bims-mepmim 2022-09-18 papers

bims-mepmim

Biomed News

on Metabolites in pathological microenvironments and immunometabolism

Issue of 2022–09–18
28 papers selected by
Erika Mariana Palmieri, NIH/NCI Laboratory of Cancer ImmunoMetabolism

Metabolic reprogramming in the OPA1-deficient cells.
Tumor-associated macrophages are shaped by intratumoral high potassium via Kir2.1.
Optimized protocol to isolate primary mouse peritoneal macrophage metabolites.
Glucocorticoids decrease thermogenic capacity and increase triacylglycerol synthesis by glycerokinase activation in the brown adipose tissue of rats.
Structure and mechanism of human cystine exporter cystinosin.
Folate enzyme MTHFD2 links one-carbon metabolism to unfolded protein response in glioblastoma.
The intestine is a major contributor to circulating succinate in mice.
OMA1-mediated integrated stress response protects against ferroptosis in mitochondrial cardiomyopathy.
Adipose tissue macrophages in remote modulation of hepatic glucose production.
The Amino Acid Homoarginine Inhibits Atherogenesis by Modulating T-Cell Function.
Enhancing arginase 2 expression using target site blockers as a strategy to modulate macrophage phenotype.
Targeting Strategies for Aberrant Lipid Metabolism Reprogramming and the Immune Microenvironment in Esophageal Cancer: A Review.
Murine blastocysts generated by in vitro fertilization show increased Warburg metabolism and altered lactate production.
Plasma metabolome predicts trained immunity responses after antituberculosis BCG vaccination.
Overexpression of UCP3 decreases mitochondrial efficiency in mouse skeletal muscle in vivo.
Specific activation of hypoxia-inducible factor-2α by propionate metabolism via a β-oxidation-like pathway stimulates MUC2 production in intestinal goblet cells.
Fatty acid metabolism in aggressive B-cell lymphoma is inhibited by tetraspanin CD37.
Sorting-free metabolic profiling uncovers the vulnerability of fatty acid β-oxidation in in vitro quiescence models.
Ketogenic diet uncovers differential metabolic plasticity of brain cells.
Liver macrophages in health and disease.
Use of cholesterol metabolism for anti-cancer strategies.
Hydropersulfides inhibit lipid peroxidation and ferroptosis by scavenging radicals.
Metabolic Tumor Imaging with Rapidly Signal-Enhanced 1-13C-Pyruvate-d3.
Iron supplementation inhibits hypoxia-induced mitochondrial damage and protects zebrafish liver cells from death.
Mild dyslipidemia accelerates tumorigenesis through expansion of Ly6Chi monocytes and differentiation to pro-angiogenic myeloid cells.
Iron metabolism mediates microglia susceptibility in ferroptosis.
Carboxylesterase 2 induces mitochondrial dysfunction via disrupting lipid homeostasis in oral squamous cell carcinoma.
Posttranslational S-nitrosylation modification regulates HMGB1 secretion and promotes its proinflammatory and neurodegenerative effects.

Cell Mol Life Sci. 2022 Sep 14. 79(10): 517

Metabolic reprogramming in the OPA1-deficient cells.

Wenting Dai, Zhichao Wang, Qiong A Wang, David Chan, Lei Jiang.

  OPA1, a dynamin-related GTPase mutated in autosomal dominant optic atrophy, is essential for the fusion of the inner mitochondrial membrane. Although OPA1 deficiency leads to impaired mitochondrial morphology, the role of OPA1 in central carbon metabolism remains unclear. Here, we aim to explore the functional role and metabolic mechanism of OPA1 in cell fitness beyond the control of mitochondrial fusion. We applied [U-13C]glucose and [U-13C]glutamine isotope tracing techniques to OPA1-knockout (OPA1-KO) mouse embryonic fibroblasts (MEFs) compared to OPA1 wild-type (OPA1-WT) controls. Furthermore, the resulting tracing data were integrated by metabolic flux analysis to understand the underlying metabolic mechanism through which OPA1 deficiency reprograms cellular metabolism. OPA1-deficient MEFs were depleted of intracellular citrate, which was consistent with the decreased oxygen consumption rate in these cells with mitochondrial fission that is not balanced by mitochondrial fusion. Whereas oxidative glucose metabolism was impaired, OPA1-deficient cells activated glutamine-dependent reductive carboxylation and subsequently relied on this reductive metabolism to produce cytosolic citrate as a predominant acetyl-CoA source for de novo fatty acid synthesis. Prevention of cytosolic glutamine reductive carboxylation by GSK321, an inhibitor of isocitrate dehydrogenase 1 (IDH1), largely repressed lipid synthesis and blocked cell proliferation in OPA1-deficient MEFs. Our data support that, when glucose oxidation failed to support lipogenesis and proliferation in cells with unbalanced mitochondrial fission, OPA1 deficiency stimulated metabolic anaplerosis into glutamine-dependent reductive carboxylation in an IDH1-mediated manner.

Keywords:  Cell growth; Citrate; De novo lipogenesis; OPA1 dysfunction; Oxidative metabolism; Reductive carboxylation

DOI:  https://doi.org/10.1007/s00018-022-04542-5
Cell Metab. 2022 Sep 07. pii: S1550-4131(22)00359-X. [Epub ahead of print]

Tumor-associated macrophages are shaped by intratumoral high potassium via Kir2.1.

Sheng Chen, Wenyu Cui, Zhexu Chi, Qian Xiao, Tianyi Hu, Qizhen Ye, Kaixiang Zhu, Weiwei Yu, Zhen Wang, Chengxuan Yu, Xiang Pan, Siqi Dai, Qi Yang, Jiacheng Jin, Jian Zhang, Mobai Li, Dehang Yang, Qianzhou Yu, Quanquan Wang, Xiafei Yu, Wei Yang, Xue Zhang, Junbin Qian, Kefeng Ding, Di Wang.

  The tumor microenvironment (TME) is a unique niche governed by constant crosstalk within and across all intratumoral cellular compartments. In particular, intratumoral high potassium (K+) has shown immune-suppressive potency on T cells. However, as a pan-cancer characteristic associated with local necrosis, the impact of this ionic disturbance on innate immunity is unknown. Here, we reveal that intratumoral high K+ suppresses the anti-tumor capacity of tumor-associated macrophages (TAMs). We identify the inwardly rectifying K+ channel Kir2.1 as a central modulator of TAM functional polarization in high K+ TME, and its conditional depletion repolarizes TAMs toward an anti-tumor state, sequentially boosting local anti-tumor immunity. Kir2.1 deficiency disturbs the electrochemically dependent glutamine uptake, engendering TAM metabolic reprogramming from oxidative phosphorylation toward glycolysis. Kir2.1 blockade attenuates both murine tumor- and patient-derived xenograft growth. Collectively, our findings reveal Kir2.1 as a determinant and potential therapeutic target for regaining the anti-tumor capacity of TAMs within ionic-imbalanced TME.

Keywords:  Kir2.1; immunometabolism; potassium; tumor microenvironment; tumor-associated macrophage

DOI:  https://doi.org/10.1016/j.cmet.2022.08.016
STAR Protoc. 2022 Sep 13. pii: S2666-1667(22)00548-2. [Epub ahead of print]3(4): 101668

Optimized protocol to isolate primary mouse peritoneal macrophage metabolites.

Adam De Jesus, Carolina M Pusec, Tivoli Nguyen, Farnaz Keyhani-Nejad, Peng Gao, Samuel E Weinberg, Hossein Ardehali.

  Peritoneal macrophages (PMs) have been shown to have higher stability compared to other macrophage subtypes. However, obtaining enough PMs from a single mouse is often a limitation for metabolomics analysis. Here, we describe a protocol to isolate metabolites from a small number of mouse primary PMs for 13C-stable glucose tracing and metabolomics. Our protocol uses X for metabolite extraction instead of methanol. Our protocol can consistently extract metabolites from low cell number samples with fewer steps than methanol-based approaches. For complete details on the use and execution of this protocol, please refer to De Jesus et al., (2022).

Keywords:  Cell isolation; Immunology; Mass spectrometry; Metabolism; Metabolomics

DOI:  https://doi.org/10.1016/j.xpro.2022.101668
Lipids. 2022 Sep 13.

Glucocorticoids decrease thermogenic capacity and increase triacylglycerol synthesis by glycerokinase activation in the brown adipose tissue of rats.

Ana Paula Assis, Karine Emanuelle Silva, Natalia Lautherbach, Henrique Jorge Novaes Morgan, Maria Antonieta Rissato Garófalo, Neusa Maria Zanon, Luiz Carlos Carvalho Navegantes, Valéria Ernestânia Chaves, Isis do Carmo Kettelhut.

  Although it is well established that glucocorticoids inactivate thermogenesis and promote lipid accumulation in interscapular brown adipose tissue (IBAT), the underlying mechanisms remain unknown. We found that dexamethasone treatment (1 mg/kg) for 7 days in rats decreased the IBAT thermogenic activity, evidenced by its lower responsiveness to noradrenaline injection associated with reduced content of mitochondrial proteins, respiratory chain protein complexes, noradrenaline, and the β3 -adrenergic receptor. In parallel, to understand better how dexamethasone increases IBAT lipid content, we also investigated the activity of the ATP citrate lyase (ACL), a key enzyme of de novo fatty acid synthesis, glucose-6-phosphate dehydrogenase (G6PD), a rate-limiting enzyme of the pentose phosphate pathway, and the three glycerol-3-P generating pathways: (1) glycolysis, estimated by 2-deoxyglucose uptake, (2) glyceroneogenesis, evaluated by phosphoenolpyruvate carboxykinase activity and pyruvate incorporation into triacylglycerol-glycerol, and (3) direct phosphorylation of glycerol, investigated by the content and activity of glycerokinase. Dexamethasone increased the mass and the lipid content of IBAT as well as plasma levels of glucose, insulin, non-esterified fatty acid, and glycerol. Furthermore, dexamethasone increased ACL and G6PD activities (79% and 48%, respectively). Despite promoting a decrease in the incorporation of U-[14 C]-glycerol into triacylglycerol (~54%), dexamethasone increased the content (~55%) and activity (~41%) of glycerokinase without affecting glucose uptake or glyceroneogenesis. Our data suggest that glucocorticoid administration reduces IBAT thermogenesis through sympathetic inactivation and stimulates glycerokinase activity and content, contributing to increased generation of glycerol-3-P, which is mostly used to esterify fatty acid and increase triacylglycerol content promoting IBAT whitening.

Keywords:  brown adipose tissue; glucocorticoids; glycerokinase; thermogenesis; triacylglycerol

DOI:  https://doi.org/10.1002/lipd.12358
Cell. 2022 Sep 09. pii: S0092-8674(22)01114-X. [Epub ahead of print]

Structure and mechanism of human cystine exporter cystinosin.

Xue Guo, Philip Schmiege, Tufa E Assafa, Rong Wang, Yan Xu, Linda Donnelly, Michael Fine, Xiaodan Ni, Jiansen Jiang, Glenn Millhauser, Liang Feng, Xiaochun Li.

  Lysosomal amino acid efflux by proton-driven transporters is essential for lysosomal homeostasis, amino acid recycling, mTOR signaling, and maintaining lysosomal pH. To unravel the mechanisms of these transporters, we focus on cystinosin, a prototypical lysosomal amino acid transporter that exports cystine to the cytosol, where its reduction to cysteine supplies this limiting amino acid for diverse fundamental processes and controlling nutrient adaptation. Cystinosin mutations cause cystinosis, a devastating lysosomal storage disease. Here, we present structures of human cystinosin in lumen-open, cytosol-open, and cystine-bound states, which uncover the cystine recognition mechanism and capture the key conformational states of the transport cycle. Our structures, along with functional studies and double electron-electron resonance spectroscopic investigations, reveal the molecular basis for the transporter's conformational transitions and protonation switch, show conformation-dependent Ragulator-Rag complex engagement, and demonstrate an unexpected activation mechanism. These findings provide molecular insights into lysosomal amino acid efflux and a potential therapeutic strategy.

Keywords:  DEER; Keywords; Ragulator-Rag complex; X-ray crystallography; cryo-EM; cystinosin; cystinosis; fast adaptation; lysosomal storage disease; lysosomal transporter; membrane protein dynamics

DOI:  https://doi.org/10.1016/j.cell.2022.08.020
Cancer Lett. 2022 Sep 08. pii: S0304-3835(22)00387-1. [Epub ahead of print] 215903

Folate enzyme MTHFD2 links one-carbon metabolism to unfolded protein response in glioblastoma.

Zhiyuan Zhu, Karrie Mei-Yee Kiang, Ning Li, Jiaxin Liu, Pingde Zhang, Lei Jin, Xiaozheng He, Shizhong Zhang, Gilberto Ka-Kit Leung.

  The mitochondrial folate enzyme methylenetetrahydrofolate dehydrogenase/cyclohydrolase (MTHFD2) has shown oncogenic roles in various cancers and may have non-metabolic functions. This study investigated the role of MTHFD2 in glioblastoma pathogenesis. We find that MTHFD2 expression is enriched in gliomas by analysing public databases and clinical specimens. RNA interference (RNAi) and inhibitor of MTHFD2 hamper the proliferation of glioblastoma and induce apoptosis in cell lines, glioma stem-like cells (GSCs) and patient-derived xenografts (PDX). Metabolomic analyses show that MTHFD2 depletion suppresses the central carbon metabolic pathways, including glycolysis, the pentose phosphate pathway (PPP), and the tricarboxylic acid (TCA) cycle. GSEA reveals a novel non-metabolic function of MTHFD2 in association with the unfolded protein response (UPR). MTHFD2 depletion activates the PERK/eIF2α axis which contributes to translation inhibition and apoptosis; these effects are attenuated by a PERK inhibitor. Mechanistically, MTHFD2 may be linked to UPR via the post-transcriptionally regulation of chaperone protein GRP78. In conclusion, MTHFD2 could be a promising therapeutic target for glioblastoma. Besides its canonical role, MTHFD2 may contribute to glioblastoma pathogenesis via UPR, highlighting a newly identified functional link between one-carbon metabolism and cell stress response.

Keywords:  ER stress; Metabolic reprogramming; Metabolomics; Non-metabolic; RNA interference

DOI:  https://doi.org/10.1016/j.canlet.2022.215903
FASEB J. 2022 10;36(10): e22546

The intestine is a major contributor to circulating succinate in mice.

Wenxin Tong, Sarah A Hannou, You Wang, Inna Astapova, Ashot Sargsyan, Ruby Monn, Venkataramana Thiriveedi, Diana Li, Jessica R McCann, John F Rawls, Jatin Roper, Guo-Fang Zhang, Mark A Herman.

  The tricarboxylic acid (TCA) cycle is the epicenter of cellular aerobic metabolism. TCA cycle intermediates facilitate energy production and provide anabolic precursors, but also function as intra- and extracellular metabolic signals regulating pleiotropic biological processes. Despite the importance of circulating TCA cycle metabolites as signaling molecules, the source of circulating TCA cycle intermediates remains uncertain. We observe that in mice, the concentration of TCA cycle intermediates in the portal blood exceeds that in tail blood indicating that the gut is a major contributor to circulating TCA cycle metabolites. With a focus on succinate as a representative of a TCA cycle intermediate with signaling activities and using a combination of gut microbiota depletion mouse models and isotopomer tracing, we demonstrate that intestinal microbiota is not a major contributor to circulating succinate. Moreover, we demonstrate that endogenous succinate production is markedly higher than intestinal succinate absorption in normal physiological conditions. Altogether, these results indicate that endogenous succinate production within the intestinal tissue is a major physiological source of circulating succinate. These results provide a foundation for an investigation into the role of the intestine in regulating circulating TCA cycle metabolites and their potential signaling effects on health and disease.

Keywords:  TCA cycle intermediates; circulating biomarkers; intestine; succinate

DOI:  https://doi.org/10.1096/fj.202200135RR
Cell Metab. 2022 Sep 08. pii: S1550-4131(22)00360-6. [Epub ahead of print]

OMA1-mediated integrated stress response protects against ferroptosis in mitochondrial cardiomyopathy.

Sofia Ahola, Pablo Rivera Mejías, Steffen Hermans, Srikanth Chandragiri, Patrick Giavalisco, Hendrik Nolte, Thomas Langer.

  Cardiomyopathy and heart failure are common manifestations in mitochondrial disease caused by deficiencies in the oxidative phosphorylation (OXPHOS) system of mitochondria. Here, we demonstrate that the cardiac-specific loss of the assembly factor Cox10 of the cytochrome c oxidase causes mitochondrial cardiomyopathy in mice, which is associated with OXPHOS deficiency, lysosomal defects, and an aberrant mitochondrial morphology. Activation of the mitochondrial peptidase Oma1 in Cox10-/- mice results in mitochondrial fragmentation and induction of the integrated stress response (ISR) along the Oma1-Dele1-Atf4 signaling axis. Ablation of Oma1 or Dele1 in Cox10-/- mice aggravates cardiomyopathy. ISR inhibition impairs the cardiac glutathione metabolism, limits the selenium-dependent accumulation of the glutathione peroxidase Gpx4, and increases lipid peroxidation in the heart, ultimately culminating in ferroptosis. Our results demonstrate a protective role of the Oma1-Dele1-mediated ISR in mitochondrial cardiomyopathy and link ferroptosis to OXPHOS deficiency and mitochondrial disease.

Keywords:  Atf4; Dele1; Gpx4; Oma1; cardiomyopathy; ferroptosis; glutathione; integrated stress response; mitochondria; selenium

DOI:  https://doi.org/10.1016/j.cmet.2022.08.017
Front Immunol. 2022 ;13 998947

Adipose tissue macrophages in remote modulation of hepatic glucose production.

Yan Tao, Quanhong Jiang, Qun Wang.

  Hepatic glucose production (HGP) is fine-regulated via glycogenolysis or gluconeogenesis to maintain physiological concentration of blood glucose during fasting-feeding cycle. Aberrant HGP leads to hyperglycemia in obesity-associated diabetes. Adipose tissue cooperates with the liver to regulate glycolipid metabolism. During these processes, adipose tissue macrophages (ATMs) change their profiles with various physio-pathological settings, producing diverse effects on HGP. Here, we briefly review the distinct phenotypes of ATMs under different nutrition states including feeding, fasting or overnutrition, and detail their effects on HGP. We discuss several pathways by which ATMs regulate hepatic gluconeogenesis or glycogenolysis, leading to favorable or unfavorable metabolic consequences. Furthermore, we summarize emerging therapeutic targets to correct metabolic disorders in morbid obesity or diabetes based on ATM-HGP axis. This review puts forward the importance and flexibility of ATMs in regulating HGP, proposing ATM-based HGP modulation as a potential therapeutic approach for obesity-associated metabolic dysfunction.

Keywords:  adipose tissue; gluconeogenesis; hepatic glucose production; liver; macrophage

DOI:  https://doi.org/10.3389/fimmu.2022.998947
Circ Res. 2022 Sep 14. 101161CIRCRESAHA122321094

The Amino Acid Homoarginine Inhibits Atherogenesis by Modulating T-Cell Function.

Katrin Nitz, Michael Lacy, Mariaelvy Bianchini, Kanin Wichapong, Irem Avcilar Kücükgöze, Cecilia A Bonfiglio, Roberta Migheli, Yuting Wu, Carina Burger, Yuanfang Li, Ignasi Forné, Constantin Ammar, Aleksandar Janjic, Sarajo Mohanta, Johan Duchene, Johan W M Heemskerk, Remco T A Megens, Edzard Schwedhelm, Stephan Huveneers, Craig A Lygate, Donato Santovito, Ralf Zimmer, Axel Imhof, Christian Weber, Esther Lutgens, Dorothee Atzler.

   BACKGROUND: Amino acid metabolism is crucial for inflammatory processes during atherogenesis. The endogenous amino acid homoarginine is a robust biomarker for cardiovascular outcome and mortality with high levels being protective. However, the underlying mechanisms remain elusive. We investigated the effect of homoarginine supplementation on atherosclerotic plaque development with a particular focus on inflammation.
METHODS: Female ApoE-deficient mice were supplemented with homoarginine (14 mg/L) in drinking water starting 2 weeks before and continuing throughout a 6-week period of Western-type diet feeding. Control mice received normal drinking water. Immunohistochemistry and flow cytometry were used for plaque- and immunological phenotyping. T cells were characterized using mass spectrometry-based proteomics, by functional in vitro approaches, for example, proliferation and migration/chemotaxis assays as well as by super-resolution microscopy.
RESULTS: Homoarginine supplementation led to a 2-fold increase in circulating homoarginine concentrations. Homoarginine-treated mice exhibited reduced atherosclerosis in the aortic root and brachiocephalic trunk. A substantial decrease in CD3+ T cells in the atherosclerotic lesions suggested a T-cell-related effect of homoarginine supplementation, which was mainly attributed to CD4+ T cells. Macrophages, dendritic cells, and B cells were not affected. CD4+ T-cell proteomics and subsequent pathway analysis together with in vitro studies demonstrated that homoarginine profoundly modulated the spatial organization of the T-cell actin cytoskeleton and increased filopodia formation via inhibition of Myh9 (myosin heavy chain 9). Further mechanistic studies revealed an inhibition of T-cell proliferation as well as a striking impairment of the migratory capacities of T cells in response to relevant chemokines by homoarginine, all of which likely contribute to its atheroprotective effects.
CONCLUSIONS: Our study unravels a novel mechanism by which the amino acid homoarginine reduces atherosclerosis, establishing that homoarginine modulates the T-cell cytoskeleton and thereby mitigates T-cell functions important during atherogenesis. These findings provide a molecular explanation for the beneficial effects of homoarginine in atherosclerotic cardiovascular disease.

Keywords:  amino acid; atherosclerosis; biomarker; cardiovascular disease; homoarginine

DOI:  https://doi.org/10.1161/CIRCRESAHA.122.321094
Mol Ther Nucleic Acids. 2022 Sep 13. 29 643-655

Enhancing arginase 2 expression using target site blockers as a strategy to modulate macrophage phenotype.

Chiara De Santi, Frances K Nally, Remsha Afzal, Conor P Duffy, Stephen Fitzsimons, Stephanie L Annett, Tracy Robson, Jennifer K Dowling, Sally-Ann Cryan, Claire E McCoy.

  Macrophages are plastic cells playing a crucial role in innate immunity. While fundamental in responding to infections, when persistently maintained in a pro-inflammatory state they can initiate and sustain inflammatory diseases. Therefore, a strategy that reprograms pro-inflammatory macrophages toward an anti-inflammatory phenotype could hold therapeutic potential in that context. We have recently shown that arginase 2 (Arg2), a mitochondrial enzyme involved in arginine metabolism, promotes the resolution of inflammation in macrophages and it is targeted by miR-155. Here, we designed and tested a target site blocker (TSB) that specifically interferes and blocks the interaction between miR-155 and Arg2 mRNA, leading to Arg2 increased expression and activity. In bone marrow-derived macrophages transfected with Arg2 TSB (in the presence or absence of the pro-inflammatory stimulus LPS), we observed an overall shift of the polarization status of macrophages toward an anti-inflammatory phenotype, as shown by significant changes in surface markers (CD80 and CD71), metabolic parameters (mitochondrial oxidative phosphorylation) and cytokines secretion (IL-1β, IL-6, and TNF). Moreover, in an in vivo model of LPS-induced acute inflammation, intraperitoneal administration of Arg2 TSB led to an overall decrease in systemic levels of pro-inflammatory cytokines. Overall, this proof-of-concept strategy represent a promising approach to modulating macrophage phenotype.

Keywords:  MT: non-coding RNAs; PLGA; arginase 2; macrophages; miR-155; microRNAs; target site blocker; transfection

DOI:  https://doi.org/10.1016/j.omtn.2022.08.004
J Oncol. 2022 ;2022 4257359

Targeting Strategies for Aberrant Lipid Metabolism Reprogramming and the Immune Microenvironment in Esophageal Cancer: A Review.

Meng-Ying Cui, Xing Yi, Zhen-Zhen Cao, Dan-Xia Zhu, Jun Wu.

Esophageal cancer is of high importance to occurrence, development, and treatment resistance. As evidenced by recent studies, pathways (e.g., Wnt/β-catenin, AMPK, and Hippo) are critical to the proliferation, differentiation, and self-renewal of esophageal cancer. In addition, the above pathways play a certain role in regulating esophageal cancer and act as potential therapeutic targets. Over the past few years, the function of lipid metabolism in controlling tumor cells and immune cells has aroused extensive attention. It has been reported that there are intricate interactions between lipid metabolism reprogramming between immune and esophageal cancer cells, whereas molecular mechanisms should be studied in depth. Immune cells have been commonly recognized as a vital player in the esophageal cancer microenvironment, having complex crosstalk with cancer cells. It is increasingly evidenced that the function of immune cells in the tumor microenvironment (TME) is significantly correlated with abnormal lipid metabolism. In this review, the latest findings in lipid metabolism reprogramming in TME are summarized, and the above findings are linked to esophageal cancer progression. Aberrant lipid metabolism and associated signaling pathways are likely to serve as a novel strategy to treat esophageal cancer through lipid metabolism reprogramming.

DOI: https://doi.org/10.1155/2022/4257359
Elife. 2022 Sep 15. pii: e79153. [Epub ahead of print]11

Murine blastocysts generated by in vitro fertilization show increased Warburg metabolism and altered lactate production.

Seok Hee Lee, Xiaowei Liu, David Jimenez-Morales, Paolo F Rinaudo.

  In vitro fertilization (IVF) has resulted in the birth of over 8 million children. Although most of IVF-conceived children are healthy, several studies suggest an increased risk of altered growth rate, cardiovascular dysfunction, and glucose intolerance in this population compared to naturally conceived children. However, a clear understanding of how embryonic metabolism is affected by culture condition and how embryos reprogram their metabolism is unknown. Here, we studied oxidative stress and metabolic alteration in blastocysts conceived by natural mating or by IVF and culture in physiologic (5%) or atmospheric (20%) oxygen. We found that IVF-generated blastocyst manifest increased reactive oxygen species, oxidative damage to DNA/lipid/proteins, and reduction in glutathione. Metabolic analysis revealed IVF-generated blastocysts display decreased mitochondria respiration and increased glycolytic activity suggestive of enhanced Warburg metabolism. These findings were corroborated by altered intracellular and extracellular pH and increased intracellular lactate levels in IVF-generated embryos. Comprehensive proteomic analysis and targeted immunofluorescence showed reduction of LDH-B and MCT1, enzymes involved in lactate metabolism. Importantly, these enzymes remained downregulated in tissues of adult IVF-conceived mice, suggesting that metabolic alterations in IVF-generated embryos may result in alteration in lactate metabolism. These findings suggest that alterations in lactate metabolism is a likely mechanism involved in genomic reprogramming and could be involved in the developmental origin of health and disease.

Keywords:  developmental biology; mouse

DOI:  https://doi.org/10.7554/eLife.79153
PLoS Biol. 2022 Sep 12. 20(9): e3001765

Plasma metabolome predicts trained immunity responses after antituberculosis BCG vaccination.

Valerie A C M Koeken, Cancan Qi, Vera P Mourits, L Charlotte J de Bree, Simone J C F M Moorlag, Vidhisha Sonawane, Heidi Lemmers, Helga Dijkstra, Leo A B Joosten, Arjan van Laarhoven, Cheng-Jian Xu, Reinout van Crevel, Mihai G Netea, Yang Li.

The antituberculosis vaccine Bacillus Calmette-Guérin (BCG) induces nonspecific protection against heterologous infections, at least partly through induction of innate immune memory (trained immunity). The amplitude of the response to BCG is variable, but the factors that influence this response are poorly understood. Metabolites, either released by cells or absorbed from the gut, are known to influence immune responses, but whether they impact BCG responses is not known. We vaccinated 325 healthy individuals with BCG, and collected blood before, 2 weeks and 3 months after vaccination, to assess the influence of circulating metabolites on the immune responses induced by BCG. Circulating metabolite concentrations after BCG vaccination were found to have a more pronounced impact on trained immunity responses, such as the increase in IL-1β and TNF-α production upon Staphylococcus aureus stimulation, than on specific adaptive immune memory, assessed as IFN-γ production in response to Mycobacterium tuberculosis. Circulating metabolites at baseline were able to predict trained immunity responses at 3 months after vaccination and enrichment analysis based on the metabolites positively associated with trained immunity revealed enrichment of the tricarboxylic acid (TCA) cycle and glutamine metabolism, both of which were previously found to be important for trained immunity. Several new metabolic pathways that influence trained immunity were identified, among which taurine metabolism associated with BCG-induced trained immunity, a finding validated in functional experiments. In conclusion, circulating metabolites are important factors influencing BCG-induced trained immunity in humans. Modulation of metabolic pathways may be a novel strategy to improve vaccine and trained immunity responses.

DOI: https://doi.org/10.1371/journal.pbio.3001765
FEBS Lett. 2022 Sep 16.

Overexpression of UCP3 decreases mitochondrial efficiency in mouse skeletal muscle in vivo.

Roberto Codella, Tiago C Alves, Douglas E Befroy, Cheol Soo Choi, Livio Luzi, Douglas L Rothman, Richard G Kibbey, Gerald I Shulman.

  Uncoupling protein-3 (UCP3) is a mitochondrial transmembrane protein highly expressed in muscle that has been implicated in regulating the efficiency of mitochondrial oxidative phosphorylation. Increasing UCP3 expression in skeletal muscle enhances proton leak across the inner mitochondrial membrane and increases oxygen consumption in isolated mitochondria, but its precise function in vivo has yet to be fully elucidated. To examine whether muscle-specific overexpression of UCP3 modulates muscle mitochondrial oxidation in vivo, rates of ATP synthesis were assessed by 31 P magnetic resonance spectroscopy (MRS) and rates of mitochondrial oxidative metabolism were measured by assessing the rate of [2-13 C]acetate incorporation into muscle [4-13 C]- , [3-13 C]-glutamate and [4-13 C]-glutamine by high resolution 13 C/1 H MRS. Using this approach we found that overexpression of UCP3 in skeletal muscle was accompanied by increased muscle mitochondrial inefficiency in vivo as reflected by a 42% reduction in the ratio of ATP synthesis to mitochondrial oxidation.

Keywords:  magnetic resonance spectroscopy; mitochondrial efficiency; mitochondrial uncoupling; muscle energy metabolism

DOI:  https://doi.org/10.1002/1873-3468.14494
Biomed Pharmacother. 2022 Sep 12. pii: S0753-3322(22)01061-7. [Epub ahead of print]155 113672

Specific activation of hypoxia-inducible factor-2α by propionate metabolism via a β-oxidation-like pathway stimulates MUC2 production in intestinal goblet cells.

Seongho Ma, Jiah Yeom, Young-Hee Lim.

  Microbiota-derived short-chain fatty acids (SCFAs) are known to stimulate mucin expression in the intestine, which contributes to the gut mucosal immune responses, and the gut mucosal immune system extends to the brain and other organs through several axes. Hypoxia-inducible factors (HIFs), especially HIF-1α, are known to act as the master regulator of mucin expression, however, underlying mechanism of mucin expression during hypoxia by SCFAs remains unclear. In this study, we investigated the mechanism of MUC2 expression by propionate, an SCFA, in intestinal goblet cells. The real time oxygen consumption rate (OCR) and ATPase activity were measured to investigate the induction of hypoxia by propionate. Using 2-dimensional electrophoresis (2-DE), microarray analysis, and siRNA-induced gene silencing, we found that propionate is metabolized via a β-oxidation-like pathway instead of the vitamin B12-dependent carboxylation pathway (also known as the methylmalonyl pathway). We verified the results by analyzing several intermediates in the pathway using LC-MS and GC-MS. Propionate metabolism via the β-oxidation-like pathway leads to the depletion of oxygen and thereby induces hypoxia. Analysis of HIFs revealed that HIF-2α is the primary HIF whose activation is induced by propionate metabolism in a hypoxic environment and that HIF-2α regulates the expression of MUC2. Thus, hypoxia induced during propionate metabolism via a β-oxidation-like pathway specifically activates HIF-2α, stimulating MUC2 production in LS 174 T goblet cells. Our findings show that propionate-induced selective HIF-2α stimulation contributes to intestinal mucosal defense.

Keywords:  Goblet cell; Hypoxia-induced factors; Mucin; Propionate; β-Oxidation-like pathway

DOI:  https://doi.org/10.1016/j.biopha.2022.113672
Nat Commun. 2022 Sep 13. 13(1): 5371

Fatty acid metabolism in aggressive B-cell lymphoma is inhibited by tetraspanin CD37.

Rens Peeters, Jorge Cuenca-Escalona, Esther A Zaal, Anna T Hoekstra, Anouk C G Balvert, Marcos Vidal-Manrique, Niek Blomberg, Sjoerd J van Deventer, Rinke Stienstra, Julia Jellusova, Martin Giera, Luciana Hannibal, Ute Spiekerkoetter, Martin Ter Beest, Celia R Berkers, Annemiek B van Spriel.

The importance of fatty acid (FA) metabolism in cancer is well-established, yet the mechanisms underlying metabolic reprogramming remain elusive. Here, we identify tetraspanin CD37, a prognostic marker for aggressive B-cell lymphoma, as essential membrane-localized inhibitor of FA metabolism. Deletion of CD37 on lymphoma cells results in increased FA oxidation shown by functional assays and metabolomics. Furthermore, CD37-negative lymphomas selectively deplete palmitate from serum in mouse studies. Mechanistically, CD37 inhibits the FA transporter FATP1 through molecular interaction. Consequently, deletion of CD37 induces uptake and processing of exogenous palmitate into energy and essential building blocks for proliferation, and inhibition of FATP1 reverses this phenotype. Large lipid deposits and intracellular lipid droplets are observed in CD37-negative lymphoma tissues of patients. Moreover, inhibition of carnitine palmitoyl transferase 1 A significantly compromises viability and proliferation of CD37-deficient lymphomas. Collectively, our results identify CD37 as a direct gatekeeper of the FA metabolic switch in aggressive B-cell lymphoma.

DOI: https://doi.org/10.1038/s41467-022-33138-7
Mol Syst Biol. 2022 Sep;18(9): e10716

Sorting-free metabolic profiling uncovers the vulnerability of fatty acid β-oxidation in in vitro quiescence models.

Karin Ortmayr, Mattia Zampieri.

  Quiescent cancer cells are rare nondiving cells with the unique ability to evade chemotherapies and resume cell division after treatment. Despite the associated risk of cancer recurrence, how cells can reversibly switch between rapid proliferation and quiescence remains a long-standing open question. By developing a unique methodology for the cell sorting-free separation of metabolic profiles in cell subpopulations in vitro, we unraveled metabolic characteristics of quiescent cells that are largely invariant to basal differences in cell types and quiescence-inducing stimuli. Consistent with our metabolome-based analysis, we show that impairing mitochondrial fatty acid β-oxidation (FAO) can induce apoptosis in quiescence-induced cells and hamper their return to proliferation. Our findings suggest that in addition to mediating energy and redox balance, FAO can play a role in preventing the buildup of toxic intermediates during transitioning to quiescence. Uncovering metabolic strategies to enter, maintain, and exit quiescence can reveal fundamental principles in cell plasticity and new potential therapeutic targets beyond cancer.

Keywords:  cellular quiescence; fatty acid oxidation; metabolic adaptation; quiescence-proliferation transition; trimetazidine

DOI:  https://doi.org/10.15252/msb.202110716
Sci Adv. 2022 Sep 16. 8(37): eabo7639

Ketogenic diet uncovers differential metabolic plasticity of brain cells.

Tim Düking, Lena Spieth, Stefan A Berghoff, Lars Piepkorn, Annika M Schmidke, Miso Mitkovski, Nirmal Kannaiyan, Leon Hosang, Patricia Scholz, Ali H Shaib, Lennart V Schneider, Dörte Hesse, Torben Ruhwedel, Ting Sun, Lisa Linhoff, Andrea Trevisiol, Susanne Köhler, Adrian Marti Pastor, Thomas Misgeld, Michael Sereda, Imam Hassouna, Moritz J Rossner, Francesca Odoardi, Till Ischebeck, Livia de Hoz, Johannes Hirrlinger, Olaf Jahn, Gesine Saher.

To maintain homeostasis, the body, including the brain, reprograms its metabolism in response to altered nutrition or disease. However, the consequences of these challenges for the energy metabolism of the different brain cell types remain unknown. Here, we generated a proteome atlas of the major central nervous system (CNS) cell types from young and adult mice, after feeding the therapeutically relevant low-carbohydrate, high-fat ketogenic diet (KD) and during neuroinflammation. Under steady-state conditions, CNS cell types prefer distinct modes of energy metabolism. Unexpectedly, the comparison with KD revealed distinct cell type-specific strategies to manage the altered availability of energy metabolites. Astrocytes and neurons but not oligodendrocytes demonstrated metabolic plasticity. Moreover, inflammatory demyelinating disease changed the neuronal metabolic signature in a similar direction as KD. Together, these findings highlight the importance of the metabolic cross-talk between CNS cells and between the periphery and the brain to manage altered nutrition and neurological disease.

DOI: https://doi.org/10.1126/sciadv.abo7639
Immunity. 2022 Sep 13. pii: S1074-7613(22)00395-8. [Epub ahead of print]55(9): 1515-1529

Liver macrophages in health and disease.

Martin Guilliams, Charlotte L Scott.

  Single-cell and spatial transcriptomic technologies have revealed an underappreciated heterogeneity of liver macrophages. This has led us to rethink the involvement of macrophages in liver homeostasis and disease. Identification of conserved gene signatures within these cells across species and diseases is enabling the correct identification of specific macrophage subsets and the generation of more specific tools to track and study the functions of these cells. Here, we discuss what is currently known about the definitions of these different macrophage populations, the markers that can be used to identify them, how they are wired within the liver, and their functional specializations in health and disease.

Keywords:  Kupffer cells; LAMs; NASH; integrated niche; lipid-associated macrophages; liver disease; liver homeostasis; liver macrophages

DOI:  https://doi.org/10.1016/j.immuni.2022.08.002
Drug Discov Today. 2022 Sep 07. pii: S1359-6446(22)00340-3. [Epub ahead of print] 103347

Use of cholesterol metabolism for anti-cancer strategies.

Meran K Ediriweera.

  Irregularities in cholesterol metabolism occur in a range of human cancers. Cholesterol precursors and derivatives support tumorigenesis and weaken immune responses. Intriguing preclinical and clinical findings demonstrate that cholesterol biosynthesis inhibition achieved by targeting major events and metabolites in cholesterol metabolism is an ideal anti-tumor strategy. Investigations addressing the effects of β-hydroxy β-methylglutaryl-CoA (HMG-CoA) reductase (HMGCR), 2,3-oxidosqualene cyclase (OSC), squalene synthase (SQS), liver X receptors (LXR), and cholesterol trafficking and esterification inhibition on cancer progression have shown encouraging results. Notably, manipulation of cholesterol metabolism strengthens the function of immune cells in the tumor microenvironment (TME). In this review, I discuss the role of cholesterol metabolism in cancer progression and the latest research related to cholesterol metabolism-based anti-cancer therapies.

Keywords:  Anti-cancer strategies; Cancer; Cholesterol metabolism; Pharmacological targets

DOI:  https://doi.org/10.1016/j.drudis.2022.103347
Nat Chem Biol. 2022 Sep 15.

Hydropersulfides inhibit lipid peroxidation and ferroptosis by scavenging radicals.

Uladzimir Barayeu, Danny Schilling, Mohammad Eid, Thamara Nishida Xavier da Silva, Lisa Schlicker, Nikolina Mitreska, Christopher Zapp, Frauke Gräter, Aubry K Miller, Reinhard Kappl, Almut Schulze, José Pedro Friedmann Angeli, Tobias P Dick.

Ferroptosis is a type of cell death caused by radical-driven lipid peroxidation, leading to membrane damage and rupture. Here we show that enzymatically produced sulfane sulfur (S0) species, specifically hydropersulfides, scavenge endogenously generated free radicals and, thereby, suppress lipid peroxidation and ferroptosis. By providing sulfur for S0 biosynthesis, cysteine can support ferroptosis resistance independently of the canonical GPX4 pathway. Our results further suggest that hydropersulfides terminate radical chain reactions through the formation and self-recombination of perthiyl radicals. The autocatalytic regeneration of hydropersulfides may explain why low micromolar concentrations of persulfides suffice to produce potent cytoprotective effects on a background of millimolar concentrations of glutathione. We propose that increased S0 biosynthesis is an adaptive cellular response to radical-driven lipid peroxidation, potentially representing a primordial radical protection system.

DOI: https://doi.org/10.1038/s41589-022-01145-w
Chemphyschem. 2022 Sep 14.

Metabolic Tumor Imaging with Rapidly Signal-Enhanced 1-13C-Pyruvate-d3.

Theresa Hune, Salvatore Mamone, Henning Schroeder, Anil P Jagtap, Sonja Sternkopf, Gabriele Stevanato, Sergey Korchak, Claudia Fokken, Christoph A Müller, Andreas B Schmidt, Dorothea Becker, Stefan Glöggler.

  The metabolism of malignant cells differs significantly from that of healthy cells and thus, it is possible to perform metabolic imaging to reveal not only the exact location of a tumor, but also intratumoral areas of high metabolic activity. Herein, we demonstrate the feasibility of metabolic tumor imaging using signal-enhanced 1- 13 C-pyruvate-d 3 , which is rapidly enhanced via para-hydrogen, and thus, the signal is amplified by several orders of magnitudes in less than a minute. Using as a model, human melanoma xenografts injected with signal-enhanced 1- 13 C-pyruvate-d3, we show that the conversion of pyruvate into lactate can be monitored along with its kinetics, which could pave the way for rapidly detecting and monitoring changes in tumor metabolism.

Keywords:  MRI; NMR; Para-hydrogen; cancer; hyperpolarization

DOI:  https://doi.org/10.1002/cphc.202200615
Front Physiol. 2022 ;13 925752

Iron supplementation inhibits hypoxia-induced mitochondrial damage and protects zebrafish liver cells from death.

Ruiqin Hu, Genfang Li, Qianghua Xu, Liangbiao Chen.

  Acute hypoxia in water has always been a thorny problem in aquaculture. Oxygen and iron play important roles and are interdependent in fish. Iron is essential for oxygen transport and its concentration tightly controlled to maintain the cellular redox homeostasis. However, it is still unclear the role and mechanism of iron in hypoxic stress of fish. In this study, we investigated the role of iron in hypoxic responses of two zebrafish-derived cell lines. We found hypoxia exposed zebrafish liver cells (ZFL) demonstrated reduced expression of Ferritin and the gene fth31 for mitochondrial iron storage, corresponding to reduction of both intracellular and mitochondrial free iron and significant decrease of ROS levels in multiple cellular components, including mitochondrial ROS and lipid peroxidation level. In parallel, the mitochondrial integrity was severely damaged. Addition of exogenous iron restored the iron and ROS levels in cellular and mitochondria, reduced mitochondrial damage through enhancing mitophagy leading to higher cell viability, while treated the cells with iron chelator (DFO) or ferroptosis inhibitor (Fer-1) showed no improvements of the cellular conditions. In contrast, in hypoxia insensitive zebrafish embryonic fibroblasts cells (ZF4), the expression of genes related to iron metabolism showed opposite trends of change and higher mitochondrial ROS level compared with the ZFL cells. These results suggest that iron homeostasis is important for zebrafish cells to maintain mitochondrial integrity in hypoxic stress, which is cell type dependent. Our study enriched the hypoxia regulation mechanism of fish, which helped to reduce the hypoxia loss in fish farming.

Keywords:  ROS; hypoxia; iron; mitochondria; mitophagy

DOI:  https://doi.org/10.3389/fphys.2022.925752
Nat Commun. 2022 Sep 14. 13(1): 5399

Mild dyslipidemia accelerates tumorigenesis through expansion of Ly6Chi monocytes and differentiation to pro-angiogenic myeloid cells.

Thi Tran, Jean-Remi Lavillegrand, Cedric Lereverend, Bruno Esposito, Lucille Cartier, Melanie Montabord, Jaouen Tran-Rajau, Marc Diedisheim, Nadège Gruel, Khadija Ouguerram, Lea Paolini, Olivia Lenoir, Emmanuel Pinteaux, Eva Brabencova, Corinne Tanchot, Pauline Urquia, Jacqueline Lehmann-Che, Richard Le Naour, Yacine Merrouche, Christian Stockmann, Ziad Mallat, Alain Tedgui, Hafid Ait-Oufella, Eric Tartour, Stephane Potteaux.

Cancer and cardiovascular disease (CVD) share common risk factors such as dyslipidemia, obesity and inflammation. However, the role of pro-atherogenic environment and its associated low-grade inflammation in tumor progression remains underexplored. Here we show that feeding C57BL/6J mice with a non-obesogenic high fat high cholesterol diet (HFHCD) for two weeks to induce mild dyslipidemia, increases the pool of circulating Ly6Chi monocytes available for initial melanoma development, in an IL-1β-dependent manner. Descendants of circulating myeloid cells, which accumulate in the tumor microenvironment of mice under HFHCD, heighten pro-angiogenic and immunosuppressive activities locally. Limiting myeloid cell accumulation or targeting VEGF-A production by myeloid cells decrease HFHCD-induced tumor growth acceleration. Reverting the HFHCD to a chow diet at the time of tumor implantation protects against tumor growth. Together, these data shed light on cross-disease communication between cardiovascular pathologies and cancer.

DOI: https://doi.org/10.1038/s41467-022-33034-0
Front Cell Neurosci. 2022 ;16 995084

Iron metabolism mediates microglia susceptibility in ferroptosis.

Lingling Jiao, Xiaolan Li, Yuxiang Luo, Junfen Wei, Xulong Ding, Huan Xiong, Xuesong Liu, Peng Lei.

  Ferroptosis is implicated in a range of brain disorders, but it is unknown whether neurons or glia in the brain are particularly effected. Here, we report that primary cortical astrocytes (PA), microglia (PM), and neurons (PN) varied in their sensitivities to ferroptosis. Specifically, PM were the most sensitive to ferroptosis, while PN were relatively insensitive. In contrast, PN and PM were equally susceptible to apoptosis, with PA being less affected, whereas all three cell types were similarly susceptible to autophagic cell death. In the tri-culture system containing PA, PM, and PN, the cells were more resistant to ferroptosis than that in the monoculture. These results demonstrated that brain cells exhibit different sensitivities under ferroptosis stress and the difference may be explained by the differentially regulated iron metabolism and the ability to handle iron. Continued elucidation of the cell death patterns of neurons and glia will provide a theoretical basis for related strategies to inhibit the death of brain cells.

Keywords:  cell death; ferroptosis; glia; iron metabolism; neurons

DOI:  https://doi.org/10.3389/fncel.2022.995084
Mol Metab. 2022 Sep 13. pii: S2212-8778(22)00169-7. [Epub ahead of print] 101600

Carboxylesterase 2 induces mitochondrial dysfunction via disrupting lipid homeostasis in oral squamous cell carcinoma.

Xijuan Chen, Qin Liu, Yingyao Chen, Lixuan Wang, Rongchun Yang, Weilin Zhang, Xue Pan, Siyuan Zhang, Chuwen Chen, Tong Wu, Juan Xia, Bin Cheng, Xiaobing Chen, Xianyue Ren.

   INTRODUCTION: Oral squamous cell carcinoma (OSCC) is characterized by high recurrence and metastasis and places a heavy burden on societies worldwide. Cancer cells thrive in a changing microenvironment by reprogramming lipidomic metabolic processes to provide nutrients and energy, activate oncogenic signaling pathways, and manage redox homeostasis to avoid lipotoxicity. The mechanism by which OSCC cells maintain lipid homeostasis during malignant progression is unclear.
METHODS: The altered expression of fatty acid (FA) metabolism genes in OSCC, compared with that in normal tissues, and in OSCC patients with or without recurrence or metastasis were determined using public data from the TCGA and GEO databases. Immunohistochemistry was performed to examine the carboxylesterase 2 (CES2) protein level in our own cohort. CCK-8 and Transwell assays and an in vivo xenograft model were used to evaluate the biological functions of CES2. Mass spectrometry and RNA sequencing were performed to determine the lipidome and transcriptome alterations induced by CES2. Mitochondrial mass, mtDNA content, mitochondrial membrane potential, ROS levels, and oxygen consumption and apoptosis rates were evaluated to determine the effects of CES2 on mitochondrial function in OSCC.
RESULTS: CES2 was downregulated in OSCC patients, especially those with recurrence or metastasis. CES2high OSCC patients showed better overall survival than CES2low OSCC patients. Restoring CES2 expression reduced OSCC cell viability and suppressed their migration and invasion in vitro, and it inhibited OSCC tumor growth in vivo. CES2 reprogrammed lipid metabolism in OSCC cells by hydrolyzing neutral lipid diacylglycerols (DGs) to release free fatty acids and reduce the membrane structure lipid phospholipids (PLs) synthesis. Free FAs were converted to acyl-carnitines (CARs) and transferred to mitochondria for oxidation, which induced reactive oxygen species (ROS) accumulation, mitochondrial damage, and apoptosis activation. Furthermore, the reduction in signaling lipids, e.g., DGs, PLs and substrates, suppressed PI3K/AKT/MYC signaling pathways. Restoring MYC rescued the diminished cell viability, suppressed migratory and invasive abilities, damaged mitochondria and reduced apoptosis rate induced by CES2.
CONCLUSIONS: We demonstrated that CES2 downregulation plays an important role in OSCC by maintaining lipid homeostasis and reducing lipotoxicity during tumor progression and may provide a potential therapeutic target for OSCC.

Keywords:  CES2; Oral squamous cell carcinoma; diacylglycerols; lipotoxicity; mitochondrial damage

DOI:  https://doi.org/10.1016/j.molmet.2022.101600
Cell Rep. 2022 Sep 13. pii: S2211-1247(22)01158-5. [Epub ahead of print]40(11): 111330

Posttranslational S-nitrosylation modification regulates HMGB1 secretion and promotes its proinflammatory and neurodegenerative effects.

Ru Yang, Yun Gao, Hui Li, Wei Huang, Dezhen Tu, Mengnan Yang, Xingqian Liu, Jau-Shyong Hong, Hui-Ming Gao.

  Nuclear protein high-mobility group box 1 (HMGB1) can be actively secreted by activated immune cells and functions as a proinflammatory cytokine. Regulation of HMGB1 secretion is critical for treatment of HMGB1-mediated inflammation and related diseases. This study demonstrates that S-nitrosylation (SNO; the covalent binding of nitric oxide [NO] to cysteine thiols) by inducible nitric oxide synthase (iNOS)-derived NO at Cys106 is essential and sufficient for inflammation-elicited HMGB1 secretion. iNOS deletion or inhibition or Cys106Ser mutation prevents lipopolysaccharide (LPS)- and/or poly(I:C)-elicited HMGB1 secretion. NO donors induce SNO of HMGB1 and reproduce inflammogen-triggered HMGB1 secretion. SNO of HMGB1 promotes its proinflammatory and neurodegenerative effects. Intranigral HMGB1 injection induces chronic microglial activation, dopaminergic neurodegeneration, and locomotor deficits, the key features of Parkinson's disease (PD), in wild-type, but not Mac1 (CD11b/CD18)-deficient, mice. This study indicates pivotal roles for SNO modification in HMGB1 secretion and HMGB1-Mac1 interaction for inflammatory neurodegeneration, identifying a mechanistic basis for PD development.

Keywords:  CP: Immunology; CP: Neuroscience; HMGB1; Mac1; Parkinson’s disease; S-nitrosylation; iNOS; macrophages; microglia; neurodegeneration; neuroinflammation; nitric oxide

DOI:  https://doi.org/10.1016/j.celrep.2022.111330