bims-mepmim Biomed News
on Metabolites in pathological microenvironments and immunometabolism
Issue of 2023–12–17
33 papers selected by
Erika Mariana Palmieri, NIH/NCI Laboratory of Cancer ImmunoMetabolism
  1. A positive feedback loop between ZEB2 and ACSL4 regulates lipid metabolism to promote breast cancer metastasis.
  2. Senescence-associated 13-HODE production promotes age-related liver steatosis by directly inhibiting catalase activity.
  3. Phenotypic profiling of solute carriers characterizes serine transport in cancer.
  4. Itaconate suppresses atherosclerosis by activating a Nrf2-dependent anti-inflammatory response in macrophages in mice.
  5. Suppression of angiopoietin-like 4 reprograms endothelial cell metabolism and inhibits angiogenesis.
  6. Re-"Formate" T-cell Antitumor Responses.
  7. Mitochondrial- and NOX4-dependent antioxidant defence mitigates progression to non-alcoholic steatohepatitis in obesity.
  8. Multiomic profiling reveals metabolic alterations mediating aberrant platelet activity and inflammation in myeloproliferative neoplasms.
  9. ROS-induced ribosome impairment underlies ZAKα-mediated metabolic decline in obesity and aging.
  10. Itaconate promotes hepatocellular carcinoma progression by epigenetic induction of CD8+ T-cell exhaustion.
  11. BACH1 promotes tissue necrosis and Mycobacterium tuberculosis susceptibility.
  12. Control of lipolysis by a population of oxytocinergic sympathetic neurons.
  13. Gp78 deficiency in hepatocytes alleviates hepatic ischemia-reperfusion injury via suppressing ACSL4-mediated ferroptosis.
  14. Cysteine desulfurase (IscS)-mediated fine-tuning of bioenergetics and SUF expression prevents Mycobacterium tuberculosis hypervirulence.
  15. Single-cell spatial metabolomics with cell-type specific protein profiling for tissue systems biology.
  16. Niacin restriction with NAMPT-inhibition is synthetic lethal to neuroendocrine carcinoma.
  17. Metabolic Messengers: ketone bodies.
  18. Critical shifts in lipid metabolism promote megakaryocyte differentiation and proplatelet formation.
  19. GRAF1 integrates PINK1-Parkin signaling and actin dynamics to mediate cardiac mitochondrial homeostasis.
  20. A metabolic perspective on nitric oxide function in melanoma.
  21. Enhanced SREBP2-driven cholesterol biosynthesis by PKCλ/ι deficiency in intestinal epithelial cells promotes aggressive serrated tumorigenesis.
  22. DPPIV+ fibro-adipogenic progenitors form the niche of adult skeletal muscle self-renewing resident macrophages.
  23. Lung dendritic-cell metabolism underlies susceptibility to viral infection in diabetes.
  24. Mitochondrial temperature homeostasis resists external metabolic stresses.
  25. CMT2A-linked MFN2 mutation, T206I promotes mitochondrial hyperfusion and predisposes cells towards mitophagy.
  26. AMPKα2 is a skeletal muscle stem cell intrinsic regulator of myonuclear accretion.
  27. AIRE is expressed in breast cancer TANs and TAMs to regulate the extrinsic apoptotic pathway and inflammation.
  28. Isolation of dermal adipocytes from mouse skin for biochemical analysis.
  29. IL-10 protects against OPC ferroptosis by regulating lipid reactive oxygen species levels post stroke.
  30. The bone-liver interaction modulates immune and hematopoietic function through Pinch-Cxcl12-Mbl2 pathway.
  31. The mitochondrial ATP synthase is a negative regulator of the mitochondrial permeability transition pore.
  32. Atlas of fetal metabolism during mid-to-late gestation and diabetic pregnancy.
  33. Database-Driven Spatially Resolved Lipidomics Highlights Heterogeneous Metabolic Alterations in Type 2 Diabetic Mice.
  1. Elife. 2023 12 11. pii: RP87510. [Epub ahead of print]12
    A positive feedback loop between ZEB2 and ACSL4 regulates lipid metabolism to promote breast cancer metastasis.
    Jiamin Lin, Pingping Zhang, Wei Liu, Guorong Liu, Juan Zhang, Min Yan, Yuyou Duan, Na Yang.
      Lipid metabolism plays a critical role in cancer metastasis. However, the mechanisms through which metastatic genes regulate lipid metabolism remain unclear. Here, we describe a new oncogenic-metabolic feedback loop between the epithelial-mesenchymal transition transcription factor ZEB2 and the key lipid enzyme ACSL4 (long-chain acyl-CoA synthetase 4), resulting in enhanced cellular lipid storage and fatty acid oxidation (FAO) to drive breast cancer metastasis. Functionally, depletion of ZEB2 or ACSL4 significantly reduced lipid droplets (LDs) abundance and cell migration. ACSL4 overexpression rescued the invasive capabilities of the ZEB2 knockdown cells, suggesting that ACSL4 is crucial for ZEB2-mediated metastasis. Mechanistically, ZEB2-activated ACSL4 expression by directly binding to the ACSL4 promoter. ACSL4 binds to and stabilizes ZEB2 by reducing ZEB2 ubiquitination. Notably, ACSL4 not only promotes the intracellular lipogenesis and LDs accumulation but also enhances FAO and adenosine triphosphate production by upregulating the FAO rate-limiting enzyme CPT1A (carnitine palmitoyltransferase 1 isoform A). Finally, we demonstrated that ACSL4 knockdown significantly reduced metastatic lung nodes in vivo. In conclusion, we reveal a novel positive regulatory loop between ZEB2 and ACSL4, which promotes LDs storage to meet the energy needs of breast cancer metastasis, and identify the ZEB2-ACSL4 signaling axis as an attractive therapeutic target for overcoming breast cancer metastasis.
    Keywords:  cancer biology; ACSL4; lipid metabolism; lipid droplets; cancer metastasis; EMT; ZEB2
    DOI:  https://doi.org/10.7554/eLife.87510
  2. Nat Commun. 2023 Dec 09. 14(1): 8151
    Senescence-associated 13-HODE production promotes age-related liver steatosis by directly inhibiting catalase activity.
    Jinjie Duan, Wenhui Dong, Guangyan Wang, Wenjing Xiu, Guangyin Pu, Jingwen Xu, Chenji Ye, Xu Zhang, Yi Zhu, Chunjiong Wang.
      Aging is a major risk factor for metabolic disorders. Polyunsaturated fatty acid-derived bioactive lipids play critical roles as signaling molecules in metabolic processes. Nonetheless, their effects on age-related liver steatosis remain unknown. Here we show that senescent liver cells induce liver steatosis in a paracrine manner. Linoleic acid-derived 9-hydroxy-octadecadienoic acid (9-HODE) and 13-HODE increase in middle-aged (12-month-old) and aged (20-month-old) male mouse livers and conditioned medium from senescent hepatocytes and macrophages. Arachidonate 15-lipoxygenase, an enzyme for 13-HODE and 9-HODE production, is upregulated in senescent cells. A 9-HODE and 13-HODE mixture induces liver steatosis and activates SREBP1. Furthermore, catalase (CAT) is a direct target of 13-HODE, and its activity is decreased by 13-HODE. CAT overexpression reduces 13-HODE-induced liver steatosis and protects male mice against age-related liver steatosis. Therefore, 13-HODE produced by senescent hepatocytes and macrophages activates SREBP1 by directly inhibiting CAT activity and promotes liver steatosis.
    DOI:  https://doi.org/10.1038/s41467-023-44026-z
  3. Nat Metab. 2023 Dec 08.
    Phenotypic profiling of solute carriers characterizes serine transport in cancer.
    Vasileios Papalazarou, Alice C Newman, Alejandro Huerta-Uribe, Nathalie M Legrave, Mattia Falcone, Tong Zhang, Lynn McGarry, Dimitris Athineos, Emma Shanks, Karen Blyth, Karen H Vousden, Oliver D K Maddocks.
      Serine is a vital amino acid in tumorigenesis. While cells can perform de novo serine synthesis, most transformed cells rely on serine uptake to meet their increased biosynthetic requirements. Solute carriers (SLCs), a family of transmembrane nutrient transport proteins, are the gatekeepers of amino acid acquisition and exchange in mammalian cells and are emerging as anticancer therapeutic targets; however, the SLCs that mediate serine transport in cancer cells remain unknown. Here we perform an arrayed RNAi screen of SLC-encoding genes while monitoring amino acid consumption and cell proliferation in colorectal cancer cells using metabolomics and high-throughput imaging. We identify SLC6A14 and SLC25A15 as major cytoplasmic and mitochondrial serine transporters, respectively. We also observe that SLC12A4 facilitates serine uptake. Dual targeting of SLC6A14 and either SLC25A15 or SLC12A4 diminishes serine uptake and growth of colorectal cancer cells in vitro and in vivo, particularly in cells with compromised de novo serine biosynthesis. Our results provide insight into the mechanisms that contribute to serine uptake and intracellular handling.
    DOI:  https://doi.org/10.1038/s42255-023-00936-2
  4. J Clin Invest. 2023 Dec 12. pii: e173034. [Epub ahead of print]
    Itaconate suppresses atherosclerosis by activating a Nrf2-dependent anti-inflammatory response in macrophages in mice.
    Jianrui Song, Yanling Zhang, Ryan A Frieler, Anthony Andren, Sherri C Wood, Daniel J Tyrrell, Peter Sajjakulnukit, Jane C Deng, Costas A Lyssiotis, Richard M Mortensen, Morgan Salmon, Daniel R Goldstein.
      Itaconate has emerged as a critical immunoregulatory metabolite. Here, we examined the therapeutic potential of itaconate in atherosclerosis. We found that both itaconate and the enzyme that synthesizes it, aconitate decarboxylase 1 (Acod1, also known as "immune-responsive gene 1"/IRG1) are upregulated during atherogenesis in mice. Deletion of Acod1 in myeloid cells exacerbated inflammation and atherosclerosis in vivo and resulted in an elevated frequency of a specific subset of M1-polarized proinflammatory macrophages in the atherosclerotic aorta. Importantly, Acod1 levels were inversely correlated with clinical occlusion in atherosclerotic human aorta specimens. Treating mice with the itaconate derivative 4-ocytyl itaconate attenuated inflammation and atherosclerosis induced by high cholesterol. Mechanistically, we found that the antioxidant transcription factor, Nuclear factor erythroid-2 Related Factor 2 (Nrf2) was required for itaconate to suppress macrophage activation induced by oxidized lipids in vitro and to decrease atherosclerotic lesion areas in vivo. Overall, our work shows that itaconate suppresses atherogenesis by inducing Nrf2-dependent inhibition of proinflammatory responses in macrophages. Activation of the itaconate pathway may represent an important approach to treat atherosclerosis.
    Keywords:  Atherosclerosis; Cardiology; Cardiovascular disease; Inflammation; Macrophages
    DOI:  https://doi.org/10.1172/JCI173034
  5. Nat Commun. 2023 Dec 12. 14(1): 8251
    Suppression of angiopoietin-like 4 reprograms endothelial cell metabolism and inhibits angiogenesis.
    Balkrishna Chaube, Kathryn M Citrin, Mahnaz Sahraei, Abhishek K Singh, Diego Saenz de Urturi, Wen Ding, Richard W Pierce, Raaisa Raaisa, Rebecca Cardone, Richard Kibbey, Carlos Fernández-Hernando, Yajaira Suárez.
      Angiopoietin-like 4 (ANGPTL4) is known to regulate various cellular and systemic functions. However, its cell-specific role in endothelial cells (ECs) function and metabolic homeostasis remains to be elucidated. Here, using endothelial-specific Angptl4 knock-out mice (Angptl4iΔEC), and transcriptomics and metabolic flux analysis, we demonstrate that ANGPTL4 is required for maintaining EC metabolic function vital for vascular permeability and angiogenesis. Knockdown of ANGPTL4 in ECs promotes lipase-mediated lipoprotein lipolysis, which results in increased fatty acid (FA) uptake and oxidation. This is also paralleled by a decrease in proper glucose utilization for angiogenic activation of ECs. Mice with endothelial-specific deletion of Angptl4 showed decreased pathological neovascularization with stable vessel structures characterized by increased pericyte coverage and reduced permeability. Together, our study denotes the role of endothelial-ANGPTL4 in regulating cellular metabolism and angiogenic functions of EC.
    DOI:  https://doi.org/10.1038/s41467-023-43900-0
  6. Cancer Discov. 2023 Dec 12. 13(12): 2507-2509
    Re-"Formate" T-cell Antitumor Responses.
    Mei-Chun Lin, Sofie Hedlund Moller, Ping-Chih Ho.
       SUMMARY: Rowe and colleagues discover that one-carbon (1C) metabolism rewiring occurs upon T-cell activation to support proliferation and cytolytic activity in CD8+ T cells and that supplementation of 1C donor formate rescues the dysfunctional T cells and their responsiveness to anti-PD-1 in selective tumor-infiltrated T-cell subsets. This finding represents an attractive strategy to overcome a metabolic vulnerability in the tumor microenvironment and improve the efficacy of immune checkpoint blockade. See related article by Rowe et al., p. 2566 (8).
    DOI:  https://doi.org/10.1158/2159-8290.CD-23-1059
  7. J Clin Invest. 2023 Dec 07. pii: e162533. [Epub ahead of print]
    Mitochondrial- and NOX4-dependent antioxidant defence mitigates progression to non-alcoholic steatohepatitis in obesity.
    Spencer Greatorex, Supreet Kaur, Chrysovalantou E Xirouchaki, Pei Kee Goh, Florian Wiede, Amanda J Genders, Melanie Tran, YaoYao Jia, Arthe Raajendiran, Wendy A Brown, Catriona A McLean, Junichi Sadoshima, Matthew J Watt, Tony Tiganis.
      Non-alcoholic fatty liver disease (NAFLD) is prevalent in the majority of obese individuals, but in a subset, this progresses to non-alcoholic steatohepatitis (NASH) and fibrosis. The mechanisms that prevent NASH and fibrosis in the majority of NAFLD patients remain unclear. Here we report that NAD(P)H oxidase (NOX)-4 and nuclear factor erythroid 2-related factor 2 (NFE2L2) were elevated in hepatocytes early in disease progression to prevent NASH/fibrosis. Mitochondrial-derived reactive oxygen species (ROS) activated NFE2L2 to induce the expression of NOX4, which in turn generated H2O2 to exacerbate the NFE2L2 antioxidant defense response. The deletion or inhibition of NOX4 in hepatocytes decreased ROS and attenuated antioxidant defense to promote mitochondrial oxidative stress, damage proteins and lipids, diminish insulin signalling and promote cell death upon oxidant challenge. Hepatocyte NOX4 deletion in high fat fed obese mice, which otherwise develop steatosis, but not NASH, resulted in hepatic oxidative damage, inflammation and T cell recruitment to drive NASH and fibrosis, whereas NOX4 overexpression tempered the development of NASH/fibrosis in mice fed a NASH-promoting diet. Thus, mitochondrial- and NOX4-derived ROS function in concert to drive a NFE2L2 antioxidant defense response to attenuate oxidative liver damage and the progression to NASH/fibrosis in obesity.
    Keywords:  Diabetes; Glucose metabolism; Hepatology; Metabolism; Obesity
    DOI:  https://doi.org/10.1172/JCI162533
  8. J Clin Invest. 2023 Dec 07. pii: e172256. [Epub ahead of print]
    Multiomic profiling reveals metabolic alterations mediating aberrant platelet activity and inflammation in myeloproliferative neoplasms.
    Fan He, Angelo B A Laranjeira, Tim Kong, Shuyang Lin, Katrina J Ashworth, Alice Liu, Nina M Lasky, Daniel Ac Fisher, Maggie J Cox, Mary C Fulbright, Lilian A Antunes Heck, LaYow C Yu, Molly Brakhane, Bei Gao, Stephen M Sykes, Angelo D'Alessandro, Jorge A Di Paola, Stephen T Oh.
      Platelets from patients with myeloproliferative neoplasms (MPNs) exhibit a hyperreactive phenotype. Here, we found elevated P-selectin exposure and platelet-leukocyte aggregates indicating activation of platelets from essential thrombocythemia (ET) patients. Single cell RNA-seq analysis of primary samples revealed significant enrichment of transcripts related to platelet activation, mTOR and oxidative phosphorylation (OXPHOS) in ET patient platelets. These observations were validated via proteomic profiling. Platelet metabolomics revealed distinct metabolic phenotypes consisting of elevated ATP generation, accompanied by increases in the levels of multiple intermediates of the tricarboxylic acid (TCA) cycle, but lower alpha-ketoglutarate (α-KG) in MPN patients. Inhibition of PI3K/AKT/mTOR signaling significantly reduced metabolic responses and hyperreactivity in MPN patient platelets, while α-KG supplementation markedly reduced oxygen consumption and ATP generation. Ex vivo incubation of platelets from both MPN patients and Jak2 V617F mice with α-KG significantly reduced platelet activation responses. Oral α-KG supplementation of Jak2 V617F mice decreased splenomegaly and reduced hematocrit, monocyte and platelet counts. Finally, α-KG incubation significantly decreased proinflammatory cytokine secretion from MPN CD14+ monocytes. Our results reveal a previously unrecognized metabolic disorder in conjunction with aberrant PI3K/AKT/mTOR signaling, contributing to platelet hyperreactivity in MPN patients.
    Keywords:  Hematology; Platelets
    DOI:  https://doi.org/10.1172/JCI172256
  9. Science. 2023 Dec 08. 382(6675): eadf3208
    ROS-induced ribosome impairment underlies ZAKα-mediated metabolic decline in obesity and aging.
    Goda Snieckute, Laura Ryder, Anna Constance Vind, Zhenzhen Wu, Frederic Schrøder Arendrup, Mark Stoneley, Sébastien Chamois, Ana Martinez-Val, Marion Leleu, René Dreos, Alexander Russell, David Michael Gay, Aitana Victoria Genzor, Beatrice So-Yun Choi, Astrid Linde Basse, Frederike Sass, Morten Dall, Lucile Chantal Marie Dollet, Melanie Blasius, Anne E Willis, Anders H Lund, Jonas T Treebak, Jesper Velgaard Olsen, Steen Seier Poulsen, Mary Elizabeth Pownall, Benjamin Anderschou Holbech Jensen, Christoffer Clemmensen, Zach Gerhart-Hines, David Gatfield, Simon Bekker-Jensen.
      The ribotoxic stress response (RSR) is a signaling pathway in which the p38- and c-Jun N-terminal kinase (JNK)-activating mitogen-activated protein kinase kinase kinase (MAP3K) ZAKα senses stalling and/or collision of ribosomes. Here, we show that reactive oxygen species (ROS)-generating agents trigger ribosomal impairment and ZAKα activation. Conversely, zebrafish larvae deficient for ZAKα are protected from ROS-induced pathology. Livers of mice fed a ROS-generating diet exhibit ZAKα-activating changes in ribosomal elongation dynamics. Highlighting a role for the RSR in metabolic regulation, ZAK-knockout mice are protected from developing high-fat high-sugar (HFHS) diet-induced blood glucose intolerance and liver steatosis. Finally, ZAK ablation slows animals from developing the hallmarks of metabolic aging. Our work highlights ROS-induced ribosomal impairment as a physiological activation signal for ZAKα that underlies metabolic adaptation in obesity and aging.
    DOI:  https://doi.org/10.1126/science.adf3208
  10. Nat Commun. 2023 Dec 09. 14(1): 8154
    Itaconate promotes hepatocellular carcinoma progression by epigenetic induction of CD8+ T-cell exhaustion.
    Xuemei Gu, Haoran Wei, Caixia Suo, Shengqi Shen, Chuxu Zhu, Liang Chen, Kai Yan, Zhikun Li, Zhenhua Bian, Pinggen Zhang, Mengqiu Yuan, Yingxuan Yu, Jinzhi Du, Huafeng Zhang, Linchong Sun, Ping Gao.
      Itaconate is a well-known immunomodulatory metabolite; however, its role in hepatocellular carcinoma (HCC) remains unclear. Here, we find that macrophage-derived itaconate promotes HCC by epigenetic induction of Eomesodermin (EOMES)-mediated CD8+ T-cell exhaustion. Our results show that the knockout of immune-responsive gene 1 (IRG1), responsible for itaconate production, suppresses HCC progression. Irg1 knockout leads to a decreased proportion of PD-1+ and TIM-3+ CD8+ T cells. Deletion or adoptive transfer of CD8+ T cells shows that IRG1-promoted tumorigenesis depends on CD8+ T-cell exhaustion. Mechanistically, itaconate upregulates PD-1 and TIM-3 expression levels by promoting succinate-dependent H3K4me3 of the Eomes promoter. Finally, ibuprofen is found to inhibit HCC progression by targeting IRG1/itaconate-dependent tumor immunoevasion, and high IRG1 expression in macrophages predicts poor prognosis in HCC patients. Taken together, our results uncover an epigenetic link between itaconate and HCC and suggest that targeting IRG1 or itaconate might be a promising strategy for HCC treatment.
    DOI:  https://doi.org/10.1038/s41467-023-43988-4
  11. Nat Microbiol. 2023 Dec 08.
    BACH1 promotes tissue necrosis and Mycobacterium tuberculosis susceptibility.
    Eduardo P Amaral, Sivaranjani Namasivayam, Artur T L Queiroz, Eduardo Fukutani, Kerry L Hilligan, Kate Aberman, Logan Fisher, Caio Cesar B Bomfim, Keith Kauffman, Jay Buchanan, Leslie Santuo, Pedro Henrique Gazzinelli-Guimaraes, Diego L Costa, Mariane Araujo Teixeira, Beatriz Barreto-Duarte, Clarissa Gurgel Rocha, Monique Freire Santana, Marcelo Cordeiro-Santos, Daniel L Barber, Robert J Wilkinson, Igor Kramnik, Kazuhiko Igarashi, Thomas Scriba, Katrin D Mayer-Barber, Bruno B Andrade, Alan Sher.
      Oxidative stress triggers ferroptosis, a form of cellular necrosis characterized by iron-dependent lipid peroxidation, and has been implicated in Mycobacterium tuberculosis (Mtb) pathogenesis. We investigated whether Bach1, a transcription factor that represses multiple antioxidant genes, regulates host resistance to Mtb. We found that BACH1 expression is associated clinically with active pulmonary tuberculosis. Bach1 deletion in Mtb-infected mice increased glutathione levels and Gpx4 expression that inhibit lipid peroxidation. Bach1-/- macrophages exhibited increased resistance to Mtb-induced cell death, while Mtb-infected Bach1-deficient mice displayed reduced bacterial loads, pulmonary necrosis and lipid peroxidation concurrent with increased survival. Single-cell RNA-seq analysis of lungs from Mtb-infected Bach1-/- mice revealed an enrichment of genes associated with ferroptosis suppression. Bach1 depletion in Mtb-infected B6.Sst1S mice that display human-like necrotic lung pathology also markedly reduced necrosis and increased host resistance. These findings identify Bach1 as a key regulator of cellular and tissue necrosis and host resistance in Mtb infection.
    DOI:  https://doi.org/10.1038/s41564-023-01523-7
  12. Nature. 2023 Dec 13.
    Control of lipolysis by a population of oxytocinergic sympathetic neurons.
    Erwei Li, Luhong Wang, Daqing Wang, Jingyi Chi, Zeran Lin, Gordon I Smith, Samuel Klein, Paul Cohen, Evan D Rosen.
      Oxytocin (OXT), a nine-amino-acid peptide produced in the hypothalamus and released by the posterior pituitary, has well-known actions in parturition, lactation and social behaviour1, and has become an intriguing therapeutic target for conditions such as autism and schizophrenia2. Exogenous OXT has also been shown to have effects on body weight, lipid levels and glucose homeostasis1,3, suggesting that it may also have therapeutic potential for metabolic disease1,4. It is unclear, however, whether endogenous OXT participates in metabolic homeostasis. Here we show that OXT is a critical regulator of adipose tissue lipolysis in both mice and humans. In addition, OXT serves to facilitate the ability of β-adrenergic agonists to fully promote lipolysis. Most surprisingly, the relevant source of OXT in these metabolic actions is a previously unidentified subpopulation of tyrosine hydroxylase-positive sympathetic neurons. Our data reveal that OXT from the peripheral nervous system is an endogenous regulator of adipose and systemic metabolism.
    DOI:  https://doi.org/10.1038/s41586-023-06830-x
  13. Cell Death Dis. 2023 Dec 08. 14(12): 810
    Gp78 deficiency in hepatocytes alleviates hepatic ischemia-reperfusion injury via suppressing ACSL4-mediated ferroptosis.
    Changbiao Li, Yichao Wu, Kangchen Chen, Ronggao Chen, Shengjun Xu, Beng Yang, Zhengxing Lian, Xiaodong Wang, Kai Wang, Haiyang Xie, Shusen Zheng, Zhikun Liu, Di Wang, Xiao Xu.
      Ferroptosis, which is driven by iron-dependent lipid peroxidation, plays an essential role in liver ischemia-reperfusion injury (IRI) during liver transplantation (LT). Gp78, an E3 ligase, has been implicated in lipid metabolism and inflammation. However, its role in liver IRI and ferroptosis remains unknown. Here, hepatocyte-specific gp78 knockout (HKO) or overexpressed (OE) mice were generated to examine the effect of gp78 on liver IRI, and a multi-omics approach (transcriptomics, proteomics, and metabolomics) was performed to explore the potential mechanism. Gp78 expression decreased after reperfusion in LT patients and mice with IRI, and gp78 expression was positively correlated with liver damage. Gp78 absence from hepatocytes alleviated liver damage in mice with IRI, ameliorating inflammation. However, mice with hepatic gp78 overexpression showed the opposite phenotype. Mechanistically, gp78 overexpression disturbed lipid homeostasis, remodeling polyunsaturated fatty acid (PUFA) metabolism, causing oxidized lipids accumulation and ferroptosis, partly by promoting ACSL4 expression. Chemical inhibition of ferroptosis or ACSL4 abrogated the effects of gp78 on ferroptosis and liver IRI. Our findings reveal a role of gp78 in liver IRI pathogenesis and uncover a mechanism by which gp78 promotes hepatocyte ferroptosis by ACSL4, suggesting the gp78-ACSL4 axis as a feasible target for the treatment of IRI-associated liver damage.
    DOI:  https://doi.org/10.1038/s41419-023-06294-x
  14. Sci Adv. 2023 Dec 15. 9(50): eadh2858
    Cysteine desulfurase (IscS)-mediated fine-tuning of bioenergetics and SUF expression prevents Mycobacterium tuberculosis hypervirulence.
    Mayashree Das, Sreesa Sreedharan, Somnath Shee, Nitish Malhotra, Meghna Nandy, Ushashi Banerjee, Sakshi Kohli, Raju S Rajmani, Nagasuma Chandra, Aswin Sai Narain Seshasayee, Sunil Laxman, Amit Singh.
      Iron-sulfur (Fe-S) biogenesis requires multiprotein assembly systems, SUF and ISC, in most prokaryotes. M. tuberculosis (Mtb) encodes a complete SUF system, the depletion of which was bactericidal. The ISC operon is truncated to a single gene iscS (cysteine desulfurase), whose function remains uncertain. Here, we show that MtbΔiscS is bioenergetically deficient and hypersensitive to oxidative stress, antibiotics, and hypoxia. MtbΔiscS resisted killing by nitric oxide (NO). RNA sequencing indicates that IscS is important for expressing regulons of DosR and Fe-S-containing transcription factors, WhiB3 and SufR. Unlike wild-type Mtb, MtbΔiscS could not enter a stable persistent state, continued replicating in mice, and showed hypervirulence. The suf operon was overexpressed in MtbΔiscS during infection in a NO-dependent manner. Suppressing suf expression in MtbΔiscS either by CRISPR interference or upon infection in inducible NO-deficient mice arrests hypervirulence. Together, Mtb redesigned the ISC system to "fine-tune" the expression of SUF machinery for establishing persistence without causing detrimental disease in the host.
    DOI:  https://doi.org/10.1126/sciadv.adh2858
  15. Nat Commun. 2023 Dec 13. 14(1): 8260
    Single-cell spatial metabolomics with cell-type specific protein profiling for tissue systems biology.
    Thomas Hu, Mayar Allam, Shuangyi Cai, Walter Henderson, Brian Yueh, Aybuke Garipcan, Anton V Ievlev, Maryam Afkarian, Semir Beyaz, Ahmet F Coskun.
      Metabolic reprogramming in cancer and immune cells occurs to support their increasing energy needs in biological tissues. Here we propose Single Cell Spatially resolved Metabolic (scSpaMet) framework for joint protein-metabolite profiling of single immune and cancer cells in male human tissues by incorporating untargeted spatial metabolomics and targeted multiplexed protein imaging in a single pipeline. We utilized the scSpaMet to profile cell types and spatial metabolomic maps of 19507, 31156, and 8215 single cells in human lung cancer, tonsil, and endometrium tissues, respectively. The scSpaMet analysis revealed cell type-dependent metabolite profiles and local metabolite competition of neighboring single cells in human tissues. Deep learning-based joint embedding revealed unique metabolite states within cell types. Trajectory inference showed metabolic patterns along cell differentiation paths. Here we show scSpaMet's ability to quantify and visualize the cell-type specific and spatially resolved metabolic-protein mapping as an emerging tool for systems-level understanding of tissue biology.
    DOI:  https://doi.org/10.1038/s41467-023-43917-5
  16. Nat Commun. 2023 Dec 13. 14(1): 8095
    Niacin restriction with NAMPT-inhibition is synthetic lethal to neuroendocrine carcinoma.
    Miyuki Nomura, Mai Ohuchi, Yoshimi Sakamoto, Kei Kudo, Keisuke Yaku, Tomoyoshi Soga, Yuki Sugiura, Mami Morita, Kayoko Hayashi, Shuko Miyahara, Taku Sato, Yoji Yamashita, Shigemi Ito, Naohiko Kikuchi, Ikuro Sato, Rintaro Saito, Nobuo Yaegashi, Tatsuro Fukuhara, Hidekazu Yamada, Hiroshi Shima, Keiichi I Nakayama, Atsushi Hirao, Kenta Kawasaki, Yoichi Arai, Shusuke Akamatsu, Sei-Ichi Tanuma, Toshiro Sato, Takashi Nakagawa, Nobuhiro Tanuma.
      Nicotinamide phosphoribosyltransferase (NAMPT) plays a major role in NAD biosynthesis in many cancers and is an attractive potential cancer target. However, factors dictating therapeutic efficacy of NAMPT inhibitors (NAMPTi) are unclear. We report that neuroendocrine phenotypes predict lung and prostate carcinoma vulnerability to NAMPTi, and that NAMPTi therapy against those cancers is enhanced by dietary modification. Neuroendocrine differentiation of tumor cells is associated with down-regulation of genes relevant to quinolinate phosphoribosyltransferase-dependent de novo NAD synthesis, promoting NAMPTi susceptibility in vitro. We also report that circulating nicotinic acid riboside (NAR), a non-canonical niacin absent in culture media, antagonizes NAMPTi efficacy as it fuels NAMPT-independent but nicotinamide riboside kinase 1-dependent NAD synthesis in tumors. In mouse transplantation models, depleting blood NAR by nutritional or genetic manipulations is synthetic lethal to tumors when combined with NAMPTi. Our findings provide a rationale for simultaneous targeting of NAR metabolism and NAMPT therapeutically in neuroendocrine carcinoma.
    DOI:  https://doi.org/10.1038/s41467-023-43630-3
  17. Nat Metab. 2023 Dec 13.
    Metabolic Messengers: ketone bodies.
    Alisa B Nelson, Eric D Queathem, Patrycja Puchalska, Peter A Crawford.
      Prospective molecular targets and therapeutic applications for ketone body metabolism have increased exponentially in the past decade. Initially considered to be restricted in scope as liver-derived alternative fuel sources during periods of carbohydrate restriction or as toxic mediators during diabetic ketotic states, ketogenesis and ketone bodies modulate cellular homeostasis in multiple physiological states through a diversity of mechanisms. Selective signalling functions also complement the metabolic fates of the ketone bodies acetoacetate and D-β-hydroxybutyrate. Here we discuss recent discoveries revealing the pleiotropic roles of ketone bodies, their endogenous sourcing, signalling mechanisms and impact on target organs, and considerations for when they are either stimulated for endogenous production by diets or pharmacological agents or administered as exogenous wellness-promoting agents.
    DOI:  https://doi.org/10.1038/s42255-023-00935-3
  18. Nat Cardiovasc Res. 2023 Sep;2 835-852
    Critical shifts in lipid metabolism promote megakaryocyte differentiation and proplatelet formation.
    Bianca de Jonckheere, Ferdinand Kollotzek, Patrick Münzer, Vanessa Göb, Melina Fischer, Kristina Mott, Cristina Coman, Nina Nicole Troppmair, Mailin-Christin Manke, Monika Zdanyte, Tobias Harm, Manuel Sigle, Dominik Kopczynski, Andrea Bileck, Christopher Gerner, Nils Hoffmann, David Heinzmann, Alice Assinger, Meinrad Gawaz, David Stegner, Harald Schulze, Oliver Borst, Robert Ahrends.
      During megakaryopoiesis, megakaryocytes (MK) undergo cellular morphological changes with strong modification of membrane composition and lipid signaling. Here we adopt a lipid-centric multiomics approach to create a quantitative map of the MK lipidome during maturation and proplatelet formation. Data reveal that MK differentiation is driven by an increased fatty acyl import and de novo lipid synthesis, resulting in an anionic membrane phenotype. Pharmacological perturbation of fatty acid import and phospholipid synthesis blocked membrane remodeling and directly reduced MK polyploidization and proplatelet formation resulting in thrombocytopenia. The anionic lipid shift during megakaryopoiesis was paralleled by lipid-dependent relocalization of the scaffold protein CKIP-1 and recruitment of the kinase CK2α to the plasma membrane, which seems to be essential for sufficient platelet biogenesis. Overall, this study provides a framework to understand how the MK lipidome is altered during maturation and the impact of MK membrane lipid remodeling on MK kinase signaling involved in thrombopoiesis.
    DOI:  https://doi.org/10.1038/s44161-023-00325-8
  19. Nat Commun. 2023 Dec 11. 14(1): 8187
    GRAF1 integrates PINK1-Parkin signaling and actin dynamics to mediate cardiac mitochondrial homeostasis.
    Qiang Zhu, Matthew E Combs, Juan Liu, Xue Bai, Wenbo B Wang, Laura E Herring, Jiandong Liu, Jason W Locasale, Dawn E Bowles, Ryan T Gross, Michelle Mendiola Pla, Christopher P Mack, Joan M Taylor.
      The serine/threonine kinase, PINK1, and the E3 ubiquitin ligase, Parkin, are known to facilitate LC3-dependent autophagosomal encasement and lysosomal clearance of dysfunctional mitochondria, and defects in this process contribute to a variety of cardiometabolic and neurological diseases. Although recent evidence indicates that dynamic actin remodeling plays an important role in PINK1/Parkin-mediated mitochondrial autophagy (mitophagy), the underlying signaling mechanisms remain unknown. Here, we identify the RhoGAP GRAF1 (Arhgap26) as a PINK1 substrate that regulates mitophagy. GRAF1 promotes the release of damaged mitochondria from F-actin anchors, regulates mitochondrial-associated Arp2/3-mediated actin remodeling and facilitates Parkin-LC3 interactions to enhance mitochondria capture by autophagosomes. Graf1 phosphorylation on PINK1-dependent sites is dysregulated in human heart failure, and cardiomyocyte-restricted Graf1 depletion in mice blunts mitochondrial clearance and attenuates compensatory metabolic adaptations to stress. Overall, we identify GRAF1 as an enzyme that coordinates cytoskeletal and metabolic remodeling to promote cardioprotection.
    DOI:  https://doi.org/10.1038/s41467-023-43889-6
  20. Biochim Biophys Acta Rev Cancer. 2023 Dec 05. pii: S0304-419X(23)00187-7. [Epub ahead of print] 189038
    A metabolic perspective on nitric oxide function in melanoma.
    John Jimenez, Parul Dubey, Bethany Carter, John Koomen, Joseph Markowitz.
      Nitric oxide (NO) generated from nitric oxide synthase (NOS) exerts a dichotomous effect in melanoma, suppressing or promoting tumor progression. This dichotomy is thought to depend on the intracellular NO concentration and the cell type in which it is generated. Due to its central role in the metabolism of multiple critical constituents involved in signaling and stress, it is crucial to explore NO's contribution to the metabolic dysfunction of melanoma. This review will discuss many known metabolites linked to NO production in melanoma. We discuss the synthesis of these metabolites, their role in biochemical pathways, and how they alter the biological processes observed in the melanoma tumor microenvironment. The metabolic pathways altered by NO and the corresponding metabolites reinforce its dual role in melanoma and support investigating this effect for potential avenues of therapeutic intervention.
    Keywords:  Melanoma; Metabolism; Nitration; Nitric oxide; S-nitrosylation; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.bbcan.2023.189038
  21. Nat Commun. 2023 Dec 13. 14(1): 8075
    Enhanced SREBP2-driven cholesterol biosynthesis by PKCλ/ι deficiency in intestinal epithelial cells promotes aggressive serrated tumorigenesis.
    Yu Muta, Juan F Linares, Anxo Martinez-Ordoñez, Angeles Duran, Tania Cid-Diaz, Hiroto Kinoshita, Xiao Zhang, Qixiu Han, Yuki Nakanishi, Naoko Nakanishi, Thekla Cordes, Gurpreet K Arora, Marc Ruiz-Martinez, Miguel Reina-Campos, Hiroaki Kasashima, Masakazu Yashiro, Kiyoshi Maeda, Ana Albaladejo-Gonzalez, Daniel Torres-Moreno, José García-Solano, Pablo Conesa-Zamora, Giorgio Inghirami, Christian M Metallo, Timothy F Osborne, Maria T Diaz-Meco, Jorge Moscat.
      The metabolic and signaling pathways regulating aggressive mesenchymal colorectal cancer (CRC) initiation and progression through the serrated route are largely unknown. Although relatively well characterized as BRAF mutant cancers, their poor response to current targeted therapy, difficult preneoplastic detection, and challenging endoscopic resection make the identification of their metabolic requirements a priority. Here, we demonstrate that the phosphorylation of SCAP by the atypical PKC (aPKC), PKCλ/ι promotes its degradation and inhibits the processing and activation of SREBP2, the master regulator of cholesterol biosynthesis. We show that the upregulation of SREBP2 and cholesterol by reduced aPKC levels is essential for controlling metaplasia and generating the most aggressive cell subpopulation in serrated tumors in mice and humans. Since these alterations are also detected prior to neoplastic transformation, together with the sensitivity of these tumors to cholesterol metabolism inhibitors, our data indicate that targeting cholesterol biosynthesis is a potential mechanism for serrated chemoprevention.
    DOI:  https://doi.org/10.1038/s41467-023-43690-5
  22. Nat Commun. 2023 Dec 13. 14(1): 8273
    DPPIV+ fibro-adipogenic progenitors form the niche of adult skeletal muscle self-renewing resident macrophages.
    Farshad Babaeijandaghi, Nasim Kajabadi, Reece Long, Lin Wei Tung, Chun Wai Cheung, Morten Ritso, Chih-Kai Chang, Ryan Cheng, Tiffany Huang, Elena Groppa, Jean X Jiang, Fabio M V Rossi.
      Adult tissue-resident macrophages (RMs) are either maintained by blood monocytes or through self-renewal. While the presence of a nurturing niche is likely crucial to support the survival and function of self-renewing RMs, evidence regarding its nature is limited. Here, we identify fibro-adipogenic progenitors (FAPs) as the main source of colony-stimulating factor 1 (CSF1) in resting skeletal muscle. Using parabiosis in combination with FAP-deficient transgenic mice (PdgfrαCreERT2 × DTA) or mice lacking FAP-derived CSF1 (PdgfrαCreERT2 × Csf1flox/null), we show that local CSF1 from FAPs is required for the survival of both TIM4- monocyte-derived and TIM4+ self-renewing RMs in adult skeletal muscle. The spatial distribution and number of TIM4+ RMs coincide with those of dipeptidyl peptidase IV (DPPIV)+ FAPs, suggesting their role as CSF1-producing niche cells for self-renewing RMs. This finding identifies opportunities to precisely manipulate the function of self-renewing RMs in situ to further unravel their role in health and disease.
    DOI:  https://doi.org/10.1038/s41467-023-43579-3
  23. Nature. 2023 Dec 13.
    Lung dendritic-cell metabolism underlies susceptibility to viral infection in diabetes.
    Samuel Philip Nobs, Aleksandra A Kolodziejczyk, Lital Adler, Nir Horesh, Christine Botscharnikow, Ella Herzog, Gayatree Mohapatra, Sophia Hejndorf, Ryan-James Hodgetts, Igor Spivak, Lena Schorr, Leviel Fluhr, Denise Kviatcovsky, Anish Zacharia, Suzanne Njuki, Dinorah Barasch, Noa Stettner, Mally Dori-Bachash, Alon Harmelin, Alexander Brandis, Tevie Mehlman, Ayelet Erez, Yiming He, Sara Ferrini, Jens Puschhof, Hagit Shapiro, Manfred Kopf, Arieh Moussaieff, Suhaib K Abdeen, Eran Elinav.
      People with diabetes feature a life-risking susceptibility to respiratory viral infection, including influenza and SARS-CoV-2 (ref. 1), whose mechanism remains unknown. In acquired and genetic mouse models of diabetes, induced with an acute pulmonary viral infection, we demonstrate that hyperglycaemia leads to impaired costimulatory molecule expression, antigen transport and T cell priming in distinct lung dendritic cell (DC) subsets, driving a defective antiviral adaptive immune response, delayed viral clearance and enhanced mortality. Mechanistically, hyperglycaemia induces an altered metabolic DC circuitry characterized by increased glucose-to-acetyl-CoA shunting and downstream histone acetylation, leading to global chromatin alterations. These, in turn, drive impaired expression of key DC effectors including central antigen presentation-related genes. Either glucose-lowering treatment or pharmacological modulation of histone acetylation rescues DC function and antiviral immunity. Collectively, we highlight a hyperglycaemia-driven metabolic-immune axis orchestrating DC dysfunction during pulmonary viral infection and identify metabolic checkpoints that may be therapeutically exploited in mitigating exacerbated disease in infected diabetics.
    DOI:  https://doi.org/10.1038/s41586-023-06803-0
  24. Elife. 2023 Dec 11. pii: RP89232. [Epub ahead of print]12
    Mitochondrial temperature homeostasis resists external metabolic stresses.
    Mügen Terzioglu, Kristo Veeroja, Toni Montonen, Teemu O Ihalainen, Tiina S Salminen, Paule Bénit, Pierre Rustin, Young-Tae Chang, Takeharu Nagai, Howard T Jacobs.
      Based on studies with a fluorescent reporter dye, Mito Thermo Yellow (MTY), and the genetically encoded gTEMP ratiometric fluorescent temperature indicator targeted to mitochondria, the temperature of active mitochondria in four mammalian and one insect cell line was estimated to be up to 15°C above that of the external environment to which the cells were exposed. High mitochondrial temperature was maintained in the face of a variety of metabolic stresses, including substrate starvation or modification, decreased ATP demand due to inhibition of cytosolic protein synthesis, inhibition of the mitochondrial adenine nucleotide transporter and, if an auxiliary pathway for electron transfer was available via the alternative oxidase, even respiratory poisons acting downstream of oxidative phosphorylation (OXPHOS) complex I. We propose that the high temperature of active mitochondria is an inescapable consequence of the biochemistry of OXPHOS and is homeostatically maintained as a primary feature of mitochondrial metabolism.
    Keywords:  D. melanogaster; OXPHOS; biochemistry; bioenergetics; cell biology; chemical biology; human; mitochondria; mouse; organelle; temperature; thermogenesis
    DOI:  https://doi.org/10.7554/eLife.89232
  25. Mitochondrion. 2023 Dec 11. pii: S1567-7249(23)00105-8. [Epub ahead of print] 101825
    CMT2A-linked MFN2 mutation, T206I promotes mitochondrial hyperfusion and predisposes cells towards mitophagy.
    Rajdeep Das, Sebabrata Maity, Palamou Das, Izaz Monir Kamal, Saikat Chakrabarti, Oishee Chakrabarti.
      Mutations in Mitofusin2 (MFN2) associated with the pathology of the debilitating neuropathy Charcot-Marie-Tooth type 2A (CMT2A) are known to alter mitochondrial morphology. Previously, such mutations have been shown to elicit two diametrically opposite phenotypes - while some mutations have been causally linked to enhanced mitochondrial fragmentation, others have been shown to induce hyperfusion. Our study identifies one such MFN2 mutant, T206I that causes mitochondrial hyperfusion. Cells expressing this MFN2 mutant have elongated and interconnected mitochondria. T206I-MFN2 mutation in the GTPase domain increases MFN2 stability and renders cells susceptible to stress. We show that cells expressing T206I-MFN2 have a higher predisposition towards mitophagy under conditions of serum starvation. We also detect increased DRP1 recruitment onto the outer mitochondrial membrane, though the total DRP1 protein level remains unchanged. Here we have characterized a lesser studied CMT2A-linked MFN2 mutant to show that its presence affects mitochondrial morphology and homeostasis.
    DOI:  https://doi.org/10.1016/j.mito.2023.101825
  26. iScience. 2023 Dec 15. 26(12): 108343
    AMPKα2 is a skeletal muscle stem cell intrinsic regulator of myonuclear accretion.
    Anita Kneppers, Sabrina Ben Larbi, Marine Theret, Audrey Saugues, Carole Dabadie, Linda Gsaier, Arnaud Ferry, Philipp Rhein, Julien Gondin, Kei Sakamoto, Rémi Mounier.
      Due to the post-mitotic nature of skeletal muscle fibers, adult muscle maintenance relies on dedicated muscle stem cells (MuSCs). In most physiological contexts, MuSCs support myofiber homeostasis by contributing to myonuclear accretion, which requires a coordination of cell-type specific events between the myofiber and MuSCs. Here, we addressed the role of the kinase AMPKα2 in the coordination of these events supporting myonuclear accretion. We demonstrate that AMPKα2 deletion impairs skeletal muscle regeneration. Through in vitro assessments of MuSC myogenic fate and EdU-based cell tracing, we reveal a MuSC-specific role of AMPKα2 in the regulation of myonuclear accretion, which is mediated by phosphorylation of the non-metabolic substrate BAIAP2. Similar cell tracing in vivo shows that AMPKα2 knockout mice have a lower rate of myonuclear accretion during regeneration, and that MuSC-specific AMPKα2 deletion decreases myonuclear accretion in response to myofiber contraction. Together, this demonstrates that AMPKα2 is a MuSC-intrinsic regulator of myonuclear accretion.
    Keywords:  Molecular biology experimental approach; Molecular mechanism of behavior; Specialized functions of cells; Stem cells research; cell Biology
    DOI:  https://doi.org/10.1016/j.isci.2023.108343
  27. J Leukoc Biol. 2023 Dec 07. pii: qiad152. [Epub ahead of print]
    AIRE is expressed in breast cancer TANs and TAMs to regulate the extrinsic apoptotic pathway and inflammation.
    Eva Källberg, Meliha Mehmeti-Ajradini, Frida Björk Gunnarsdottir, Marcus Göransson, Caroline Bergenfelz, Roni Allaoui Fredriksson, Catharina Hagerling, Martin E Johansson, Charlotte Welinder, Karin Jirström, Karin Leandersson.
      Autoimmune regulator (AIRE) is a transcriptional regulator expressed in the thymus and necessary for maintaining immunological self-tolerance. Extra-thymic AIRE expression is rare and a role for AIRE in tumor-associated innate immune cells has not yet been established. In this study we show that AIRE is expressed in human pro-tumor neutrophils. In breast cancer, AIRE was primarily located to tumor associated neutrophils (TANs), and to a lesser extent to tumor associated macrophages (TAMs) and tumor cells. Expression of AIRE in TAN/TAMs, but not in cancer cells, was associated with an adverse prognosis. We show that the functional role for AIRE in neutrophils and macrophages is to regulate expression of immune mediators and the extrinsic apoptotic pathway involving the Fas/TNFR death receptors and Cathepsin G. We here propose that the role for AIRE in TAN/TAMs in breast tumors is to regulate cell death and inflammation, thus promoting tumor progression.
    Keywords:  AIRE; N2; TAM; TAN; apoptosis; breast cancer; human; neutrophil
    DOI:  https://doi.org/10.1093/jleuko/qiad152
  28. STAR Protoc. 2023 Dec 06. pii: S2666-1667(23)00732-3. [Epub ahead of print]4(4): 102765
    Isolation of dermal adipocytes from mouse skin for biochemical analysis.
    Paul F Gehle, Sabrina Satzinger, Sebastian Willenborg, Sabine A Eming.
      The role of dermal white adipose tissue in regulating skin homeostasis and self-renewal processes has recently attracted interest. However, the isolation of proteins from dermal adipocytes for biochemical analysis is challenging. Here, we provide a protocol for the isolation of murine dermal adipocytes. We describe steps for inducing adipocyte-specific gene deletion, adipocyte isolation, protein purification, and western blot analysis. The reliability of the protocol is demonstrated by verifying efficient adipocyte-specific Atgl gene deletion in a tamoxifen-inducible Cre/loxP-based mouse model. For complete details on the use and execution of this protocol, please refer to Zhang et al. (2019).1.
    Keywords:  Cell isolation; Metabolism; Protein Biochemistry
    DOI:  https://doi.org/10.1016/j.xpro.2023.102765
  29. Redox Biol. 2023 Dec 05. pii: S2213-2317(23)00383-X. [Epub ahead of print]69 102982
    IL-10 protects against OPC ferroptosis by regulating lipid reactive oxygen species levels post stroke.
    Weihua Wu, Zhaoli Luo, Danmin Shen, Ting Lan, Zhongnan Xiao, Meng Liu, Liye Hu, Tingting Sun, Yamei Wang, Jian-Nan Zhang, Chenguang Zhang, Peipei Wang, Yabin Lu, Fei Yang, Qian Li.
      Accumulation of reactive oxygen species (ROS), especially on lipids, induces massive cell death in neurons and oligodendrocyte progenitor cells (OPCs) and causes severe neurologic deficits post stroke. While small compounds, such as deferoxamine, lipostatin-1, and ferrostatin-1, have been shown to be effective in reducing lipid ROS, the mechanisms by which endogenously protective molecules act against lipid ROS accumulation and subsequent cell death are still unclear, especially in OPCs, which are critical for maintaining white matter integrity and improving long-term outcomes after stroke. Here, using mouse primary OPC cultures, we demonstrate that interleukin-10 (IL-10), a cytokine playing roles in reducing neuroinflammation and promoting hematoma clearance, significantly reduced hemorrhage-induced lipid ROS accumulation and subsequent ferroptosis in OPCs. Mechanistically, IL-10 activated the IL-10R/STAT3 signaling pathway and upregulated the DLK1/AMPK/ACC axis. Subsequently, IL-10 reprogrammed lipid metabolism and reduced lipid ROS accumulation. In addition, in an autologous blood injection intracerebral hemorrhagic stroke (ICH) mouse model, deficiency of the endogenous Il-10, specific knocking out Il10r or Dlk1 in OPCs, or administration of ACC inhibitor was associated with increased OPC cell death, demyelination, axonal sprouting, and the cognitive deficits during the chronic phase of ICH and vice versa. These data suggest that IL-10 protects against OPC loss and white matter injury by reducing lipid ROS, supporting further development of potential clinical applications to benefit patients with stroke and related disorders.
    Keywords:  Ferroptosis; Interleukin-10; Intracerebral hemorrhagic stroke; Lipid reactive oxygen species; Oligodendrocyte progenitor cells
    DOI:  https://doi.org/10.1016/j.redox.2023.102982
  30. Cell Death Differ. 2023 Dec 07.
    The bone-liver interaction modulates immune and hematopoietic function through Pinch-Cxcl12-Mbl2 pathway.
    Tailin He, Bo Zhou, Guohuan Sun, Qinnan Yan, Sixiong Lin, Guixing Ma, Qing Yao, Xiaohao Wu, Yiming Zhong, Donghao Gan, Shaochuan Huo, Wenfei Jin, Di Chen, Xiaochun Bai, Tao Cheng, Huiling Cao, Guozhi Xiao.
      Mesenchymal stromal cells (MSCs) are used to treat infectious and immune diseases and disorders; however, its mechanism(s) remain incompletely defined. Here we find that bone marrow stromal cells (BMSCs) lacking Pinch1/2 proteins display dramatically reduced ability to suppress lipopolysaccharide (LPS)-induced acute lung injury and dextran sulfate sodium (DSS)-induced inflammatory bowel disease in mice. Prx1-Cre; Pinch1f/f; Pinch2-/- transgenic mice have severe defects in both immune and hematopoietic functions, resulting in premature death, which can be restored by intravenous injection of wild-type BMSCs. Single cell sequencing analyses reveal dramatic alterations in subpopulations of the BMSCs in Pinch mutant mice. Pinch loss in Prx1+ cells blocks differentiation and maturation of hematopoietic cells in the bone marrow and increases production of pro-inflammatory cytokines TNF-α and IL-1β in monocytes. We find that Pinch is critical for expression of Cxcl12 in BMSCs; reduced production of Cxcl12 protein from Pinch-deficient BMSCs reduces expression of the Mbl2 complement in hepatocytes, thus impairing the innate immunity and thereby contributing to infection and death. Administration of recombinant Mbl2 protein restores the lethality induced by Pinch loss in mice. Collectively, we demonstrate that the novel Pinch-Cxcl12-Mbl2 signaling pathway promotes the interactions between bone and liver to modulate immunity and hematopoiesis and may provide a useful therapeutic target for immune and infectious diseases.
    DOI:  https://doi.org/10.1038/s41418-023-01243-9
  31. Proc Natl Acad Sci U S A. 2023 Dec 19. 120(51): e2303713120
    The mitochondrial ATP synthase is a negative regulator of the mitochondrial permeability transition pore.
    Ryan Pekson, Felix G Liang, Joshua L Axelrod, Jaehoon Lee, Dongze Qin, Andre J H Wittig, Victor M Paulino, Min Zheng, Pablo M Peixoto, Richard N Kitsis.
      The mitochondrial permeability transition pore (mPTP) is a channel in the inner mitochondrial membrane whose sustained opening in response to elevated mitochondrial matrix Ca2+ concentrations triggers necrotic cell death. The molecular identity of mPTP is unknown. One proposed candidate is the mitochondrial ATP synthase, whose canonical function is to generate most ATP in multicellular organisms. Here, we present mitochondrial, cellular, and in vivo evidence that, rather than serving as mPTP, the mitochondrial ATP synthase inhibits this pore. Our studies confirm previous work showing persistence of mPTP in HAP1 cell lines lacking an assembled mitochondrial ATP synthase. Unexpectedly, however, we observe that Ca2+-induced pore opening is markedly sensitized by loss of the mitochondrial ATP synthase. Further, mPTP opening in cells lacking the mitochondrial ATP synthase is desensitized by pharmacological inhibition and genetic depletion of the mitochondrial cis-trans prolyl isomerase cyclophilin D as in wild-type cells, indicating that cyclophilin D can modulate mPTP through substrates other than subunits in the assembled mitochondrial ATP synthase. Mitoplast patch clamping studies showed that mPTP channel conductance was unaffected by loss of the mitochondrial ATP synthase but still blocked by cyclophilin D inhibition. Cardiac mitochondria from mice whose heart muscle cells we engineered deficient in the mitochondrial ATP synthase also demonstrate sensitization of Ca2+-induced mPTP opening and desensitization by cyclophilin D inhibition. Further, these mice exhibit strikingly larger myocardial infarctions when challenged with ischemia/reperfusion in vivo. We conclude that the mitochondrial ATP synthase does not function as mPTP and instead negatively regulates this pore.
    Keywords:  mitochondrial ATP synthase; mitochondrial permeability transition pore; necrosis
    DOI:  https://doi.org/10.1073/pnas.2303713120
  32. Cell. 2023 Nov 28. pii: S0092-8674(23)01228-X. [Epub ahead of print]
    Atlas of fetal metabolism during mid-to-late gestation and diabetic pregnancy.
    Cesar A Perez-Ramirez, Haruko Nakano, Richard C Law, Nedas Matulionis, Jennifer Thompson, Andrew Pfeiffer, Junyoung O Park, Atsushi Nakano, Heather R Christofk.
      Mounting evidence suggests metabolism instructs stem cell fate decisions. However, how fetal metabolism changes during development and how altered maternal metabolism shapes fetal metabolism remain unexplored. We present a descriptive atlas of in vivo fetal murine metabolism during mid-to-late gestation in normal and diabetic pregnancy. Using 13C-glucose and liquid chromatography-mass spectrometry (LC-MS), we profiled the metabolism of fetal brains, hearts, livers, and placentas harvested from pregnant dams between embryonic days (E)10.5 and 18.5. Our analysis revealed metabolic features specific to a hyperglycemic environment and signatures that may denote developmental transitions during euglycemic development. We observed sorbitol accumulation in fetal tissues and altered neurotransmitter levels in fetal brains isolated from hyperglycemic dams. Tracing 13C-glucose revealed disparate fetal nutrient sourcing depending on maternal glycemic states. Regardless of glycemic state, histidine-derived metabolites accumulated in late-stage fetal tissues. Our rich dataset presents a comprehensive overview of in vivo fetal tissue metabolism and alterations due to maternal hyperglycemia.
    Keywords:  development; diabetes; fetal metabolism; isotope tracing; metabolism; metabolomics; pregnancy
    DOI:  https://doi.org/10.1016/j.cell.2023.11.011
  33. Anal Chem. 2023 Dec 13.
    Database-Driven Spatially Resolved Lipidomics Highlights Heterogeneous Metabolic Alterations in Type 2 Diabetic Mice.
    Xinzhu Li, Qingce Zang, Ying Zhu, Xinyi Tu, Jialin Liu, Ting Li, Shiyu Zhu, Lingzhi Wang, Zeper Abliz, Ruiping Zhang.
      Spatially resolved lipidomics is pivotal for detecting and interpreting lipidomes within spatial contexts using the mass spectrometry imaging (MSI) technique. However, comprehensive and efficient lipid identification in MSI remains challenging. Herein, we introduce a high-coverage, database-driven approach combined with air-flow-assisted desorption electrospray ionization (AFADESI)-MSI to generate spatial lipid profiles across whole-body mice. Using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS), we identified 2868 unique lipids in the serum and various organs of mice. Subsequently, we systematically evaluated the distinct ionization properties of the lipids between LC-MS and MSI and created a detailed MSI database containing 14 123 ions. This method enabled the visualization of aberrant fatty acid and phospholipid metabolism across organs in a diabetic mouse model. As a powerful extension incorporated into the MSIannotator tool, our strategy facilitates the rapid and accurate annotation of lipids, providing new research avenues for probing spatially resolved heterogeneous metabolic changes in response to diseases.
    DOI:  https://doi.org/10.1021/acs.analchem.3c03765
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