bims-celmim Biomed News
on Cellular and mitochondrial metabolism
Issue of 2024–09–22
seventeen papers selected by
Marc Segarra Mondejar
  1. In vivo biosensing of subcellular pyruvate pools reveals photosynthesis-dependent metabolite dynamics in Nicotiana benthamiana.
  2. Sex-dependent metabolic remodeling of kidneys revealed by arteriovenous metabolomics.
  3. Profiling of metabolic dysregulation in ovarian cancer tissues and biofluids.
  4. The p53 target DRAM1 modulates calcium homeostasis and ER stress by promoting contact between lysosomes and the ER through STIM1.
  5. Coenzymes in a pre-enzymatic metabolism.
  6. An intelligent NIR fluorescent dye with dual response to pH and viscosity for investigating the interactions between LDs and mitochondria.
  7. Technologies for Decoding Cancer Metabolism with Spatial Resolution.
  8. IF1 is a cold-regulated switch of ATP synthase hydrolytic activity to support thermogenesis in brown fat.
  9. ER-plasma membrane contact sites deliver ER lipids and proteins for rapid cell surface expansion.
  10. A FRET biosensor constructed using pH sensitive G-quadruplex DNA for detecting mitochondrial autophagy.
  11. TBK1 adaptor AZI2/NAP1 regulates NDP52-driven mitochondrial autophagy.
  12. Atomic vacancies of molybdenum disulfide nanoparticles stimulate mitochondrial biogenesis.
  13. mLumiOpto is a Mitochondrial-Targeted Gene Therapy for Treating Cancer.
  14. Metabolic interdependencies in thermophilic communities are revealed using co-occurrence and complementarity networks.
  15. Activation induces shift in nutrient utilization that differentially impacts cell functions in human neutrophils.
  16. Proteogenomic reconstruction of organ-specific metabolic networks in an environmental sentinel species, the amphipod Gammarus fossarum.
  17. Bidirectional dysregulation of synaptic glutamate signaling after transient metabolic failure.
  1. J Exp Bot. 2024 Sep 20. pii: erae398. [Epub ahead of print]
    In vivo biosensing of subcellular pyruvate pools reveals photosynthesis-dependent metabolite dynamics in Nicotiana benthamiana.
    Jan Multhoff, Jan-Ole Niemeier, Ke Zheng, Magdiel Sheng Satha Lim, Pedro Barreto, Jule Meret Niebisch, Till Ischebeck, Markus Schwarzländer.
      Pyruvate is central to metabolism across biology. It acts as a metabolic hub linking key pathways including glycolysis, the Krebs cycle, fermentation, and synthesis of amino acids, fatty acids, isoprenoids and nucleotides. Even though the central role of pyruvate is well established biochemically, there is a remarkable void in our understanding of how pyruvate levels behave within cells, where pyruvate is distributed across different compartments, and differential changes in pyruvate pools may occur rapidly upon changes in metabolic fluxes. Recently, this problem has been addressed by the development of a genetically-encoded pyruvate biosensor to provide first insights into the pyruvate dynamics in animal cells. Here, we establish in vivo biosensing of pyruvate in plants. We provide advanced characterisation of the biosensor properties and demonstrate the functionality of the sensor in the cytosol, the mitochondria and the chloroplasts of Nicotiana benthamiana epidermal cells. Finally, we harnessed the tool to investigate the impact of photosynthesis on pyruvate with unprecedented spatial and temporal resolution, revealing pronounced changes in cytosolic pyruvate pools. While highlighting the current limitations of the biosensor, this study provides proof-of-concept for how the dynamics and regulation of central carbon metabolites can be revealed in the context of living plant tissues.
    Keywords:   Nicotiana benthamiana ; in vivo biosensing; Dark-Light-Transitions; Fluorescent protein-based biosensor; Metabolism; On-stage illumination; Photosynthesis; PyronicSF; Pyruvate
    DOI:  https://doi.org/10.1093/jxb/erae398
  2. bioRxiv. 2024 Sep 02. pii: 2024.09.02.610869. [Epub ahead of print]
    Sex-dependent metabolic remodeling of kidneys revealed by arteriovenous metabolomics.
    Miranda E Kelly, Lauren A Hoffner, Cuauhtemoc B Ramirez, Alexis L Anica, Joohwan Kim, Gregory Tong, Yeojin Kim, Wonsuk Choi, Kihong Jang, Yasmine H Alam, Sunhee Jung, Johnny Le, Ian Tamburini, Miranda L Lopez, Hosung Bae, Yujin Chun, Won-Suk Song, Thomas F Martinez, Cholsoon Jang, Gina Lee.
      Sex is a fundamental biological variable important in biomedical research, drug development, clinical trials, and prevention approaches. Among many organs, kidneys are known to exhibit remarkable structural, histological, and pathological differences between sexes. However, whether and how kidneys display distinct metabolic activities between sexes is poorly understood. By developing kidney-specific arteriovenous (AV) metabolomics combined with transcriptomics, we report striking sex differences in both basal metabolic activities and adaptive metabolic remodeling of kidneys after a fat-enriched ketogenic diet (KD), a regimen known to mitigate kidney diseases and improve immunotherapy for renal cancer. At the basal state, female kidneys show highly accumulated aldosterone and various acylcarnitines. In response to the KD, aldosterone levels remain high selectively in females but the sex difference in acylcarnitines disappears. AV data revealed that, under KD, female kidneys avidly take up circulating fatty acids and release 3-hydroxybutyrate (3-HB) whereas male kidneys barely absorb fatty acids but consistently take up 3-HB. Although both male and female kidneys take up gluconeogenic substrates such as glycerol, glutamine and lactate, only female kidneys exhibit net glucose release. Kidney transcriptomics data incompletely predict these sex differences, suggesting post-transcriptional/translational regulation mechanisms. This study provides foundational insights into the sex-dependent and diet-elicited metabolic flexibility of the kidneys in vivo, serving as a unique resource for understanding variable disease prevalence and drug responses between male and female kidneys.
    DOI:  https://doi.org/10.1101/2024.09.02.610869
  3. Sci Rep. 2024 09 16. 14(1): 21555
    Profiling of metabolic dysregulation in ovarian cancer tissues and biofluids.
    Tsuyoshi Ohta, Masahiro Sugimoto, Yasufumi Ito, Shota Horikawa, Yosuke Okui, Hirotsugu Sakaki, Manabu Seino, Makoto Sunamura, Satoru Nagase.
      Ovarian cancer (OC) is the most lethal gynecologic cancer, mainly due to late diagnosis with widespread peritoneal spread at first presentation. We performed metabolomic analyses of ovarian and paired control tissues using capillary electrophoresis-mass spectrometry and liquid chromatography-mass spectrometry to understand its metabolomic dysregulation. Of the 130 quantified metabolites, 96 metabolites of glycometabolism, including glycolysis, tricarboxylic acid cycles, urea cycles, and one-carbon metabolites, showed significant differences between the samples. To evaluate the local and systemic metabolomic differences in OC, we also analyzed low or non-invasively available biofluids, including plasma, urine, and saliva collected from patients with OC and benign gynecological diseases. All biofluids and tissue samples showed consistently elevated concentrations of N1,N12-diacetylspermine compared to controls. Four metabolites, polyamines, and betaine, were significantly and consistently elevated in both plasma and tissue samples. These data indicate that plasma metabolic dysregulation, which the most reflected by those of OC tissues. Our metabolomic profiles contribute to our understanding of metabolomic abnormalities in OC and their effects on biofluids.
    Keywords:  Biofluids; Cancer tissues; Metabolomic dysfunction; Normal tissue; Ovarian cancer
    DOI:  https://doi.org/10.1038/s41598-024-72938-3
  4. Proc Natl Acad Sci U S A. 2024 Sep 24. 121(39): e2400531121
    The p53 target DRAM1 modulates calcium homeostasis and ER stress by promoting contact between lysosomes and the ER through STIM1.
    Xiying Wang, Ji Geng, Suman Rimal, Yuxiu Sui, Jie Pan, Zhenghong Qin, Bingwei Lu.
      It is well established that DNA Damage Regulated Autophagy Modulator 1 (DRAM1), a lysosomal protein and a target of p53, participates in autophagy. The cellular functions of DRAM1 beyond autophagy remain elusive. Here, we show p53-dependent upregulation of DRAM1 in mitochondrial damage-induced Parkinson's disease (PD) models and exacerbation of disease phenotypes by DRAM1. We find that the lysosomal location of DRAM1 relies on its intact structure including the cytosol-facing C-terminal domain. Excess DRAM1 disrupts endoplasmic reticulum (ER) structure, triggers ER stress, and induces protective ER-phagy. Mechanistically, DRAM1 interacts with stromal interacting molecule 1 (STIM1) to tether lysosomes to the ER and perturb STIM1 function in maintaining intracellular calcium homeostasis. STIM1 overexpression promotes cellular health by restoring calcium homeostasis, ER stress response, ER-phagy, and AMP-activated protein kinase (AMPK)-Unc-51 like autophagy activating kinase 1 (ULK1) signaling in cells with excess DRAM1. Thus, by promoting organelle contact between lysosomes and the ER, DRAM1 modulates ER structure and function and cell survival under stress. Our results suggest that DRAM1 as a lysosomal protein performs diverse roles in cellular homeostasis and stress response. These findings may have significant implications for our understanding of the role of the p53/DRAM1 axis in human diseases, from cancer to neurodegenerative diseases.
    Keywords:  DRAM1; ER; ER-phagy; calcium homeostasis; lysosome
    DOI:  https://doi.org/10.1073/pnas.2400531121
  5. Sci Adv. 2024 Sep 20. 10(38): eadr5357
    Coenzymes in a pre-enzymatic metabolism.
    Quentin Dherbassy, Robert J Mayer, Joseph Moran.
      Experiments now support theoretical suggestions that coenzymes mediated key metabolic reactions before the emergence of enzymes. Three coenzymes believed essential to the core metabolism of the last universal common ancestor to extant life (pyridoxal phosphate, adenosine diphosphate, and nicotinamide adenine dinucleotide) were recently found to be active in their corresponding metabolic reactions in the absence of enzymes. These findings suggest an earlier contribution of coenzymes to abiogenesis, ultimately yielding insights into the prebiotic origins of metabolism.
    DOI:  https://doi.org/10.1126/sciadv.adr5357
  6. Talanta. 2024 Sep 12. pii: S0039-9140(24)01228-1. [Epub ahead of print]281 126849
    An intelligent NIR fluorescent dye with dual response to pH and viscosity for investigating the interactions between LDs and mitochondria.
    Wei Zhang, Xing Tian, Yanxi Zhu, Lei Yang, Zhanxian Li, Mingming Yu.
      The interaction between lipid droplets and mitochondria plays a pivotal role in biological processes including cellular stress, metabolic homeostasis, cellular autophagy and apoptosis. Deciphering the complex interplay between lipid droplets and mitochondria is essential for gaining insights into the fundamental workings of the cell and can have broad implications for the development of therapeutic strategies for various diseases, including metabolic disorders, neurodegenerative diseases, and cancer. In this study, we develop a pH and viscosity-responsive near-infrared (NIR) fluorescent probe PTOH to investigate the interaction between lipid droplets and mitochondria. This probe demonstrates a significant enhancement in fluorescence intensity at 470 nm when the pH increases, while under acidic conditions, its fluorescence intensity at 730 nm intensifies by a factor of 35 with rising system viscosity. Cell imaging experiments revealed that PTOH can effectively discriminate between normal and cancerous cells, as well as detect intracellular pH and viscosity alterations induced by drugs. Additionally, PTOH is utilized to visualize the interaction between lipid droplets and mitochondria and to differentiate between cellular autophagy and apoptosis phenomena, providing a valuable tool for elucidating the mechanisms underlying lipid droplet-mitochondria interactions and their associated diseases.
    Keywords:  Apoptosis; Autophagy; Lipid droplets; Mitochondria; Viscosity; pH
    DOI:  https://doi.org/10.1016/j.talanta.2024.126849
  7. Cold Spring Harb Perspect Med. 2024 Sep 16. pii: a041553. [Epub ahead of print]
    Technologies for Decoding Cancer Metabolism with Spatial Resolution.
    Walter W Chen, Michael E Pacold, David M Sabatini, Naama Kanarek.
      It is increasingly appreciated that cancer cells adapt their metabolic pathways to support rapid growth and proliferation as well as survival, often even under the poor nutrient conditions that characterize some tumors. Cancer cells can also rewire their metabolism to circumvent chemotherapeutics that inhibit core metabolic pathways, such as nucleotide synthesis. A critical approach to the study of cancer metabolism is metabolite profiling (metabolomics), the set of technologies, usually based on mass spectrometry, that allow for the detection and quantification of metabolites in cancer cells and their environments. Metabolomics is a burgeoning field, driven by technological innovations in mass spectrometers, as well as novel approaches to isolate cells, subcellular compartments, and rare fluids, such as the interstitial fluid of tumors. Here, we discuss three emerging metabolomic technologies: spatial metabolomics, single-cell metabolomics, and organellar metabolomics. The use of these technologies along with more established profiling methods, like single-cell transcriptomics and proteomics, is likely to underlie new discoveries and questions in cancer research.
    DOI:  https://doi.org/10.1101/cshperspect.a041553
  8. EMBO J. 2024 Sep 16.
    IF1 is a cold-regulated switch of ATP synthase hydrolytic activity to support thermogenesis in brown fat.
    Henver S Brunetta, Anna S Jung, Fernando Valdivieso-Rivera, Stepheny C de Campos Zani, Joel Guerra, Vanessa O Furino, Annelise Francisco, Marcelo Berçot, Pedro M Moraes-Vieira, Susanne Keipert, Martin Jastroch, Laurent O Martinez, Carlos H Sponton, Roger F Castilho, Marcelo A Mori, Alexander Bartelt.
      While mechanisms controlling uncoupling protein-1 (UCP1) in thermogenic adipocytes play a pivotal role in non-shivering thermogenesis, it remains unclear whether F1Fo-ATP synthase function is also regulated in brown adipose tissue (BAT). Here, we show that inhibitory factor 1 (IF1, encoded by Atp5if1), an inhibitor of ATP synthase hydrolytic activity, is a critical negative regulator of brown adipocyte energy metabolism. In vivo, IF1 levels are diminished in BAT of cold-adapted mice compared to controls. Additionally, the capacity of ATP synthase to generate mitochondrial membrane potential (MMP) through ATP hydrolysis (the so-called "reverse mode" of ATP synthase) is increased in brown fat. In cultured brown adipocytes, IF1 overexpression results in an inability of mitochondria to sustain the MMP upon adrenergic stimulation, leading to a quiescent-like phenotype in brown adipocytes. In mice, adeno-associated virus-mediated IF1 overexpression in BAT suppresses adrenergic-stimulated thermogenesis and decreases mitochondrial respiration in BAT. Taken together, our work identifies downregulation of IF1 upon cold as a critical event for the facilitation of the reverse mode of ATP synthase as well as to enable energetic adaptation of BAT to effectively support non-shivering thermogenesis.
    Keywords:  Adipocytes; Metabolism; Mitochondria; Thermogenesis; UCP1
    DOI:  https://doi.org/10.1038/s44318-024-00215-0
  9. J Cell Biol. 2024 Dec 02. pii: e202308137. [Epub ahead of print]223(12):
    ER-plasma membrane contact sites deliver ER lipids and proteins for rapid cell surface expansion.
    Madison Smith, Lincoln Gay, Markus Babst.
      As a consequence of hypoosmotic shock, yeast cells swell rapidly and increase the surface area by ∼20% in 20 s. Approximately, 35% of this surface increase is mediated by the ER-plasma membrane contact sites, specifically the tricalbins, which are required for the delivery of both lipids and the GPI-anchored protein Crh2 from the cortical ER to the plasma membrane. Therefore, we propose a new function for the tricalbins: mediating the fusion of the ER to the plasma membrane at contact sites. This proposed fusion is triggered by calcium influx via the stretch-gated channel Cch1 and is supported by the anoctamin Ist2.
    DOI:  https://doi.org/10.1083/jcb.202308137
  10. Talanta. 2024 Sep 14. pii: S0039-9140(24)01264-5. [Epub ahead of print]281 126885
    A FRET biosensor constructed using pH sensitive G-quadruplex DNA for detecting mitochondrial autophagy.
    Dawei Yang, Ranran Sun, Hongxia Sun, Qian Li, Hong Zhang, Xiufeng Zhang, Lei Shi, Li Yao, Yalin Tang.
      Mitochondria are crucial powerhouses and central organelles for maintaining normal physiological activities in eukaryotic cells. The use of highly specific optical biosensors to monitor mitochondrial autophagy (mitophagy) is an important way for detecting mitochondrial abnormalities. Herein, we report a pH responsive G-quadruplex (G4) structure folded by the oligonucleotide named P24. P24 is composed of four GGCCTG repeating units, and the high guanine content allows it to form an antiparallel G4 topology at pH 4.5 (lysosomal pH). However, when pH increases to around 7.4 (mitochondrial pH), P24 further transforms into a double-stranded structure. Unlike most oligonucleotides that enter lysosomes, P24 highly targets mitochondria in live cells. These characteristics enable P24 to construct a pH responsive optical biosensor by linking a pair of fluorescence resonance energy transfer (FRET) fluorophores. The P24 based biosensor demonstrates reliable applications in detecting mitophagy in live cells.
    Keywords:  Autophagy; Biosensor; G-quadruplex; Mitochondrion; pH responsive
    DOI:  https://doi.org/10.1016/j.talanta.2024.126885
  11. J Biol Chem. 2024 Sep 12. pii: S0021-9258(24)02276-2. [Epub ahead of print] 107775
    TBK1 adaptor AZI2/NAP1 regulates NDP52-driven mitochondrial autophagy.
    Ryu Endo, Hiroki Kinefuchi, Momoha Sawada, Reika Kikuchi, Waka Kojima, Noriyuki Matsuda, Koji Yamano.
      Damaged mitochondria are selectively eliminated in a process called mitophagy. PINK1 and Parkin amplify ubiquitin signals on damaged mitochondria, which are then recognized by autophagy adaptors to induce local autophagosome formation. NDP52 and OPTN, two essential mitophagy adaptors, facilitate de novo synthesis of pre-autophagosomal membranes near damaged mitochondria by linking ubiquitinated mitochondria and ATG8 family proteins and by recruiting core autophagy initiation components. The multifunctional serine/threonine kinase TBK1 also plays important roles in mitophagy. OPTN directly binds TBK1 to form a positive feedback loop for isolation membrane expansion. TBK1 is also thought to indirectly interact with NDP52; however, its role in NDP52-driven mitophagy remains largely unknown. Here, we focused on two TBK1 adaptors, AZI2/NAP1 and TBKBP1/SINTBAD, that are thought to mediate the TBK1-NDP52 interaction. We found that both AZI2 and TBKBP1 are recruited to damaged mitochondria during Parkin-mediated mitophagy. Further, a series of AZI2 and TBKBP1 knockout constructs combined with an OPTN knockout showed that AZI2, but not TBKBP1, impacts NDP52-driven mitophagy. In addition, we found that AZI2 at S318 is phosphorylated during mitophagy, the impairment of which slightly inhibits mitochondrial degradation. These results suggest that AZI2, in concert with TBK1, plays an important role in NDP52-driven mitophagy.
    Keywords:  autophagy; mitochondria; mitophagy; polyubiquitin chain; serine/threonine protein kinase
    DOI:  https://doi.org/10.1016/j.jbc.2024.107775
  12. Nat Commun. 2024 Sep 17. 15(1): 8136
    Atomic vacancies of molybdenum disulfide nanoparticles stimulate mitochondrial biogenesis.
    Kanwar Abhay Singh, John Soukar, Mohammad Zulkifli, Anna Kersey, Giriraj Lokhande, Sagnika Ghosh, Aparna Murali, Natalie M Garza, Harman Kaur, Justin N Keeney, Ramu Banavath, Hatice Ceylan Koydemir, Raquel Sitcheran, Irtisha Singh, Vishal M Gohil, Akhilesh K Gaharwar.
      Diminished mitochondrial function underlies many rare inborn errors of energy metabolism and contributes to more common age-associated metabolic and neurodegenerative disorders. Thus, boosting mitochondrial biogenesis has been proposed as a potential therapeutic approach for these diseases; however, currently we have a limited arsenal of compounds that can stimulate mitochondrial function. In this study, we designed molybdenum disulfide (MoS2) nanoflowers with predefined atomic vacancies that are fabricated by self-assembly of individual two-dimensional MoS2 nanosheets. Treatment of mammalian cells with MoS2 nanoflowers increased mitochondrial biogenesis by induction of PGC-1α and TFAM, which resulted in increased mitochondrial DNA copy number, enhanced expression of nuclear and mitochondrial-DNA encoded genes, and increased levels of mitochondrial respiratory chain proteins. Consistent with increased mitochondrial biogenesis, treatment with MoS2 nanoflowers enhanced mitochondrial respiratory capacity and adenosine triphosphate production in multiple mammalian cell types. Taken together, this study reveals that predefined atomic vacancies in MoS2 nanoflowers stimulate mitochondrial function by upregulating the expression of genes required for mitochondrial biogenesis.
    DOI:  https://doi.org/10.1038/s41467-024-52276-8
  13. Cancer Res. 2024 Sep 17.
    mLumiOpto is a Mitochondrial-Targeted Gene Therapy for Treating Cancer.
    Kai Chen, Patrick Ernst, Anusua Sarkar, Seulhee Kim, Yingnan Si, Tanvi Varadkar, Matthew D Ringel, Xiaoguang Liu, Lufang Zhou.
      Mitochondria are important in various aspects of cancer development and progression. Targeting mitochondria in cancer cells holds great therapeutic promise, yet current strategies to specifically and effectively destroy cancer mitochondria in vivo are limited. Here, we developed mLumiOpto, an innovative mitochondrial-targeted luminoptogenetics gene therapy designed to directly disrupt the inner mitochondrial membrane (IMM) potential and induce cancer cell death. The therapeutic approach included synthesis of a blue light-gated cationic channelrhodopsin (CoChR) in the IMM and co-expression of a blue bioluminescence-emitting nanoluciferase (NLuc) in the cytosol of the same cells. The mLumiOpto genes were selectively delivered to cancer cells in vivo by an adeno-associated virus (AAV) carrying a cancer-specific promoter or cancer-targeted monoclonal antibody-tagged exosome-associated AAV (mAb-Exo-AAV). Induction with NLuc luciferin elicited robust endogenous bioluminescence, which activated CoChR, triggering cancer cell mitochondrial depolarization and subsequent cell death. Importantly, mLumiOpto demonstrated remarkable efficacy in reducing tumor burden and killing tumor cells in glioblastoma and triple-negative breast cancer xenograft mouse models. Furthermore, the approach induced an anti-tumor immune response, increasing infiltration of dendritic cells and CD8+ T cells in the tumor microenvironment. These findings establish mLumiOpto as a promising therapeutic strategy by targeting cancer cell mitochondria in vivo.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-0984
  14. Nat Commun. 2024 Sep 17. 15(1): 8166
    Metabolic interdependencies in thermophilic communities are revealed using co-occurrence and complementarity networks.
    Xi Peng, Shang Wang, Miaoxiao Wang, Kai Feng, Qing He, Xingsheng Yang, Weiguo Hou, Fangru Li, Yuxiang Zhao, Baolan Hu, Xiao Zou, Ye Deng.
      Microbial communities exhibit intricate interactions underpinned by metabolic dependencies. To elucidate these dependencies, we present a workflow utilizing random matrix theory on metagenome-assembled genomes to construct co-occurrence and metabolic complementarity networks. We apply this approach to a temperature gradient hot spring, unraveling the interplay between thermal stress and metabolic cooperation. Our analysis reveals an increase in the frequency of metabolic interactions with rising temperatures. Amino acids, coenzyme A derivatives, and carbohydrates emerge as key exchange metabolites, forming the foundation for syntrophic dependencies, in which commensalistic interactions take a greater proportion than mutualistic ones. These metabolic exchanges are most prevalent between phylogenetically distant species, especially archaea-bacteria collaborations, as a crucial adaptation to harsh environments. Furthermore, we identify a significant positive correlation between basal metabolite exchange and genome size disparity, potentially signifying a means for streamlined genomes to leverage cooperation with metabolically richer partners. This phenomenon is also confirmed by another composting system which has a similar wide range of temperature fluctuations. Our workflow provides a feasible way to decipher the metabolic complementarity mechanisms underlying microbial interactions, and our findings suggested environmental stress regulates the cooperative strategies of thermophiles, while these dependencies have been potentially hardwired into their genomes during co-evolutions.
    DOI:  https://doi.org/10.1038/s41467-024-52532-x
  15. Proc Natl Acad Sci U S A. 2024 Sep 24. 121(39): e2321212121
    Activation induces shift in nutrient utilization that differentially impacts cell functions in human neutrophils.
    Emily C Britt, Xin Qing, James A Votava, Jorgo Lika, Andrew S Wagner, Simone Shen, Nicholas L Arp, Hamidullah Khan, Stefan M Schieke, Christopher D Fletcher, Anna Huttenlocher, Jing Fan.
      Neutrophils utilize a variety of metabolic sources to support their crucial functions as the first responders in innate immunity. Here, through in vivo and ex vivo isotopic tracing, we examined the contributions of different nutrients to neutrophil metabolism under specific conditions. Human peripheral blood neutrophils, in contrast to a neutrophil-like cell line, rely on glycogen storage as a major metabolic source under resting state but rapidly switch to primarily using extracellular glucose upon activation with various stimuli. This shift is driven by a substantial increase in glucose uptake, enabled by rapidly increased GLUT1 on cell membrane, that dominates the simultaneous increase in gross glycogen cycling capacity. Shifts in nutrient utilization impact neutrophil functions in a function-specific manner: oxidative burst depends on glucose utilization, whereas NETosis and phagocytosis can be flexibly supported by either glucose or glycogen, and neutrophil migration and fungal control are enhanced by the shift from glycogen utilization to glucose utilization. This work provides a quantitative and dynamic understanding of fundamental features in neutrophil metabolism and elucidates how metabolic remodeling shapes neutrophil functions, which has broad health relevance.
    Keywords:  immunometabolism; neutrophil; nutrient dependence; nutrient preference switch
    DOI:  https://doi.org/10.1073/pnas.2321212121
  16. Comp Biochem Physiol Part D Genomics Proteomics. 2024 Sep 10. pii: S1744-117X(24)00136-9. [Epub ahead of print]52 101323
    Proteogenomic reconstruction of organ-specific metabolic networks in an environmental sentinel species, the amphipod Gammarus fossarum.
    Natacha Koenig, Patrice Baa-Puyoulet, Amélie Lafont, Isis Lorenzo-Colina, Vincent Navratil, Maxime Leprêtre, Kevin Sugier, Nicolas Delorme, Laura Garnero, Hervé Queau, Jean-Charles Gaillard, Mélodie Kielbasa, Sophie Ayciriex, Federica Calevro, Arnaud Chaumot, Hubert Charles, Jean Armengaud, Olivier Geffard, Davide Degli Esposti.
      Metabolic pathways are affected by the impacts of environmental contaminants underlying a large variability of toxic effects across different species. However, the systematic reconstruction of metabolic pathways remains limited in environmental sentinel species due to the lack of available genomic data in many taxa of animal diversity. In this study we used a multi-omics approach to reconstruct the most comprehensive map of metabolic pathways for a crustacean model in biomonitoring, the amphipod Gammarus fossarum in order to improve the knowledge of the metabolism of this sentinel species. We revisited the assembly of RNA-seq data by de novo approaches to reduce RNA contaminants and transcript redundancy. We also acquired extensive mass spectrometry shotgun proteomic data on several organs from a reference population of G. fossarum males and females to identify organ-specific metabolic profiles. The G. fossarum metabolic pathway reconstruction (available through the metabolic database GamfoCyc) was performed by adapting the genomic tool CycADS and we identified 377 pathways representing 7630 annotated enzymes, 2610 enzymatic reactions and the expression of 858 enzymes was experimentally validated by proteomics. To our knowledge, our analysis provides for the first time a systematic metabolic pathway reconstruction and the proteome profiles of these pathways at the organ level in this sentinel species. As an example, we show an elevated abundance in enzymes involved in ATP biosynthesis and fatty acid beta-oxidation indicative of the high-energy requirement of the gills, or the key anabolic and detoxification role of the hepatopancreatic caeca, as exemplified by the specific expression of the retinoid biosynthetic pathways and glutathione synthesis. In conclusion, the multi-omics data integration performed in this study provides new resources to investigate metabolic processes in crustacean amphipods and their role in mediating the effects of environmental contaminant exposures in sentinel species. SYNOPSIS: This study provide the first evidence that it is possible to combine multiple omics data to exhaustively describe the metabolic network of a model species in ecotoxicology, Gammarus fossarum, for which a reference genome is not yet available.
    Keywords:  Amphipods; Gammarus fossarum; Metabolic network; Multi-omics integration; Proteomics; Shotgun proteomics; Transcriptomics
    DOI:  https://doi.org/10.1016/j.cbd.2024.101323
  17. Elife. 2024 Sep 17. pii: RP98834. [Epub ahead of print]13
    Bidirectional dysregulation of synaptic glutamate signaling after transient metabolic failure.
    Stefan Passlick, Ghanim Ullah, Christian Henneberger.
      Ischemia leads to a severe dysregulation of glutamate homeostasis and excitotoxic cell damage in the brain. Shorter episodes of energy depletion, for instance during peri-infarct depolarizations, can also acutely perturb glutamate signaling. It is less clear if such episodes of metabolic failure also have persistent effects on glutamate signaling and how the relevant mechanisms such as glutamate release and uptake are differentially affected. We modeled acute and transient metabolic failure by using a chemical ischemia protocol and analyzed its effect on glutamatergic synaptic transmission and extracellular glutamate signals by electrophysiology and multiphoton imaging, respectively, in the mouse hippocampus. Our experiments uncover a duration-dependent bidirectional dysregulation of glutamate signaling. Whereas short chemical ischemia induces a lasting potentiation of presynaptic glutamate release and synaptic transmission, longer episodes result in a persistent postsynaptic failure of synaptic transmission. We also observed unexpected differences in the vulnerability of the investigated cellular mechanisms. Axonal action potential firing and glutamate uptake were surprisingly resilient compared to postsynaptic cells, which overall were most vulnerable to acute and transient metabolic stress. We conclude that short perturbations of energy supply lead to a lasting potentiation of synaptic glutamate release, which may increase glutamate excitotoxicity well beyond the metabolic incident.
    Keywords:  glutamate release; glutamate uptake; ischemia; metabolic failure; mouse; neuroscience; stroke; synaptic transmission
    DOI:  https://doi.org/10.7554/eLife.98834
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