascular fraction (SVF) cells and profiled metabolites before and after adipogenic differentiation to identify metabolic signatures associated with these distinct cellular states. We found that differentiation alters nucleotide accumulation. Furthermore, inhibition of nucleotide biosynthesis prevented lipid storage within adipocytes and downregulated the expression of lipogenic factors. In contrast to proliferating cells, in which mTORC1 is activated by purine accumulation, mTORC1 signaling was unaffected by purine levels in differentiating adipocytes. Rather, our data indicated that purines regulate transcriptional activators of adipogenesis, PPARγ and C/EBPα to promote differentiation. Although de novo nucleotide biosynthesis has mainly been studied in proliferation, our study points to its requirement in adipocyte differentiation.
    Keywords:  adipocytes; adipogenesis; lipid droplets; metabolism; nucleotides; purine; pyrimidine
    DOI:  https://doi.org/10.1016/j.jbc.2023.104635
  4. bioRxiv. 2023 Mar 11. pii: 2023.03.11.532207. [Epub ahead of print]
    Nitric oxide regulates metabolism in murine stress erythroid progenitors to promote recovery during inflammatory anemia.
    Baiye Ruan, Yuanting Chen, Sara Trimidal, Imhoi Koo, Fenghua Qian, Jingwei Cai, John Mcguigan, Molly A Hall, Andrew D Patterson, K Sandeep Prabhu, Robert F Paulson.
      Inflammation skews bone marrow hematopoiesis increasing the production of myeloid effector cells at the expense of steady-state erythropoiesis. A compensatory stress erythropoiesis response is induced to maintain homeostasis until inflammation is resolved. In contrast to steady-state erythroid progenitors, stress erythroid progenitors (SEPs) utilize signals induced by inflammatory stimuli. However, the mechanistic basis for this is not clear. Here we reveal a nitric oxide (NO)-dependent regulatory network underlying two stages of stress erythropoiesis, namely proliferation, and the transition to differentiation. In the proliferative stage, immature SEPs and cells in the niche increased expression of inducible nitric oxide synthase ( Nos2 or iNOS ) to generate NO. Increased NO rewires SEP metabolism to increase anabolic pathways, which drive the biosynthesis of nucleotides, amino acids and other intermediates needed for cell division. This NO-dependent metabolism promotes cell proliferation while also inhibiting erythroid differentiation leading to the amplification of a large population of non-committed progenitors. The transition of these progenitors to differentiation is mediated by the activation of nuclear factor erythroid 2-related factor 2 (Nfe2l2 or Nrf2). Nrf2 acts as an anti-inflammatory regulator that decreases NO production, which removes the NO-dependent erythroid inhibition and allows for differentiation. These data provide a paradigm for how alterations in metabolism allow inflammatory signals to amplify immature progenitors prior to differentiation.Key points: Nitric-oxide (NO) dependent signaling favors an anabolic metabolism that promotes proliferation and inhibits differentiation.Activation of Nfe2l2 (Nrf2) decreases NO production allowing erythroid differentiation.
    DOI:  https://doi.org/10.1101/2023.03.11.532207
  5. J Exp Med. 2023 Jun 05. pii: e20212062. [Epub ahead of print]220(6):
    Stromal and therapy-induced macrophage proliferation promotes PDAC progression and susceptibility to innate immunotherapy.
    Chong Zuo, John M Baer, Brett L Knolhoff, Jad I Belle, Xiuting Liu, Angela Alarcon De La Lastra, Christina Fu, Graham D Hogg, Natalie L Kingston, Marcus A Breden, Paarth B Dodhiawala, Daniel Cui Zhou, Varintra E Lander, C Alston James, Li Ding, Kian-Huat Lim, Ryan C Fields, William G Hawkins, Jason D Weber, Guoyan Zhao, David G DeNardo.
      Tumor-associated macrophages (TAMs) are abundant in pancreatic ductal adenocarcinomas (PDACs). While TAMs are known to proliferate in cancer tissues, the impact of this on macrophage phenotype and disease progression is poorly understood. We showed that in PDAC, proliferation of TAMs could be driven by colony stimulating factor-1 (CSF1) produced by cancer-associated fibroblasts. CSF1 induced high levels of p21 in macrophages, which regulated both TAM proliferation and phenotype. TAMs in human and mouse PDACs with high levels of p21 had more inflammatory and immunosuppressive phenotypes. p21 expression in TAMs was induced by both stromal interaction and/or chemotherapy treatment. Finally, by modeling p21 expression levels in TAMs, we found that p21-driven macrophage immunosuppression in vivo drove tumor progression. Serendipitously, the same p21-driven pathways that drive tumor progression also drove response to CD40 agonist. These data suggest that stromal or therapy-induced regulation of cell cycle machinery can regulate both macrophage-mediated immune suppression and susceptibility to innate immunotherapy.
    DOI:  https://doi.org/10.1084/jem.20212062
  6. Redox Biol. 2023 Mar 14. pii: S2213-2317(23)00073-3. [Epub ahead of print]62 102672
    Nrf2 regulates glucose uptake and metabolism in neurons and astrocytes.
    Noemí Esteras, Thomas S Blacker, Evgeny A Zherebtsov, Olga A Stelmashuk, Ying Zhang, W Christian Wigley, Michael R Duchen, Albena T Dinkova-Kostova, Andrey Y Abramov.
      The transcription factor Nrf2 and its repressor Keap1 mediate cell stress adaptation by inducing expression of genes regulating cellular detoxification, antioxidant defence and energy metabolism. Energy production and antioxidant defence employ NADH and NADPH respectively as essential metabolic cofactors; both are generated in distinct pathways of glucose metabolism, and both pathways are enhanced by Nrf2 activation. Here, we examined the role of Nrf2 on glucose distribution and the interrelation between NADH production in energy metabolism and NADPH homeostasis using glio-neuronal cultures isolated from wild-type, Nrf2-knockout and Keap1-knockdown mice. Employing advanced microscopy imaging of single live cells, including multiphoton fluorescence lifetime imaging microscopy (FLIM) to discriminate between NADH and NADPH, we found that Nrf2 activation increases glucose uptake into neurons and astrocytes. Glucose consumption is prioritized in brain cells for mitochondrial NADH and energy production, with a smaller contribution to NADPH synthesis in the pentose phosphate pathway for redox reactions. As Nrf2 is suppressed during neuronal development, this strategy leaves neurons reliant on astrocytic Nrf2 to maintain redox balance and energy homeostasis.
    Keywords:  Astrocytes; Brain; Glucose metabolism; Mitochondria; NADH; NADPH; Neurons; Nrf2
    DOI:  https://doi.org/10.1016/j.redox.2023.102672
  7. Redox Biol. 2023 Mar 11. pii: S2213-2317(23)00070-8. [Epub ahead of print]62 102669
    Oxoglutarate dehydrogenase complex controls glutamate-mediated neuronal death.
    Adelheid Weidinger, Nadja Milivojev, Arthur Hosmann, J Catharina Duvigneau, Csaba Szabo, Gabor Törö, Laurin Rauter, Annette Vaglio-Garro, Garik V Mkrtchyan, Lidia Trofimova, Rinat R Sharipov, Alexander M Surin, Irina A Krasilnikova, Vsevolod G Pinelis, Laszlo Tretter, Rudolf Moldzio, Hülya Bayır, Valerian E Kagan, Victoria I Bunik, Andrey V Kozlov.
      Brain injury is accompanied by neuroinflammation, accumulation of extracellular glutamate and mitochondrial dysfunction, all of which cause neuronal death. The aim of this study was to investigate the impact of these mechanisms on neuronal death. Patients from the neurosurgical intensive care unit suffering aneurysmal subarachnoid hemorrhage (SAH) were recruited retrospectively from a respective database. In vitro experiments were performed in rat cortex homogenate, primary dissociated neuronal cultures, B35 and NG108-15 cell lines. We employed methods including high resolution respirometry, electron spin resonance, fluorescent microscopy, kinetic determination of enzymatic activities and immunocytochemistry. We found that elevated levels of extracellular glutamate and nitric oxide (NO) metabolites correlated with poor clinical outcome in patients with SAH. In experiments using neuronal cultures we showed that the 2-oxoglutarate dehydrogenase complex (OGDHC), a key enzyme of the glutamate-dependent segment of the tricarboxylic acid (TCA) cycle, is more susceptible to the inhibition by NO than mitochondrial respiration. Inhibition of OGDHC by NO or by succinyl phosphonate (SP), a highly specific OGDHC inhibitor, caused accumulation of extracellular glutamate and neuronal death. Extracellular nitrite did not substantially contribute to this NO action. Reactivation of OGDHC by its cofactor thiamine (TH) reduced extracellular glutamate levels, Ca2+ influx into neurons and cell death rate. Salutary effect of TH against glutamate toxicity was confirmed in three different cell lines. Our data suggest that the loss of control over extracellular glutamate, as described here, rather than commonly assumed impaired energy metabolism, is the critical pathological manifestation of insufficient OGDHC activity, leading to neuronal death.
    DOI:  https://doi.org/10.1016/j.redox.2023.102669
  8. STAR Protoc. 2023 Mar 22. pii: S2666-1667(23)00139-9. [Epub ahead of print]4(2): 102181
    1H-NMR protocol for rapid diagnosis of purine and pyrimidine metabolic disorders in urine.
    Elmarie Davoren, Shayne Mason.
      Purine and pyrimidine disorders are often difficult to diagnose. Here, we present a 1H-NMR analysis protocol for the quantification of purines and pyrimidines in urine to diagnose associated disorders. We describe steps for pH adjustment, sample preparation, and 1H-NMR analysis and data analysis. The use of 1H-NMR requires a relatively small sample volume (1 mL) and minimal sample preparation. Analysis time produces accurate and reproducible data within 2 h.
    Keywords:  Metabolism; Metabolomics; NMR
    DOI:  https://doi.org/10.1016/j.xpro.2023.102181
  9. Sci Adv. 2023 Mar 24. 9(12): eadd9554
    The lactate dehydrogenase (LDH) isoenzyme spectrum enables optimally controlling T cell glycolysis and differentiation.
    Xuyong Chen, Lingling Liu, Siwen Kang, Jn Rashida Gnanaprakasam, Ruoning Wang.
      Isoenzyme divergence is a prevalent mechanism governing tissue-specific and developmental stage-specific metabolism in mammals. The lactate dehydrogenase (LDH) isoenzyme spectrum reflects the tissue-specific metabolic status. We found that three tetrameric isoenzymes composed of LDHA and LDHB (LDH-3/4/5) comprise the LDH spectrum in T cells. Genetically deleting LDHA or LDHB altered the isoenzyme spectrum by removing all heterotetramers and leaving T cells with LDH-1 (the homotetramer of LDHB) or LDH-5 (the homotetramer of LDHA), respectively. Accordingly, deleting LDHA suppressed glycolysis, cell proliferation, and differentiation. Unexpectedly, deleting LDHB enhanced glycolysis but suppressed T cell differentiation, indicating that an optimal zone of glycolytic activity is required to maintain cell fitness. Mechanistically, the LDH isoenzyme spectrum imposed by LDHA and LDHB is necessary to optimize glycolysis to maintain a balanced nicotinamide adenine dinucleotide/nicotinamide adenine dinucleotide hydrogen pool. Our results suggest that the LDH isoenzyme spectrum enables "Goldilocks levels" of glycolytic and redox activity to control T cell differentiation.
    DOI:  https://doi.org/10.1126/sciadv.add9554
  10. Cell Metab. 2023 Mar 17. pii: S1550-4131(23)00084-0. [Epub ahead of print]
    Molecular and metabolic heterogeneity of astrocytes and microglia.
    Philip Hasel, William H Aisenberg, F Chris Bennett, Shane A Liddelow.
      Astrocytes and microglia are central players in a myriad of processes in the healthy and diseased brain, ranging from metabolism to immunity. The crosstalk between these two cell types contributes to pathology in many if not all neuroinflammatory and neurodegenerative diseases. Recent advancements in integrative multimodal sequencing techniques have begun to highlight how heterogeneous both cell types are and the importance of metabolism to their regulation. We discuss here the transcriptomic, metabolic, and functional heterogeneity of astrocytes and microglia and highlight their interaction in health and disease.
    DOI:  https://doi.org/10.1016/j.cmet.2023.03.006
  11. Nat Microbiol. 2023 Mar 23.
    ATG7 and ATG14 restrict cytosolic and phagosomal Mycobacterium tuberculosis replication in human macrophages.
    Beren Aylan, Elliott M Bernard, Enrica Pellegrino, Laure Botella, Antony Fearns, Natalia Athanasiadi, Claudio Bussi, Pierre Santucci, Maximiliano G Gutierrez.
      Autophagy is a cellular innate-immune defence mechanism against intracellular microorganisms, including Mycobacterium tuberculosis (Mtb). How canonical and non-canonical autophagy function to control Mtb infection in phagosomes and the cytosol remains unresolved. Macrophages are the main host cell in humans for Mtb. Here we studied the contributions of canonical and non-canonical autophagy in the genetically tractable human induced pluripotent stem cell-derived macrophages (iPSDM), using a set of Mtb mutants generated in the same genetic background of the common lab strain H37Rv. We monitored replication of Mtb mutants that are either unable to trigger canonical autophagy (Mtb ΔesxBA) or reportedly unable to block non-canonical autophagy (Mtb ΔcpsA) in iPSDM lacking either ATG7 or ATG14 using single-cell high-content imaging. We report that deletion of ATG7 by CRISPR-Cas9 in iPSDM resulted in increased replication of wild-type Mtb but not of Mtb ΔesxBA or Mtb ΔcpsA. We show that deletion of ATG14 resulted in increased replication of both Mtb wild type and the mutant Mtb ΔesxBA. Using Mtb reporters and quantitative imaging, we identified a role for ATG14 in regulating fusion of phagosomes containing Mtb with lysosomes, thereby enabling intracellular bacteria restriction. We conclude that ATG7 and ATG14 are both required for restricting Mtb replication in human macrophages.
    DOI:  https://doi.org/10.1038/s41564-023-01335-9
  12. Cell Rep. 2023 Mar 22. pii: S2211-1247(23)00314-5. [Epub ahead of print]42(4): 112303
    Saturated fatty acids dampen the immunogenicity of cancer by suppressing STING.
    Blake R Heath, Wang Gong, Hülya F Taner, Luke Broses, Kohei Okuyama, Wanqing Cheng, Max Jin, Zackary R Fitzsimonds, Andriana Manousidaki, Yuesong Wu, Shaoping Zhang, Haitao Wen, Steven B Chinn, Eric Bartee, Yuying Xie, James J Moon, Yu Leo Lei.
      Oncogenes destabilize STING in epithelial cell-derived cancer cells, such as head and neck squamous cell carcinomas (HNSCCs), to promote immune escape. Despite the abundance of tumor-infiltrating myeloid cells, HNSCC presents notable resistance to STING stimulation. Here, we show how saturated fatty acids in the microenvironment dampen tumor response to STING stimulation. Using single-cell analysis, we found that obesity creates an IFN-I-deprived tumor microenvironment with a massive expansion of suppressive myeloid cell clusters and contraction of effector T cells. Saturated fatty acids, but not unsaturated fatty acids, potently inhibit the STING-IFN-I pathway in HNSCC cells. Myeloid cells from obese mice show dampened responses to STING stimulation and are more suppressive of T cell activation. In agreement, obese hosts exhibited increased tumor burden and lower responsiveness to STING agonist. As a mechanism, saturated fatty acids induce the expression of NLRC3, depletion of which results in a T cell inflamed tumor microenvironment and IFN-I-dependent tumor control.
    Keywords:  CP: Cancer; CP: Immunology; NLRC3; STING; head and neck cancer; immunogenicity; innate immunity; metabolism; obesity; saturated fatty acids; type-I interferon
    DOI:  https://doi.org/10.1016/j.celrep.2023.112303
  13. J Biol Chem. 2023 Mar 17. pii: S0021-9258(23)00266-1. [Epub ahead of print] 104624
    H2O2 transit through the mitochondrial intermembrane space promotes tumor cell growth in vitro and in vivo.
    SimranS Sabharwal, V Joseph Dudley, Charlène Landwerlin, PaulT Schumacker.
      Cancer cells experience increased levels of oxidant stress as a consequence of oncogene activation, nucleotide biosynthesis, and growth factor receptor signaling. Mitochondria contribute to this redox stress by generating reactive oxygen species (ROS) along the electron transport chain (ETC), which are released to the matrix and the intermembrane space (IMS). Assessing the contribution of mitochondrial ROS in cancer cells is technically difficult, as ETC inhibitors can increase or decrease ROS generation, while they also block oxidative phosphorylation and ATP synthesis. Mitochondria-targeted antioxidant compounds can scavenge ROS in the matrix compartment, but do not act on ROS released to the intermembrane space. We assessed the importance of mitochondrial ROS for tumor cell proliferation, survival, and for tumor xenograft growth by stably expressing a hydrogen peroxide (H2O2) scavenger, peroxiredoxin-5, in the mitochondrial IMS (IMS-Prdx5) in 143B osteosarcoma and HCT116 colorectal cancer cell lines. IMS-Prdx5 attenuates hypoxia-induced ROS signaling as assessed independently in cytosol and IMS, HIF-1α stabilization and activity, and cellular proliferation under normoxic and hypoxic culture conditions. It also suppressed tumor growth in vivo. Stable expression of non-degradable HIF-1α only partially rescued proliferation in IMS-Prdx5-expressing cells, indicating that mitochondrial H2O2 signaling contributes to tumor cell proliferation and survival through HIF-dependent and HIF-independent mechanisms.
    Keywords:  Hypoxia-Inducible Factor-1; Reactive oxygen species; cancer; mitochondrial intermembrane space; peroxiredoxin-5; redox signaling
    DOI:  https://doi.org/10.1016/j.jbc.2023.104624
  14. J Lipid Res. 2023 Mar 21. pii: S0022-2275(23)00034-2. [Epub ahead of print] 100361
    Identification of bile acid-CoA:amino acid N-acyltransferase as the hepatic N-acyl taurine synthase for polyunsaturated fatty acids.
    Samuel A J Trammell, Luke F Gamon, Kamil Gotfryd, Katja Thorøe Michler, Bandar D Alrehaili, Iben Rix, Filip K Knop, Pontus Gourdon, Yoon-Kwang Lee, Michael J Davies, Matthew P Gillum, Trisha J Grevengoed.
      N-acyl taurines (NATs) are bioactive lipids with emerging roles in glucose homeostasis and lipid metabolism. The acyl-chains of hepatic and biliary NATs are enriched in poly-unsaturated fatty acids (PUFAs). Dietary supplementation with a class of PUFAs, the omega-3 fatty acids, increases their cognate NATs in mice and humans. However, the synthesis pathway of the PUFA-containing NATs remains undiscovered. Here, we report that human livers synthesize NATs and that the acyl-chain preference is similar in murine liver homogenates. In the mouse, we found that hepatic NAT synthase activity localizes to the peroxisome and depends upon an active-site cysteine. Using unbiased metabolomics and proteomics, we identified bile acid-CoA:amino acid N-acyltransferase (BAAT) as the likely hepatic NAT synthase in vitro. Subsequently, we confirmed that BAAT knockout livers lack up to 90% of NAT synthase activity and that biliary PUFA-containing NATs are significantly reduced compared to wildtype. In conclusion, we identified the in vivo PUFA-NAT synthase in the murine liver and expanded the known substrates of the bile acid-conjugating enzyme, BAAT, beyond classic bile acids to the synthesis of a novel class of bioactive lipids.
    Keywords:  Bile acids and salts/biosynthesis; Bile acids and salts/metabolism, Liver; N-acyl amino acid; N-acyl taurine; Omega-3 fatty acids; fatty acid amide hydrolase; metabolomics; peroxisomes; proteomics
    DOI:  https://doi.org/10.1016/j.jlr.2023.100361
  15. Elife. 2023 Mar 24. pii: e85345. [Epub ahead of print]12
    Defects in lipid homeostasis reflect the function of TANGO2 in phospholipid and neutral lipid metabolism.
    Agustin Leonardo Lujan, Ombretta Foresti, Conor Sugden, Nathalie Brouwers, Alex Mateo Farre, Alessio Vignoli, Mahshid Azamian, Alicia Turner, Jose Wojnacki, Vivek Malhotra.
      We show that TANGO2 in mammalian cells localizes predominantly to mitochondria and partially at mitochondria sites juxtaposed to lipid droplets (LDs) and the endoplasmic reticulum. HepG2 cells and fibroblasts of patients lacking TANGO2 exhibit enlarged LDs. Quantitative lipidomics revealed a marked increase in lysophosphatidic acid (LPA) and a concomitant decrease in its biosynthetic precursor phosphatidic acid (PA). These changes were exacerbated in nutrient-starved cells. Based on our data, we suggest that TANGO2 function is linked to acyl-CoA metabolism, which is necessary for the acylation of LPA to generate PA. The defect in acyl-CoA availability impacts the metabolism of many other fatty acids, generates high levels of reactive oxygen (ROS), and promotes lipid peroxidation. We suggest that the increased size of LDs is a combination of enrichment in peroxidized lipids and a defect in their catabolism. Our findings help explain the physiological consequence of mutations in TANGO2 that induce acute metabolic crises, including rhabdomyolysis, cardiomyopathy, and cardiac arrhythmias, often leading to fatality upon starvation and stress.
    Keywords:  cell biology; human
    DOI:  https://doi.org/10.7554/eLife.85345
  16. Nat Metab. 2023 Mar 23.
    Loss of fatty acid degradation by astrocytic mitochondria triggers neuroinflammation and neurodegeneration.
    Yashi Mi, Guoyuan Qi, Francesca Vitali, Yuan Shang, Adam C Raikes, Tian Wang, Yan Jin, Roberta D Brinton, Haiwei Gu, Fei Yin.
      Astrocytes provide key neuronal support, and their phenotypic transformation is implicated in neurodegenerative diseases. Metabolically, astrocytes possess low mitochondrial oxidative phosphorylation (OxPhos) activity, but its pathophysiological role in neurodegeneration remains unclear. Here, we show that the brain critically depends on astrocytic OxPhos to degrade fatty acids (FAs) and maintain lipid homeostasis. Aberrant astrocytic OxPhos induces lipid droplet (LD) accumulation followed by neurodegeneration that recapitulates key features of Alzheimer's disease (AD), including synaptic loss, neuroinflammation, demyelination and cognitive impairment. Mechanistically, when FA load overwhelms astrocytic OxPhos capacity, elevated acetyl-CoA levels induce astrocyte reactivity by enhancing STAT3 acetylation and activation. Intercellularly, lipid-laden reactive astrocytes stimulate neuronal FA oxidation and oxidative stress, activate microglia through IL-3 signalling, and inhibit the biosynthesis of FAs and phospholipids required for myelin replenishment. Along with LD accumulation and impaired FA degradation manifested in an AD mouse model, we reveal a lipid-centric, AD-resembling mechanism by which astrocytic mitochondrial dysfunction progressively induces neuroinflammation and neurodegeneration.
    DOI:  https://doi.org/10.1038/s42255-023-00756-4
  17. Elife. 2023 Mar 23. pii: e85289. [Epub ahead of print]12
    Lipid hydroperoxides promote sarcopenia through carbonyl stress.
    Hiroaki Eshima, Justin L Shahtout, Piyarat Siripoksup, MacKenzie J Pearson, Ziad S Mahmassani, Patrick J Ferrara, Alexis W Lyons, John Alan Maschek, Alek D Peterlin, Anthony R P Verkerke, Jordan M Johnson, Anahy Salcedo, Jonathan J Petrocelli, Edwin R Miranda, Ethan J Anderson, Sihem Boudina, Qitao Ran, James E Cox, Micah J Drummond, Katsuhiko Funai.
      Reactive oxygen species (ROS) accumulation is a cardinal feature of skeletal muscle atrophy. ROS refers to a collection of radical molecules whose cellular signals are vast, and it is unclear which downstream consequences of ROS are responsible for the loss of muscle mass and strength. Here we show that lipid hydroperoxides (LOOH) are increased with age and disuse, and the accumulation of LOOH by deletion of glutathione peroxidase 4 (GPx4) is sufficient to augment muscle atrophy. LOOH promoted atrophy in a lysosomal-dependent, proteasomal-independent manner. In young and old mice, genetic and pharmacologic neutralization of LOOH or their secondary reactive lipid aldehydes robustly prevented muscle atrophy and weakness, indicating that LOOH-derived carbonyl stress mediates age- and disuse-induced muscle dysfunction. Our findings provide novel insights for the role of LOOH in sarcopenia including a therapeutic implication by pharmacologic suppression.
    Keywords:  cell biology; mouse
    DOI:  https://doi.org/10.7554/eLife.85289
  18. J Cell Sci. 2023 Mar 21. pii: jcs.260049. [Epub ahead of print]
    SLC25A46 promotes mitochondrial fission and mediates resistance to lipotoxic stress in INS-1E insulin secreting cells.
    Jaime Santo-Domingo, Steve Lassueur, Antonio Núñez Galindo, Pilar Alvarez-Illera, Silvia Romero-Sanz, Elena Caldero-Escudero, Sergio de la Fuente, Loïc Dayon, Andreas Wiederkehr.
      Glucose sensing in pancreatic beta-cells depends on oxidative phosphorylation and mitochondria-derived signals that promote insulin secretion. Using mass spectrometry-based phosphoproteomics to search for down-stream effectors of glucose dependent signal transduction in INS-1E insulinoma cells, we identified the outer mitochondrial membrane protein SLC25A46. Under resting glucose concentrations, SLC25A46 was phosphorylated on a pair of threonine residues (T44/T45) and was dephosphorylated in response to glucose-induced calcium signals. Overexpression of SLC25A46 in INS-1E cells caused complete mitochondrial fragmentation, resulting in a mild mitochondrial defect associated with lowered glucose-induced insulin secretion. In contrast, inactivation of the SLC25A46 gene resulted in dramatic mitochondrial hyperfusion but without affecting respiratory activity or insulin secretion. Consequently, SLC25A46 is not essential for metabolism-secretion coupling under normal nutrient conditions. Importantly, insulin secreting cells lacking SLC25A46 had an exacerbated sensitivity to lipotoxic conditions undergoing massive apoptosis when exposed to palmitate. Therefore, in addition to its role in mitochondrial dynamics, SLC25A46 plays a role in preventing mitochondria-induced apoptosis in INS-E cells exposed to nutrient stress. By protecting mitochondria, SLC25A46 may help to maintain beta-cell mass essential for blood glucose control.
    Keywords:  Beta-cell; Mitochondria; Mitochondrial dynamics
    DOI:  https://doi.org/10.1242/jcs.260049
  19. iScience. 2023 Apr 21. 26(4): 106319
    Systematic analysis of the aberrances and functional implications of cuproptosis in cancer.
    Jiangbing Li, Boyan Li, Rongrong Zhao, Gang Li.
      Cuproptosis is a novel form of cell death driven by a copper-dependent proteotoxic stress response whose comprehensive landscape in tumors remains unclear. Here, we comprehensively characterized cuproptosis-related genes (CRGs) across 33 cancers using multi-omic data from The Cancer Genome Atlas (TCGA), showing complicated and diverse results in different cancers. We also explored the relationships between CRGs and cancer metabolic patterns, pathway activity, and tumor microenvironment (TME), suggesting that they played critical roles in tumor progression and TME cell infiltration. We further established the cuproptosis potential index (CPI) to reveal the functional roles of cuproptosis, and characterized multi-omic molecular features associated with cuproptosis. In clinical applications, we performed a combined analysis of the sensitivity of CRGs and CPI to drug response and immunotherapy. This study provides a rich resource for understanding cuproptosis, offering a broad molecular perspective for future functional and therapeutic studies of multiple cancer pathways mediated by cuproptosis.
    Keywords:  Cancer systems biology; Cell biology; Omics
    DOI:  https://doi.org/10.1016/j.isci.2023.106319
  20. iScience. 2023 Apr 21. 26(4): 106302
    Single-cell RNA sequencing reveals maturation trajectory in human pluripotent stem cell-derived cardiomyocytes in engineered tissues.
    Shangli Cheng, David Brenière-Letuffe, Virpi Ahola, Andy O T Wong, Hoi Yee Keung, Bimal Gurung, Zongli Zheng, Kevin D Costa, Deborah K Lieu, Wendy Keung, Ronald A Li.
      Cardiac in vitro models have become increasingly obtainable and affordable with the optimization of human pluripotent stem cell-derived cardiomyocyte (hPSC-CM) differentiation. However, these CMs are immature compared to their in vivo counterparts. Here we study the cellular phenotype of hPSC-CMs by comparing their single-cell gene expression and functional profiles in three engineered cardiac tissue configurations: human ventricular (hv) cardiac anisotropic sheet, cardiac tissue strip, and cardiac organoid chamber (hvCOC), with spontaneously aggregated 3D cardiac spheroids (CS) as control. The CM maturity was found to increase with increasing levels of complexity of the engineered tissues from CS to hvCOC. The contractile components are the first function to mature, followed by electrophysiology and oxidative metabolism. Notably, the 2D tissue constructs show a higher cellular organization whereas metabolic maturity preferentially increases in the 3D constructs. We conclude that the tissue engineering models resembling configurations of native tissues may be reliable for drug screening or disease modeling.
    Keywords:  Cell biology; Stem cells research; Tissue Engineering
    DOI:  https://doi.org/10.1016/j.isci.2023.106302
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