bims-mepmim Biomed News
on Metabolites in pathological microenvironments and immunometabolism
Issue of 2024‒02‒25
twenty-one papers selected by
Erika Mariana Palmieri, NIH/NCI Laboratory of Cancer ImmunoMetabolism
  1. Hyperacetylated histone H4 is a source of carbon contributing to lipid synthesis.
  2. Monocarboxylate transporters facilitate succinate uptake into brown adipocytes.
  3. M2 macrophages independently promote beige adipogenesis via blocking adipocyte Ets1.
  4. IL-10 constrains sphingolipid metabolism to limit inflammation.
  5. Mitochondrial quinone redox states as a marker of mitochondrial metabolism.
  6. Intestinal IL-22RA1 signaling regulates intrinsic and systemic lipid and glucose metabolism to alleviate obesity-associated disorders.
  7. Editorial: Understanding how myeloid cell development and function meet tissue distinct metabolic requirements.
  8. NINJ1 induces plasma membrane rupture and release of damage-associated molecular pattern molecules during ferroptosis.
  9. MCT1 helps brown fat suck up succinate.
  10. IgG is an aging factor that drives adipose tissue fibrosis and metabolic decline.
  11. UDP-glucose dehydrogenase supports autophagy-deficient PDAC growth via increasing hyaluronic acid biosynthesis.
  12. Tumor associated macrophages transfer ceruloplasmin mRNA to fibrosarcoma cells and protect them from ferroptosis.
  13. Cardiomyocyte-specific deletion of GCN5L1 reduces lysine acetylation and attenuates diastolic dysfunction in aged mice by improving cardiac fatty acid oxidation.
  14. PRMT1 sustains de novo fatty acid synthesis by methylating PHGDH to drive chemoresistance in triple-negative breast cancer.
  15. Identification of MIMAS, a multifunctional mega-assembly integrating metabolic and respiratory biogenesis factors of mitochondria.
  16. Single-cell transcriptomics identifies the differentiation trajectory from inflammatory monocytes to pro-resolving macrophages in a mouse skin allergy model.
  17. An engineered biosensor enables dynamic aspartate measurements in living cells.
  18. Enhancing CAR-T cell metabolism to overcome hypoxic conditions in the brain tumor microenvironment.
  19. The shifting lipidomic landscape of blood monocytes and neutrophils during pneumonia.
  20. Modeling embryo-endometrial interface recapitulating human embryo implantation.
  21. Piezo1 mechanosensing regulates integrin-dependent chemotactic migration in human T cells.
  1. EMBO J. 2024 Feb 21.
    Hyperacetylated histone H4 is a source of carbon contributing to lipid synthesis.
    Evelina Charidemou, Roberta Noberini, Chiara Ghirardi, Polymnia Georgiou, Panayiota Marcou, Andria Theophanous, Katerina Strati, Hector Keun, Volker Behrends, Tiziana Bonaldi, Antonis Kirmizis.
      Histone modifications commonly integrate environmental cues with cellular metabolic outputs by affecting gene expression. However, chromatin modifications such as acetylation do not always correlate with transcription, pointing towards an alternative role of histone modifications in cellular metabolism. Using an approach that integrates mass spectrometry-based histone modification mapping and metabolomics with stable isotope tracers, we demonstrate that elevated lipids in acetyltransferase-depleted hepatocytes result from carbon atoms derived from deacetylation of hyperacetylated histone H4 flowing towards fatty acids. Consistently, enhanced lipid synthesis in acetyltransferase-depleted hepatocytes is dependent on histone deacetylases and acetyl-CoA synthetase ACSS2, but not on the substrate specificity of the acetyltransferases. Furthermore, we show that during diet-induced lipid synthesis the levels of hyperacetylated histone H4 decrease in hepatocytes and in mouse liver. In addition, overexpression of acetyltransferases can reverse diet-induced lipogenesis by blocking lipid droplet accumulation and maintaining the levels of hyperacetylated histone H4. Overall, these findings highlight hyperacetylated histones as a metabolite reservoir that can directly contribute carbon to lipid synthesis, constituting a novel function of chromatin in cellular metabolism.
    Keywords:  Acetylation; Epigenetics; Histone Reservoirs; Lipid Metabolism
    DOI:  https://doi.org/10.1038/s44318-024-00053-0
  2. Nat Metab. 2024 Feb 20.
    Monocarboxylate transporters facilitate succinate uptake into brown adipocytes.
    Anita Reddy, Sally Winther, Nhien Tran, Haopeng Xiao, Josefine Jakob, Ryan Garrity, Arianne Smith, Martha Ordonez, Dina Laznik-Bogoslavski, Jeffrey D Rothstein, Evanna L Mills, Edward T Chouchani.
      Uptake of circulating succinate by brown adipose tissue (BAT) and beige fat elevates whole-body energy expenditure, counteracts obesity and antagonizes systemic tissue inflammation in mice. The plasma membrane transporters that facilitate succinate uptake in these adipocytes remain undefined. Here we elucidate a mechanism underlying succinate import into BAT via monocarboxylate transporters (MCTs). We show that succinate transport is strongly dependent on the proportion that is present in the monocarboxylate form. MCTs facilitate monocarboxylate succinate uptake, which is promoted by alkalinization of the cytosol driven by adrenoreceptor stimulation. In brown adipocytes, we show that MCT1 primarily facilitates succinate import. In male mice, we show that both acute pharmacological inhibition of MCT1 and congenital depletion of MCT1 decrease succinate uptake into BAT and consequent catabolism. In sum, we define a mechanism of succinate uptake in BAT that underlies its protective activity in mouse models of metabolic disease.
    DOI:  https://doi.org/10.1038/s42255-024-00981-5
  3. Nat Commun. 2024 Feb 22. 15(1): 1646
    M2 macrophages independently promote beige adipogenesis via blocking adipocyte Ets1.
    Suyang Wu, Chen Qiu, Jiahao Ni, Wenli Guo, Jiyuan Song, Xingyin Yang, Yulin Sun, Yanjun Chen, Yunxia Zhu, Xiaoai Chang, Peng Sun, Chunxia Wang, Kai Li, Xiao Han.
      Adipose tissue macrophages can promote beige adipose thermogenesis by altering local sympathetic activity. Here, we perform sympathectomy in mice and further eradicate subcutaneous adipose macrophages and discover that these macrophages have a direct beige-promoting function that is independent of sympathetic system. We further identify adipocyte Ets1 as a vital mediator in this process. The anti-inflammatory M2 macrophages suppress Ets1 expression in adipocytes, transcriptionally activate mitochondrial biogenesis, as well as suppress mitochondrial clearance, thereby increasing the mitochondrial numbers and promoting the beiging process. Male adipocyte Ets1 knock-in mice are completely cold intolerant, whereas male mice lacking Ets1 in adipocytes show enhanced energy expenditure and are resistant to metabolic disorders caused by high-fat-diet. Our findings elucidate a direct communication between M2 macrophages and adipocytes, and uncover a function for Ets1 in responding to macrophages and negatively governing mitochondrial content and beige adipocyte formation.
    DOI:  https://doi.org/10.1038/s41467-024-45899-4
  4. Nature. 2024 Feb 21.
    IL-10 constrains sphingolipid metabolism to limit inflammation.
    Autumn G York, Mathias H Skadow, Joonseok Oh, Rihao Qu, Quan D Zhou, Wei-Yuan Hsieh, Walter K Mowel, J Richard Brewer, Eleanna Kaffe, Kevin J Williams, Yuval Kluger, Stephen T Smale, Jason M Crawford, Steven J Bensinger, Richard A Flavell.
      Interleukin-10 (IL-10) is a key anti-inflammatory cytokine that can limit immune cell activation and cytokine production in innate immune cell types1. Loss of IL-10 signalling results in life-threatening inflammatory bowel disease in humans and mice-however, the exact mechanism by which IL-10 signalling subdues inflammation remains unclear2-5. Here we find that increased saturated very long chain (VLC) ceramides are critical for the heightened inflammatory gene expression that is a hallmark of IL-10 deficiency. Accordingly, genetic deletion of ceramide synthase 2 (encoded by Cers2), the enzyme responsible for VLC ceramide production, limited the exacerbated inflammatory gene expression programme associated with IL-10 deficiency both in vitro and in vivo. The accumulation of saturated VLC ceramides was regulated by a decrease in metabolic flux through the de novo mono-unsaturated fatty acid synthesis pathway. Restoring mono-unsaturated fatty acid availability to cells deficient in IL-10 signalling limited saturated VLC ceramide production and the associated inflammation. Mechanistically, we find that persistent inflammation mediated by VLC ceramides is largely dependent on sustained activity of REL, an immuno-modulatory transcription factor. Together, these data indicate that an IL-10-driven fatty acid desaturation programme rewires VLC ceramide accumulation and aberrant activation of REL. These studies support the idea that fatty acid homeostasis in innate immune cells serves as a key regulatory node to control pathologic inflammation and suggests that 'metabolic correction' of VLC homeostasis could be an important strategy to normalize dysregulated inflammation caused by the absence of IL-10.
    DOI:  https://doi.org/10.1038/s41586-024-07098-5
  5. Biochim Biophys Acta Bioenerg. 2024 Feb 16. pii: S0005-2728(24)00003-3. [Epub ahead of print] 149033
    Mitochondrial quinone redox states as a marker of mitochondrial metabolism.
    M Martins Pinto, S Ransac, J P Mazat, L Schwartz, M Rigoulet, S Arbault, P Paumard, A Devin.
      Mitochondrial and thus cellular energetics are highly regulated both thermodynamically and kinetically. Cellular energetics is of prime importance in the regulation of cellular functions since it provides ATP for their accomplishment. However, cellular energetics is not only about ATP production but also about the ability to re-oxidize reduced coenzymes at a proper rate, such that the cellular redox potential remains at a level compatible with enzymatic reactions. However, this parameter is not only difficult to assess due to its dual compartmentation (mitochondrial and cytosolic) but also because it is well known that most NADH in the cells is bound to the enzymes. In this paper, we investigated the potential relevance of mitochondrial quinones redox state as a marker of mitochondrial metabolism and more particularly mitochondrial redox state. We were able to show that Q2 is an appropriate redox mediator to assess the mitochondrial quinone redox states. On isolated mitochondria, the mitochondrial quinone redox states depend on the mitochondrial substrate and the mitochondrial energetic state (phosphorylating or not phosphorylating). Last but not least, we show that the quinones redox state response allows to better understand the Krebs cycle functioning and respiratory substrates oxidation. Taken together, our results suggest that the quinones redox state is an excellent marker of mitochondrial metabolism.
    Keywords:  Bioenergetics; Mitochondria respiratory chain; Quinones; Redox state
    DOI:  https://doi.org/10.1016/j.bbabio.2024.149033
  6. Nat Commun. 2024 Feb 21. 15(1): 1597
    Intestinal IL-22RA1 signaling regulates intrinsic and systemic lipid and glucose metabolism to alleviate obesity-associated disorders.
    Stephen J Gaudino, Ankita Singh, Huakang Huang, Jyothi Padiadpu, Makheni Jean-Pierre, Cody Kempen, Tej Bahadur, Kiyoshi Shiomitsu, Richard Blumberg, Kenneth R Shroyer, Semir Beyaz, Natalia Shulzhenko, Andrey Morgun, Pawan Kumar.
      IL-22 is critical for ameliorating obesity-induced metabolic disorders. However, it is unknown where IL-22 acts to mediate these outcomes. Here we examine the importance of tissue-specific IL-22RA1 signaling in mediating long-term high fat diet (HFD) driven metabolic disorders. To do so, we generated intestinal epithelium-, liver-, and white adipose tissue (WAT)-specific Il22ra1 knockout and littermate control mice. Intestinal epithelium- and liver-specific IL-22RA1 signaling upregulated systemic glucose metabolism. Intestinal IL-22RA1 signaling also mediated liver and WAT metabolism in a microbiota-dependent manner. We identified an association between Oscillibacter and elevated WAT inflammation, likely induced by Mmp12 expressing macrophages. Mechanistically, transcription of intestinal lipid metabolism genes is regulated by IL-22 and potentially IL-22-induced IL-18. Lastly, we show that Paneth cell-specific IL-22RA1 signaling, in part, mediates systemic glucose metabolism after HFD. Overall, these results elucidate a key role of intestinal epithelium-specific IL-22RA1 signaling in regulating intestinal metabolism and alleviating systemic obesity-associated disorders.
    DOI:  https://doi.org/10.1038/s41467-024-45568-6
  7. Front Immunol. 2024 ;15 1373468
    Editorial: Understanding how myeloid cell development and function meet tissue distinct metabolic requirements.
    Erika M Palmieri, Robert J Salmond, Alessio Menga.
      
    Keywords:  cross talk; immunometabolism; macrophage; metabolic pathway; microenvironment; myeloid cell; tissue niche
    DOI:  https://doi.org/10.3389/fimmu.2024.1373468
  8. EMBO J. 2024 Feb 23.
    NINJ1 induces plasma membrane rupture and release of damage-associated molecular pattern molecules during ferroptosis.
    Saray Ramos, Ella Hartenian, José Carlos Santos, Philipp Walch, Petr Broz.
      Ferroptosis is a regulated form of necrotic cell death caused by iron-dependent accumulation of oxidized phospholipids in cellular membranes, culminating in plasma membrane rupture (PMR) and cell lysis. PMR is also a hallmark of other types of programmed necrosis, such as pyroptosis and necroptosis, where it is initiated by dedicated pore-forming cell death-executing factors. However, whether ferroptosis-associated PMR is also actively executed by proteins or driven by osmotic pressure remains unknown. Here, we investigate a potential ferroptosis role of ninjurin-1 (NINJ1), a recently identified executor of pyroptosis-associated PMR. We report that NINJ1 oligomerizes during ferroptosis, and that Ninj1-deficiency protects macrophages and fibroblasts from ferroptosis-associated PMR. Mechanistically, we find that NINJ1 is dispensable for the initial steps of ferroptosis, such as lipid peroxidation, channel-mediated calcium influx, and cell swelling. In contrast, NINJ1 is required for early loss of plasma membrane integrity, which precedes complete PMR. Furthermore, NINJ1 mediates the release of cytosolic proteins and danger-associated molecular pattern (DAMP) molecules from ferroptotic cells, suggesting that targeting NINJ1 could be a therapeutic option to reduce ferroptosis-associated inflammation.
    Keywords:  Cell Death; Ferroptosis; Inflammation; Ninjurin-1; Plasma Membrane Rupture
    DOI:  https://doi.org/10.1038/s44318-024-00055-y
  9. Nat Metab. 2024 Feb 20.
    MCT1 helps brown fat suck up succinate.
    Jens Lund, Marie Sophie Isidor, Zachary Gerhart-Hines.
      
    DOI:  https://doi.org/10.1038/s42255-024-00979-z
  10. Cell Metab. 2024 Feb 12. pii: S1550-4131(24)00015-9. [Epub ahead of print]
    IgG is an aging factor that drives adipose tissue fibrosis and metabolic decline.
    Lexiang Yu, Qianfen Wan, Qiongming Liu, Yong Fan, Qiuzhong Zhou, Alicja A Skowronski, Summer Wang, Zhengping Shao, Chen-Yu Liao, Lei Ding, Brian K Kennedy, Shan Zha, Jianwen Que, Charles A LeDuc, Lei Sun, Liheng Wang, Li Qiang.
      Aging is underpinned by pronounced metabolic decline; however, the drivers remain obscure. Here, we report that IgG accumulates during aging, particularly in white adipose tissue (WAT), to impair adipose tissue function and metabolic health. Caloric restriction (CR) decreases IgG accumulation in WAT, whereas replenishing IgG counteracts CR's metabolic benefits. IgG activates macrophages via Ras signaling and consequently induces fibrosis in WAT through the TGF-β/SMAD pathway. Consistently, B cell null mice are protected from aging-associated WAT fibrosis, inflammation, and insulin resistance, unless exposed to IgG. Conditional ablation of the IgG recycling receptor, neonatal Fc receptor (FcRn), in macrophages prevents IgG accumulation in aging, resulting in prolonged healthspan and lifespan. Further, targeting FcRn by antisense oligonucleotide restores WAT integrity and metabolic health in aged mice. These findings pinpoint IgG as a hidden culprit in aging and enlighten a novel strategy to rejuvenate metabolic health.
    Keywords:  IgG; adipose tissue; aging; fibrosis; metabolic dysfunction
    DOI:  https://doi.org/10.1016/j.cmet.2024.01.015
  11. Cell Rep. 2024 Feb 16. pii: S2211-1247(24)00136-0. [Epub ahead of print]43(2): 113808
    UDP-glucose dehydrogenase supports autophagy-deficient PDAC growth via increasing hyaluronic acid biosynthesis.
    Minghe Fan, Sihan Huo, Yuyao Guo, Ruoxuan Wang, Wenqin Hao, Ziyang Zhang, Lina Wang, Ying Zhao.
      Autophagy is an essential degradation and recycling process that maintains cellular homeostasis during stress or nutrient deprivation. However, certain types of tumors such as pancreatic cancers can circumvent autophagy inhibition to sustain growth. The mechanism that autophagy-deficient pancreatic ductal adenocarcinoma (PDAC) uses to grow under nutrient deprivation is poorly understood. Our data show that nutrient deprivation in PDAC results in UDP-glucose dehydrogenase (UGDH) degradation, which is dependent on autophagic cargo receptor sequestosome 1 (p62). Moreover, we demonstrate that accumulated UGDH is indispensable for autophagy-deficient PDAC cells proliferation by promoting hyaluronic acid (HA) synthesis upon energy deprivation. Using an orthotopic mouse model of PDAC, we find that inhibition of HA synthesis by targeting UGDH in PDAC reduces tumor weight. Thus, the combined inhibition of HA and autophagy might be an attractive strategy for PDAC treatment.
    Keywords:  CP: Cancer; CP: Metabolism; HA; PDAC; UDP-glucose dehydrogenase; UGDH; autophagy; hyaluronic acid; p62; pancreatic ductal adenocarcinoma; sequestosome 1
    DOI:  https://doi.org/10.1016/j.celrep.2024.113808
  12. Redox Biol. 2024 Feb 17. pii: S2213-2317(24)00069-7. [Epub ahead of print]71 103093
    Tumor associated macrophages transfer ceruloplasmin mRNA to fibrosarcoma cells and protect them from ferroptosis.
    Anna Schwantes, Anja Wickert, Sabrina Becker, Patrick C Baer, Andreas Weigert, Bernhard Brüne, Dominik C Fuhrmann.
      Solid tumors are characterized by hypoxic areas, which are prone for macrophage infiltration. Once infiltrated, macrophages polarize to tumor associated macrophages (TAM) to support tumor progression. Therefore, the crosstalk between TAMs and tumor cells is of current interest for the development of novel therapeutic strategies. These may comprise induction of an iron- and lipid peroxidation-dependent form of cell death, known as ferroptosis. To study the macrophage - tumor cell crosstalk we polarized primary human macrophages towards a TAM-like phenotype, co-cultured them with HT1080 fibrosarcoma cells, and analyzed the tumor cell response to ferroptosis induction. In TAMs the expression of ceruloplasmin mRNA increased, which was driven by hypoxia inducible factor 2 and signal transducer and activator of transcription 1. Subsequently, ceruloplasmin mRNA was transferred from TAMs to HT1080 cells via extracellular vesicles. In tumor cells, mRNA was translated into protein to protect HT1080 cells from RSL3-induced ferroptosis. Mechanistically this was based on reduced iron abundance and lipid peroxidation. Interestingly, in naïve macrophages also hypoxia induced ceruloplasmin under hypoxia and a co-culture of HT1080 cells with hypoxic macrophages recapitulated the protective effect observed in TAM co-cultures. In conclusion, TAMs provoke tumor cells to release iron and thereby protect them from lipid peroxidation/ferroptosis.
    Keywords:  Extracellular vesicles; HIF-2; Hypoxia; Iron; STAT1
    DOI:  https://doi.org/10.1016/j.redox.2024.103093
  13. Biochem J. 2024 Feb 23. pii: BCJ20230421. [Epub ahead of print]
    Cardiomyocyte-specific deletion of GCN5L1 reduces lysine acetylation and attenuates diastolic dysfunction in aged mice by improving cardiac fatty acid oxidation.
    Jackson E Stewart, Jenna M Crawford, William E Mullen, Angelica Jacques, Michael W Stoner, Iain Scott, Dharendra Thapa.
      Cardiac mitochondrial dysfunction is a critical contributor to the pathogenesis of aging and many age-related conditions. As such, complete control of mitochondrial function is critical to maintain cardiac efficiency in the aged heart. Lysine acetylation is a reversible post-translational modification shown to regulate several mitochondrial metabolic and biochemical processes. In the present study, we investigated how mitochondrial lysine acetylation regulates fatty acid oxidation and cardiac function in the aged heart. We found a significant increase in mitochondrial protein acetylation in the aged heart which correlated with increased level of mitochondrial acetyltransferase-related protein GCN5L1. We showed that acetylation status of several fatty acid and glucose oxidation enzymes (long-chain acyl-CoA dehydrogenase, hydroxyacyl-coA dehydrogenase, and pyruvate dehydrogenase) were significantly upregulated in aged heart which correlated with decreased enzymatic activities. Using a cardiac-specific GCN5L1 knockout animal model, we showed that overall acetylation of mitochondrial proteins was decreased in aged knockout animals, including fatty acid oxidation proteins which led to improved fatty acid oxidation activity and attenuated cardiac diastolic dysfunction observed in the aged heart. Together, these findings indicate that lysine acetylation regulates fatty acid oxidation in the aged heart which results in improved cardiac diastolic function and this is in part regulated by GCN5L1.
    Keywords:  aging; cardiac function; fatty acid oxidation; lysine acetylation; mitochondria
    DOI:  https://doi.org/10.1042/BCJ20230421
  14. Cancer Res. 2024 Feb 22.
    PRMT1 sustains de novo fatty acid synthesis by methylating PHGDH to drive chemoresistance in triple-negative breast cancer.
    Takehiro Yamamoto, Tetsu Hayashida, Yohei Masugi, Kiyotaka Oshikawa, Noriyo Hayakawa, Mai Itoh, Chiyoko Nishime, Masami Suzuki, Aiko Nagayama, Yuko Kawai, Takako Hishiki, Tomomi Matsuura, Yoshiko Naito, Akiko Kubo, Arisa Yamamoto, Yujiro Yoshioka, Tomokazu Kurahori, Misa Nagasaka, Minako Takizawa, Naoharu Takano, Koji Kawakami, Michiie Sakamoto, Masatoshi Wakui, Takushi Yamamoto, Yuko Kitagawa, Yasuaki Kabe, Kenichi Horisawa, Atsushi Suzuki, Masaki Matsumoto, Makoto Suematsu.
      Triple-negative breast cancer (TNBC) chemoresistance hampers the ability to effectively treat patients. Identification of mechanisms driving chemoresistance can lead to strategies to improve treatment. Here, we revealed that protein arginine methyltransferase-1 (PRMT1) simultaneously methylates D-3-phosphoglycerate dehydrogenase (PHGDH), a critical enzyme in serine synthesis, and the glycolytic enzymes PFKFB3 and PKM2 in TNBC cells. 13C metabolic flux analyses showed that PRMT1 methylation of these three enzymes diverts glucose toward intermediates in the serine-synthesizing and serine/glycine cleavage pathways, thereby accelerating the production of methyl donors in TNBC cells. Mechanistically, PRMT1-dependent methylation of PHGDH at R54 or R20 activated its enzymatic activity by stabilizing 3-phosphoglycerate binding and suppressing polyubiquitination. PRMT1-mediated PHGDH methylation drove chemoresistance independently of glutathione synthesis. Rather, activation of the serine synthesis pathway supplied α-ketoglutarate and citrate to increase palmitate levels through activation of fatty acid synthase (FASN). Increased palmitate induced protein S-palmitoylation of PHGDH and FASN to further enhance fatty acid synthesis in a PRMT1-dependent manner. Loss of PRMT1 or pharmacological inhibition of FASN or protein S-palmitoyltransferase reversed chemoresistance in TNBC. Furthermore, immunohistochemistry coupled with imaging mass spectrometry in clinical TNBC specimens substantiated that PRMT1-mediated methylation of PHGDH, PFKFB3, and PKM2 correlates with chemoresistance and that metabolites required for methylation and fatty acid synthesis are enriched in TNBC. Together, these results suggest that enhanced de novo fatty acid synthesis mediated by coordinated protein arginine methylation and protein S-palmitoylation is a therapeutic target for overcoming chemoresistance in TNBC.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-23-2266
  15. Cell Rep. 2024 Feb 21. pii: S2211-1247(24)00100-1. [Epub ahead of print]43(3): 113772
    Identification of MIMAS, a multifunctional mega-assembly integrating metabolic and respiratory biogenesis factors of mitochondria.
    Patrick Horten, Kuo Song, Joshua Garlich, Robert Hardt, Lilia Colina-Tenorio, Susanne E Horvath, Uwe Schulte, Bernd Fakler, Martin van der Laan, Thomas Becker, Rosemary A Stuart, Nikolaus Pfanner, Heike Rampelt.
      The mitochondrial inner membrane plays central roles in bioenergetics and metabolism and contains several established membrane protein complexes. Here, we report the identification of a mega-complex of the inner membrane, termed mitochondrial multifunctional assembly (MIMAS). Its large size of 3 MDa explains why MIMAS has escaped detection in the analysis of mitochondria so far. MIMAS combines proteins of diverse functions from respiratory chain assembly to metabolite transport, dehydrogenases, and lipid biosynthesis but not the large established supercomplexes of the respiratory chain, ATP synthase, or prohibitin scaffold. MIMAS integrity depends on the non-bilayer phospholipid phosphatidylethanolamine, in contrast to respiratory supercomplexes whose stability depends on cardiolipin. Our findings suggest that MIMAS forms a protein-lipid mega-assembly in the mitochondrial inner membrane that integrates respiratory biogenesis and metabolic processes in a multifunctional platform.
    Keywords:  CP: Metabolism; CP: Molecular biology; membrane protein complex; metabolism; metabolite carriers; mitochondria; phosphatidylethanolamine; phospholipids; protein assembly; respiratory chain
    DOI:  https://doi.org/10.1016/j.celrep.2024.113772
  16. Nat Commun. 2024 Feb 23. 15(1): 1666
    Single-cell transcriptomics identifies the differentiation trajectory from inflammatory monocytes to pro-resolving macrophages in a mouse skin allergy model.
    Kensuke Miyake, Junya Ito, Kazufusa Takahashi, Jun Nakabayashi, Frank Brombacher, Shigeyuki Shichino, Soichiro Yoshikawa, Sachiko Miyake, Hajime Karasuyama.
      Both monocytes and macrophages are heterogeneous populations. It was traditionally understood that Ly6Chi classical (inflammatory) monocytes differentiate into pro-inflammatory Ly6Chi macrophages. Accumulating evidence has suggested that Ly6Chi classical monocytes can also differentiate into Ly6Clo pro-resolving macrophages under certain conditions, while their differentiation trajectory remains to be fully elucidated. The present study with scRNA-seq and flow cytometric analyses reveals that Ly6ChiPD-L2lo classical monocytes recruited to the allergic skin lesion sequentially differentiate into Ly6CloPD-L2hi pro-resolving macrophages, via intermediate Ly6ChiPD-L2hi macrophages but not Ly6Clo non-classical monocytes, in an IL-4 receptor-dependent manner. Along the differentiation, classical monocyte-derived macrophages display anti-inflammatory signatures followed by metabolic rewiring concordant with their ability to phagocytose apoptotic neutrophils and allergens, therefore contributing to the resolution of inflammation. The failure in the generation of these pro-resolving macrophages drives the IL-1α-mediated cycle of inflammation with abscess-like accumulation of necrotic neutrophils. Thus, we clarify the stepwise differentiation trajectory from Ly6Chi classical monocytes toward Ly6Clo pro-resolving macrophages that restrain neutrophilic aggravation of skin allergic inflammation.
    DOI:  https://doi.org/10.1038/s41467-024-46148-4
  17. Elife. 2024 Feb 23. pii: RP90024. [Epub ahead of print]12
    An engineered biosensor enables dynamic aspartate measurements in living cells.
    Kristian Davidsen, Jonathan S Marvin, Abhi Aggarwal, Timothy A Brown, Lucas B Sullivan.
      Intracellular levels of the amino acid aspartate are responsive to changes in metabolism in mammalian cells and can correspondingly alter cell function, highlighting the need for robust tools to measure aspartate abundance. However, comprehensive understanding of aspartate metabolism has been limited by the throughput, cost, and static nature of the mass spectrometry (MS)-based measurements that are typically employed to measure aspartate levels. To address these issues, we have developed a green fluorescent protein (GFP)-based sensor of aspartate (jAspSnFR3), where the fluorescence intensity corresponds to aspartate concentration. As a purified protein, the sensor has a 20-fold increase in fluorescence upon aspartate saturation, with dose-dependent fluorescence changes covering a physiologically relevant aspartate concentration range and no significant off target binding. Expressed in mammalian cell lines, sensor intensity correlated with aspartate levels measured by MS and could resolve temporal changes in intracellular aspartate from genetic, pharmacological, and nutritional manipulations. These data demonstrate the utility of jAspSnFR3 and highlight the opportunities it provides for temporally resolved and high-throughput applications of variables that affect aspartate levels.
    Keywords:  aspartate; biochemistry; biosensor; cell biology; chemical biology; glutamine; human; metabolism; mitochondria; protein engineering
    DOI:  https://doi.org/10.7554/eLife.90024
  18. JCI Insight. 2024 Feb 22. pii: e177141. [Epub ahead of print]
    Enhancing CAR-T cell metabolism to overcome hypoxic conditions in the brain tumor microenvironment.
    Ryusuke Hatae, Keith Kyewalabye, Akane Yamamichi, Tiffany Chen, Su Phyu, Pavlina Chuntova, Takahide Nejo, Lauren S Levine, Matthew H Spitzer, Hideho Okada.
      The efficacy of chimeric antigen receptor (CAR)-T therapy has been limited against brain tumors to date. CAR-T cells infiltrating syngeneic intracerebral SB28-EGFRvIII glioma revealed impaired mitochondrial ATP production and a markedly hypoxic status compared to ones migrating to subcutaneous tumors. Drug screenings to improve metabolic states of T cells under hypoxic conditions led us to evaluate the combination of AMPK activator Metformin and the mTOR inhibitor Rapamycin (Met+Rap). Met+Rap-pretreated mouse CAR-T cells showed activated PPAR-gamma coactivator 1α (PGC-1α) through mTOR inhibition and AMPK activation, and a higher level of mitochondrial spare respiratory capacity than those pretreated with individual drugs or without pretreatment. Moreover, Met+Rap-pretreated CAR-T cells demonstrated persistent and effective anti-glioma cytotoxic activities in the hypoxic condition. Furthermore, a single intravenous infusion of Met+Rap-pretreated CAR-T cells significantly extended the survival of mice bearing intracerebral SB28-EGFRvIII gliomas. Mass cytometric analyses highlighted increased glioma-infiltrating CAR-T cells in the Met+Rap group with fewer Ly6c+ CD11b+ monocytic myeloid-derived suppressor cells in the tumors. Finally, human CAR-T cells pretreated with Met+Rap recapitulated the observations with murine CAR-T cells, demonstrating improved functions in vitro hypoxic conditions. These findings advocate for translational and clinical exploration of Met+Rap-pretreated CAR-T cells in human trials.
    Keywords:  Brain cancer; Cancer immunotherapy; Hypoxia; Immunology; Otology
    DOI:  https://doi.org/10.1172/jci.insight.177141
  19. JCI Insight. 2024 Feb 22. pii: e164400. [Epub ahead of print]9(4):
    The shifting lipidomic landscape of blood monocytes and neutrophils during pneumonia.
    Alex R Schuurman, Osoul Chouchane, Joe M Butler, Hessel Peters-Sengers, Sebastiaan Joosten, Xanthe Brands, Bastiaan W Haak, Natasja A Otto, Fabrice Uhel, Augustijn Klarenbeek, Christine Ca van Linge, Antoine van Kampen, Mia Pras-Raves, Michel van Weeghel, Marco van Eijk, Maria J Ferraz, Daniël R Faber, Alex de Vos, Brendon P Scicluna, Frédéric M Vaz, W Joost Wiersinga, Tom van der Poll.
      The lipidome of immune cells during infection has remained unexplored, although evidence of the importance of lipids in the context of immunity is mounting. In this study, we performed untargeted lipidomic analysis of blood monocytes and neutrophils from patients hospitalized for pneumonia and age- and sex-matched noninfectious control volunteers. We annotated 521 and 706 lipids in monocytes and neutrophils, respectively, which were normalized to an extensive set of internal standards per lipid class. The cellular lipidomes were profoundly altered in patients, with both common and distinct changes between the cell types. Changes involved every level of the cellular lipidome: differential lipid species, class-wide shifts, and altered saturation patterns. Overall, differential lipids were mainly less abundant in monocytes and more abundant in neutrophils from patients. One month after hospital admission, lipidomic changes were fully resolved in monocytes and partially in neutrophils. Integration of lipidomic and concurrently collected transcriptomic data highlighted altered sphingolipid metabolism in both cell types. Inhibition of ceramide and sphingosine-1-phosphate synthesis in healthy monocytes and neutrophils resulted in blunted cytokine responses upon stimulation with lipopolysaccharide. These data reveal major lipidomic remodeling in immune cells during infection, and link the cellular lipidome to immune functionality.
    Keywords:  Immunology; Infectious disease; Innate immunity; Molecular biology; Neutrophils
    DOI:  https://doi.org/10.1172/jci.insight.164400
  20. Sci Adv. 2024 Feb 23. 10(8): eadi4819
    Modeling embryo-endometrial interface recapitulating human embryo implantation.
    Shun Shibata, Shun Endo, Luis A E Nagai, Eri H Kobayashi, Akira Oike, Norio Kobayashi, Akane Kitamura, Takeshi Hori, Yuji Nashimoto, Ryuichiro Nakato, Hirotaka Hamada, Hirokazu Kaji, Chie Kikutake, Mikita Suyama, Masatoshi Saito, Nobuo Yaegashi, Hiroaki Okae, Takahiro Arima.
      The initiation of human pregnancy is marked by the implantation of an embryo into the uterine environment; however, the underlying mechanisms remain largely elusive. To address this knowledge gap, we developed hormone-responsive endometrial organoids (EMO), termed apical-out (AO)-EMO, which emulate the in vivo architecture of endometrial tissue. The AO-EMO comprise an exposed apical epithelium surface, dense stromal cells, and a self-formed endothelial network. When cocultured with human embryonic stem cell-derived blastoids, the three-dimensional feto-maternal assembloid system recapitulates critical implantation stages, including apposition, adhesion, and invasion. Endometrial epithelial cells were subsequently disrupted by syncytial cells, which invade and fuse with endometrial stromal cells. We validated this fusion of syncytiotrophoblasts and stromal cells using human blastocysts. Our model provides a foundation for investigating embryo implantation and feto-maternal interactions, offering valuable insights for advancing reproductive medicine.
    DOI:  https://doi.org/10.1126/sciadv.adi4819
  21. Elife. 2024 Feb 23. pii: RP91903. [Epub ahead of print]12
    Piezo1 mechanosensing regulates integrin-dependent chemotactic migration in human T cells.
    Chinky Shiu Chen Liu, Tithi Mandal, Parijat Biswas, Md Asmaul Hoque, Purbita Bandopadhyay, Bishnu Prasad Sinha, Jafar Sarif, Ranit D'Rozario, Deepak Kumar Sinha, Bidisha Sinha, Dipyaman Ganguly.
      T cells are crucial for efficient antigen-specific immune responses and thus their migration within the body, to inflamed tissues from circulating blood or to secondary lymphoid organs, plays a very critical role. T cell extravasation in inflamed tissues depends on chemotactic cues and interaction between endothelial adhesion molecules and cellular integrins. A migrating T cell is expected to sense diverse external and membrane-intrinsic mechano-physical cues, but molecular mechanisms of such mechanosensing in cell migration are not established. We explored if the professional mechanosensor Piezo1 plays any role during integrin-dependent chemotaxis of human T cells. We found that deficiency of Piezo1 in human T cells interfered with integrin-dependent cellular motility on ICAM-1-coated surface. Piezo1 recruitment at the leading edge of moving T cells is dependent on and follows focal adhesion formation at the leading edge and local increase in membrane tension upon chemokine receptor activation. Piezo1 recruitment and activation, followed by calcium influx and calpain activation, in turn, are crucial for the integrin LFA1 (CD11a/CD18) recruitment at the leading edge of the chemotactic human T cells. Thus, we find that Piezo1 activation in response to local mechanical cues constitutes a membrane-intrinsic component of the 'outside-in' signaling in human T cells, migrating in response to chemokines, that mediates integrin recruitment to the leading edge.
    Keywords:  F-actin; LFA1; Piezo1; cell biology; cell migration; chemotaxis; confocal microscopy; focal adhesion kinase; human; human T cells; immunology; inflammation; interference reflection microscopy; mechanosensing
    DOI:  https://doi.org/10.7554/eLife.91903
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