bims-celmim Biomed News
on Cellular and mitochondrial metabolism
Issue of 2024‒07‒28
24 papers selected by
Marc Segarra Mondejar
  1. Extracellular Flux Assay (Seahorse Assay): Diverse Applications in Metabolic Research Across Biological Disciplines.
  2. Ring around the mitochondria.
  3. Phospholipid biosynthesis modulates nucleotide metabolism and reductive capacity.
  4. Metabolism and HSC fate: what NADPH is made for.
  5. 100 years of the Warburg effect: A cancer metabolism endeavor.
  6. Targeting Cellular Adaptive Responses to Glutaminolysis Perturbation for Cancer Therapy.
  7. Enhancing mitochondrial pyruvate metabolism ameliorates ischemic reperfusion injury in the heart.
  8. 13C Tracer Analysis and Metabolomics in Dormant Cancer Cells.
  9. An NAD+-dependent metabolic checkpoint regulates hematopoietic stem cell activation and aging.
  10. Sweetening mitochondria: Hexokinase shields mitochondria from fission when glucose is low.
  11. Multi-omic analysis of bat versus human fibroblasts reveals altered central metabolism.
  12. Spatially and temporally probing distinctive glycerophospholipid alterations in Alzheimer's disease mouse brain via high-resolution ion mobility-enabled sn-position resolved lipidomics.
  13. SLC7A11: the Achilles heel of tumor?
  14. The HuMet Repository: Watching human metabolism at work.
  15. Effects of lactate dehydrogenase A and GLUT1 inhibition on human endothelial cell migration in relation to their intracellular nucleotide pool.
  16. ER calcium depletion as a key driver for impaired ER-to-mitochondria calcium transfer and mitochondrial dysfunction in Wolfram syndrome.
  17. Genome-scale community modelling elucidates the metabolic interaction in Indian type-2 diabetic gut microbiota.
  18. Metabolic heterogeneity in humans.
  19. The AKT2/SIRT5/TFEB pathway as a potential therapeutic target in non-neovascular AMD.
  20. Therapeutic resurgence of 6-diazo-5-oxo-l-norleucine (DON) through tissue-targeted prodrugs.
  21. Complex roles for mitochondrial complexes in microglia.
  22. From nets to networks: tools for deciphering phytoplankton metabolic interactions within communities and their global significance.
  23. Intramuscular administration of fractalkine modulates mitochondrial properties and promotes fast glycolytic phenotype.
  24. Spatial molecular profiling of mixed invasive ductal and lobular breast cancers reveals heterogeneity in intrinsic molecular subtypes, oncogenic signatures, and mutations.
  1. Mol Cells. 2024 Jul 18. pii: S1016-8478(24)00120-1. [Epub ahead of print] 100095
    Extracellular Flux Assay (Seahorse Assay): Diverse Applications in Metabolic Research Across Biological Disciplines.
    Inhwan Yoo, Ihyeon Ahn, Jihyeon Lee, Namgyu Lee.
      Metabolic networks are fundamental to cellular processes, driving energy production, biosynthesis, redox regulation, and cellular signaling. Recent advancements in metabolic research tools have provided unprecedented insights into cellular metabolism. Among these tools, the extracellular flux analyzer stands out for its real-time measurement of key metabolic parameters: glycolysis, mitochondrial respiration, and fatty acid oxidation (FAO), leading to its widespread use. This review provides a comprehensive summary of the basic principles and workflow of the extracellular flux assay (the Seahorse assay) and its diverse applications. We highlight the assay's versatility across various biological models, including cancer cells, immunocytes, C. elegans, tissues, isolated mitochondria, and 3D structures like organoids, and summarize key considerations for using extracellular flux assay in these models. Additionally, we discuss the limitations of the Seahorse assay and propose future directions for its development. This review aims to enhance the understanding of extracellular flux assay and its significance in biological studies.
    Keywords:  ETC; Extracellular Flux Assay; Glycolysis; Metabolism; Mitochondria; Seahorse assay
    DOI:  https://doi.org/10.1016/j.mocell.2024.100095
  2. Sci Signal. 2024 Jul 23. 17(846): eadr8314
    Ring around the mitochondria.
    Wei Wong.
      Hexokinase 1 forms constricting rings around mitochondria that prevent fission induced by energy stress.
    DOI:  https://doi.org/10.1126/scisignal.adr8314
  3. Nat Chem Biol. 2024 Jul 26.
    Phospholipid biosynthesis modulates nucleotide metabolism and reductive capacity.
    Yibing Zhu, Xiaomeng Tong, Jingyuan Xue, Hong Qiu, Dan Zhang, Dao-Qiong Zheng, Zong-Cai Tu, Cunqi Ye.
      Phospholipid and nucleotide syntheses are fundamental metabolic processes in eukaryotic organisms, with their dysregulation implicated in various disease states. Despite their importance, the interplay between these pathways remains poorly understood. Using genetic and metabolic analyses in Saccharomyces cerevisiae, we elucidate how cytidine triphosphate usage in the Kennedy pathway for phospholipid synthesis influences nucleotide metabolism and redox balance. We find that deficiencies in the Kennedy pathway limit nucleotide salvage, prompting compensatory activation of de novo nucleotide synthesis and the pentose phosphate pathway. This metabolic shift enhances the production of antioxidants such as NADPH and glutathione. Moreover, we observe that the Kennedy pathway for phospholipid synthesis is inhibited during replicative aging, indicating its role in antioxidative defense as an adaptive mechanism in aged cells. Our findings highlight the critical role of phospholipid synthesis pathway choice in the integrative regulation of nucleotide metabolism, redox balance and membrane properties for cellular defense.
    DOI:  https://doi.org/10.1038/s41589-024-01689-z
  4. Trends Cell Biol. 2024 Jul 24. pii: S0962-8924(24)00141-7. [Epub ahead of print]
    Metabolism and HSC fate: what NADPH is made for.
    Claudia Morganti, Massimo Bonora, Keisuke Ito.
      Mitochondrial metabolism plays a central role in the regulation of hematopoietic stem cell (HSC) biology. Mitochondrial fatty acid oxidation (FAO) is pivotal in controlling HSC self-renewal and differentiation. Herein, we discuss recent evidence suggesting that NADPH generated in the mitochondria can influence the fate of HSCs. Although NADPH has multiple functions, HSCs show high levels of NADPH that are preferentially used for cholesterol biosynthesis. Endogenous cholesterol supports the biogenesis of extracellular vesicles (EVs), which are essential for maintaining HSC properties. We also highlight the significance of EVs in hematopoiesis through autocrine signaling. Elucidating the mitochondrial NADPH-cholesterol axis as part of the metabolic requirements of healthy HSCs will facilitate the development of new therapies for hematological disorders.
    Keywords:  FAO; HSC self-renewal; cholesterol; exosome; hematopoiesis; mitochondrial metabolism
    DOI:  https://doi.org/10.1016/j.tcb.2024.07.003
  5. Cell. 2024 Jul 25. pii: S0092-8674(24)00700-1. [Epub ahead of print]187(15): 3824-3828
    100 years of the Warburg effect: A cancer metabolism endeavor.
    Sarah-Maria Fendt.
      If you are a scientist and you only know one thing about tumor metabolism, it's likely the Warburg effect. But who was Otto Warburg, and how did his discoveries regarding the metabolism of tumors shape our current thinking about the metabolic needs of cancer cells?
    DOI:  https://doi.org/10.1016/j.cell.2024.06.026
  6. Mol Cells. 2024 Jul 20. pii: S1016-8478(24)00121-3. [Epub ahead of print] 100096
    Targeting Cellular Adaptive Responses to Glutaminolysis Perturbation for Cancer Therapy.
    Minjoong Kim, Sunsook Hwang, Seung Min Jeong.
      Metabolic aberrations, notably deviations in glutamine metabolism, are crucial in the oncogenic process, offering vital resources for the unlimited proliferation and enhanced survival capabilities of cancer cells. The dependency of malignant cells on glutamine metabolism has led to the proposition of targeted therapeutic strategies. However, the capability of cancer cells to initiate adaptive responses undermines the efficacy of these therapeutic interventions. This review meticulously examines the multifaceted adaptive mechanisms that cancer cells deploy to sustain survival and growth following the disruption of glutamine metabolism. Emphasis is placed on the roles of transcription factors, alterations in metabolic pathways, the mTORC1 signaling axis, autophagy, macropinocytosis, nucleotide biosynthesis, and the scavenging of reactive oxygen species. Thus, the delineation and subsequent targeting of these adaptive responses in the context of therapies aimed at glutamine metabolism offer a promising avenue for circumventing drug resistance in cancer treatment.
    Keywords:  adaptive response; cancer therapy; glutamine metabolism
    DOI:  https://doi.org/10.1016/j.mocell.2024.100096
  7. JCI Insight. 2024 Jul 25. pii: e180906. [Epub ahead of print]
    Enhancing mitochondrial pyruvate metabolism ameliorates ischemic reperfusion injury in the heart.
    Joseph R Visker, Ahmad A Cluntun, Jesse N Velasco-Silva, David R Eberhardt, Luis Cedeno-Rosario, Thirupura S Shankar, Rana Hamouche, Jing Ling, Hyoin Kwak, J Yanni Hillas, Ian Aist, Eleni Tseliou, Sutip Navankasattusas, Dipayan Chaudhuri, Gregory S Ducker, Stavros G Drakos, Jared Rutter.
      The clinical therapy for treating acute myocardial infarction is primary percutaneous coronary intervention (PPCI). PPCI is effective at reperfusing the heart, however the rapid re-introduction of blood can cause ischemia-reperfusion (I/R). Reperfusion injury is responsible for up to half of the final myocardial damage, but there are no pharmacological interventions to reduce I/R. We previously demonstrated that inhibiting monocarboxylate transporter 4 (MCT4) and re-directing pyruvate towards oxidation can blunt hypertrophy. We hypothesized this pathway might be important during I/R. Here, we establish that the pyruvate-lactate axis plays a role in determining myocardial salvage following injury. Post-I/R, the mitochondrial pyruvate carrier (MPC), required for pyruvate oxidation, is upregulated in the surviving myocardium. In cardiomyocytes lacking the MPC, there was increased cell death and less salvage after I/R, which was associated with an upregulation of MCT4. To determine the importance of pyruvate oxidation, we inhibited MCT4 with a small-molecule drug (VB124) at reperfusion. This strategy normalized reactive oxygen species (ROS), mitochondrial membrane potential (∆Ψ), and Ca2+, increased pyruvate entry to TCA cycle, increased oxygen consumption, improved myocardial salvage and functional outcomes following I/R. Our data suggests normalizing pyruvate-lactate metabolism by inhibiting MCT4 is a promising therapy to mitigate I/R injury.
    Keywords:  Carbohydrate metabolism; Cardiology; Cardiovascular disease; Metabolism; Mitochondria
    DOI:  https://doi.org/10.1172/jci.insight.180906
  8. Methods Mol Biol. 2024 ;2811 195-206
    13C Tracer Analysis and Metabolomics in Dormant Cancer Cells.
    Patricia Altea-Manzano, Sarah-Maria Fendt, Laura Vera-Ramirez.
      Over the last two decades, major advances in the field of tumor dormancy have been made. Yet, it is not completely understood how dormant disseminated tumor cells survive and transition to a proliferative state to generate a metastatic lesion. On the other hand, metabolic rewiring has been shown to influence metastasis development through the modulation of both intracellular signaling and the crosstalk between metastatic cells and their microenvironment. Thus, studying the metabolic features of dormant disseminated tumor cells has gained importance in understanding the dormancy process. Here, we describe a method to perform metabolomics and 13C tracer analysis in 3D cultures of dormant breast cancer cells.
    Keywords:  13C tracing; 3D cell culture; Cancer; Disseminated tumor cells; Mass spectrometry; Metabolomics; Metastasis; Tumor cell dormancy
    DOI:  https://doi.org/10.1007/978-1-0716-3882-8_15
  9. Nat Aging. 2024 Jul 23.
    An NAD+-dependent metabolic checkpoint regulates hematopoietic stem cell activation and aging.
    Zehan Song, Sang Hee Park, Wei-Chieh Mu, Yufan Feng, Chih-Ling Wang, Yifei Wang, Marine Barthez, Ayane Maruichi, Jiayue Guo, Fanghan Yang, Anita Wong Lin, Kartoosh Heydari, Claudia C S Chini, Eduardo N Chini, Cholsoon Jang, Danica Chen.
      How hematopoietic stem cells (HSCs) maintain metabolic homeostasis to support tissue repair and regeneration throughout the lifespan is elusive. Here, we show that CD38, an NAD+-dependent metabolic enzyme, promotes HSC proliferation by inducing mitochondrial Ca2+ influx and mitochondrial metabolism in young mice. Conversely, aberrant CD38 upregulation during aging is a driver of HSC deterioration in aged mice due to dysregulated NAD+ metabolism and compromised mitochondrial stress management. The mitochondrial calcium uniporter, a mediator of mitochondrial Ca2+ influx, also supports HSC proliferation in young mice yet drives HSC decline in aged mice. Pharmacological inactivation of CD38 reverses HSC aging and the pathophysiological changes of the aging hematopoietic system in aged mice. Together, our study highlights an NAD+ metabolic checkpoint that balances mitochondrial activation to support HSC proliferation and mitochondrial stress management to enhance HSC self-renewal throughout the lifespan, and links aberrant Ca2+ signaling to HSC aging.
    DOI:  https://doi.org/10.1038/s43587-024-00670-8
  10. Mol Cell. 2024 Jul 25. pii: S1097-2765(24)00542-2. [Epub ahead of print]84(14): 2593-2595
    Sweetening mitochondria: Hexokinase shields mitochondria from fission when glucose is low.
    Antigoni Diokmetzidou, Luca Scorrano.
      In this issue of Molecular Cell, Pilic et al.1 show that hexokinase, the first enzyme of glycolysis, forms perimitochondrial rings that prevent mitochondrial fragmentation when ATP levels drop.
    DOI:  https://doi.org/10.1016/j.molcel.2024.06.035
  11. Elife. 2024 Jul 22. pii: e94007. [Epub ahead of print]13
    Multi-omic analysis of bat versus human fibroblasts reveals altered central metabolism.
    N Suhas Jagannathan, Javier Yu Peng Koh, Younghwan Lee, Radoslaw Mikolaj Sobota, Aaron T Irving, Lin-Fa Wang, Yoko Itahana, Koji Itahana, Lisa Tucker-Kellogg.
      Bats have unique characteristics compared to other mammals, including increased longevity and higher resistance to cancer and infectious disease. While previous studies have analyzed the metabolic requirements for flight, it is still unclear how bat metabolism supports these unique features, and no study has integrated metabolomics, transcriptomics, and proteomics to characterize bat metabolism. In this work, we performed a multi-omics data analysis using a computational model of metabolic fluxes to identify fundamental differences in central metabolism between primary lung fibroblast cell lines from the black flying fox fruit bat (Pteropus alecto) and human. Bat cells showed higher expression levels of Complex I components of electron transport chain (ETC), but, remarkably, a lower rate of oxygen consumption. Computational modeling interpreted these results as indicating that Complex II activity may be low or reversed, similar to an ischemic state. An ischemic-like state of bats was also supported by decreased levels of central metabolites and increased ratios of succinate to fumarate in bat cells. Ischemic states tend to produce reactive oxygen species (ROS), which would be incompatible with the longevity of bats. However, bat cells had higher antioxidant reservoirs (higher total glutathione and higher ratio of NADPH to NADP) despite higher mitochondrial ROS levels. In addition, bat cells were more resistant to glucose deprivation and had increased resistance to ferroptosis, one of the characteristics of which is oxidative stress. Thus, our studies revealed distinct differences in the ETC regulation and metabolic stress responses between human and bat cells.
    Keywords:  bat metabolism; cell biology; computational biology; ferroptosis; flux modeling; ischemia; succinate accumulation; systems biology
    DOI:  https://doi.org/10.7554/eLife.94007
  12. Nat Commun. 2024 Jul 24. 15(1): 6252
    Spatially and temporally probing distinctive glycerophospholipid alterations in Alzheimer's disease mouse brain via high-resolution ion mobility-enabled sn-position resolved lipidomics.
    Shuling Xu, Zhijun Zhu, Daniel G Delafield, Michael J Rigby, Gaoyuan Lu, Megan Braun, Luigi Puglielli, Lingjun Li.
      Dysregulated glycerophospholipid (GP) metabolism in the brain is associated with the progression of neurodegenerative diseases including Alzheimer's disease (AD). Routine liquid chromatography-mass spectrometry (LC-MS)-based large-scale lipidomic methods often fail to elucidate subtle yet important structural features such as sn-position, hindering the precise interrogation of GP molecules. Leveraging high-resolution demultiplexing (HRdm) ion mobility spectrometry (IMS), we develop a four-dimensional (4D) lipidomic strategy to resolve GP sn-position isomers. We further construct a comprehensive experimental 4D GP database of 498 GPs identified from the mouse brain and an in-depth extended 4D library of 2500 GPs predicted by machine learning, enabling automated profiling of GPs with detailed acyl chain sn-position assignment. Analyzing three mouse brain regions (hippocampus, cerebellum, and cortex), we successfully identify a total of 592 GPs including 130 pairs of sn-position isomers. Further temporal GPs analysis in the three functional brain regions illustrates their metabolic alterations in AD progression.
    DOI:  https://doi.org/10.1038/s41467-024-50299-9
  13. Front Immunol. 2024 ;15 1438807
    SLC7A11: the Achilles heel of tumor?
    Yulang Jiang, Mingyu Sun.
      The non-natriuretic-dependent glutamate/cystine inverse transporter-system Xc- is composed of two protein subunits, SLC7A11 and SLC3A2, with SLC7A11 serving as the primary functional component responsible for cystine uptake and glutathione biosynthesis. SLC7A11 is implicated in tumor development through its regulation of redox homeostasis, amino acid metabolism, modulation of immune function, and induction of programmed cell death, among other processes relevant to tumorigenesis. In this paper, we summarize the structure and biological functions of SLC7A11, and discuss its potential role in tumor therapy, which provides a new direction for precision and personalized treatment of tumors.
    Keywords:  SLC7A11; cell death; immune; redox homeostasis; tumor metabolism
    DOI:  https://doi.org/10.3389/fimmu.2024.1438807
  14. Cell Rep. 2024 Jul 20. pii: S2211-1247(24)00745-9. [Epub ahead of print]43(8): 114416
    The HuMet Repository: Watching human metabolism at work.
    Patrick Weinisch, Johannes Raffler, Werner Römisch-Margl, Matthias Arnold, Robert P Mohney, Manuela J Rist, Cornelia Prehn, Thomas Skurk, Hans Hauner, Hannelore Daniel, Karsten Suhre, Gabi Kastenmüller.
      Metabolism oscillates between catabolic and anabolic states depending on food intake, exercise, or stresses that change a multitude of metabolic pathways simultaneously. We present the HuMet Repository for exploring dynamic metabolic responses to oral glucose/lipid loads, mixed meals, 36-h fasting, exercise, and cold stress in healthy subjects. Metabolomics data from blood, urine, and breath of 15 young, healthy men at up to 56 time points are integrated and embedded within an interactive web application, enabling researchers with and without computational expertise to search, visualize, analyze, and contextualize the dynamic metabolite profiles of 2,656 metabolites acquired on multiple platforms. With examples, we demonstrate the utility of the resource for research into the dynamics of human metabolism, highlighting differences and similarities in systemic metabolic responses across challenges and the complementarity of metabolomics platforms. The repository, providing a reference for healthy metabolite changes to six standardized physiological challenges, is freely accessible through a web portal.
    Keywords:  CP: Metabolism; dynamic metabolic responses in health; exercise metabolism; metabolic flexibility; metabolomics platform comparison; oral glucose tolerance test; oral lipid tolerance test; postprandial metabolism; prolonged/extended fasting; standardized physiological challenge tests; time-series metabolomics
    DOI:  https://doi.org/10.1016/j.celrep.2024.114416
  15. Nucleosides Nucleotides Nucleic Acids. 2024 Jul 22. 1-9
    Effects of lactate dehydrogenase A and GLUT1 inhibition on human endothelial cell migration in relation to their intracellular nucleotide pool.
    Gabriela Harasim, Marika A Frańczak, Filippo Minutolo, Carlotta Granchi, Elisa Giovannetti, Ewa M Słomińska, Ryszard T Smoleński, Godefridus J Peters.
      The expression of both lactate dehydrogenase A (LDH-A) and glucose transporter type 1 (GLUT1) is high in pancreatic, thoracic and many other types of cancer. GLUT1 is also highly expressed in endothelial cells (EC), that play an important role in tumor metastasis. We investigated the effect of inhibition of LDH-A by NHI-2 and GLUT1 by PGL14 on cellular migration, a hallmark of metastasis, in relation to changes in intracellular purine nucleotide and nicotinamide adenine dinucleotide pools in a human microvascular endothelial cell line (HMEC-1). HMEC-1 were treated with NHI-2 and PGL14 alone or in combination. Cell migration was tested by the wound healing assay. The intracellular purine nucleotides and NAD+/NADH concentrations were measured using Reversed-Phase High Performance Liquid Chromatography (RP-HPLC). Both NHI-2 at 15 µM and 45 µM and PGL14 at 10 µM and 30 µM inhibited migration by 5 to 28% while the combination led to 46% inhibition. The drugs also decreased intracellular nucleotide pools, but only 45 µM NHI-2 altered energy charge and redox status in HMEC-1 cells. Inhibitors of glycolysis attenuated migration and the energy charge of EC and support further development of LDH-A and GLUT1 inhibitors to target cancer aggressiveness and metastasis.
    Keywords:  Lactate dehydrogenase A; cell energy status; glucose transporter type 1; human endothelial cells; malignant cancer; metastasis
    DOI:  https://doi.org/10.1080/15257770.2024.2379321
  16. Nat Commun. 2024 Jul 21. 15(1): 6143
    ER calcium depletion as a key driver for impaired ER-to-mitochondria calcium transfer and mitochondrial dysfunction in Wolfram syndrome.
    Mailis Liiv, Annika Vaarmann, Dzhamilja Safiulina, Vinay Choubey, Ruby Gupta, Malle Kuum, Lucia Janickova, Zuzana Hodurova, Michal Cagalinec, Akbar Zeb, Miriam A Hickey, Yi-Long Huang, Nana Gogichaishvili, Merle Mandel, Mario Plaas, Eero Vasar, Jens Loncke, Tim Vervliet, Ting-Fen Tsai, Geert Bultynck, Vladimir Veksler, Allen Kaasik.
      Wolfram syndrome is a rare genetic disease caused by mutations in the WFS1 or CISD2 gene. A primary defect in Wolfram syndrome involves poor ER Ca2+ handling, but how this disturbance leads to the disease is not known. The current study, performed in primary neurons, the most affected and disease-relevant cells, involving both Wolfram syndrome genes, explains how the disturbed ER Ca2+ handling compromises mitochondrial function and affects neuronal health. Loss of ER Ca2+ content and impaired ER-mitochondrial contact sites in the WFS1- or CISD2-deficient neurons is associated with lower IP3R-mediated Ca2+ transfer from ER to mitochondria and decreased mitochondrial Ca2+ uptake. In turn, reduced mitochondrial Ca2+ content inhibits mitochondrial ATP production leading to an increased NADH/NAD+ ratio. The resulting bioenergetic deficit and reductive stress compromise the health of the neurons. Our work also identifies pharmacological targets and compounds that restore Ca2+ homeostasis, enhance mitochondrial function and improve neuronal health.
    DOI:  https://doi.org/10.1038/s41467-024-50502-x
  17. Sci Rep. 2024 Jul 27. 14(1): 17259
    Genome-scale community modelling elucidates the metabolic interaction in Indian type-2 diabetic gut microbiota.
    Satyajit Beura, Pritam Kundu, Amit Kumar Das, Amit Ghosh.
      Type-2 diabetes (T2D) is a rapidly growing multifactorial metabolic disorder that induces the onset of various diseases in the human body. The compositional and metabolic shift of the gut microbiota is a crucial factor behind T2D. Hence, gaining insight into the metabolic profile of the gut microbiota is essential for revealing their role in regulating the metabolism of T2D patients. Here, we have focused on the genome-scale community metabolic model reconstruction of crucial T2D-associated gut microbes. The model-based analysis of biochemical flux in T2D and healthy gut conditions showed distinct biochemical signatures and diverse metabolic interactions in the microbial community. The metabolic interactions encompass cross-feeding of short-chain fatty acids, amino acids, and vitamins among individual microbes within the community. In T2D conditions, a reduction in the metabolic flux of acetate, butyrate, vitamin B5, and bicarbonate was observed in the microbial community model, which can impact carbohydrate metabolism. The decline in butyrate levels is correlated with both insulin resistance and diminished glucose metabolism in T2D patients. Compared to the healthy gut, an overall reduction in glucose consumption and SCFA production flux was estimated in the T2D gut environment. Moreover, the decreased consumption profiles of branch chain amino acids (BCAAs) and aromatic amino acids (AAAs) in the T2D gut microbiota can be a distinct biomarker for T2D. Hence, the flux-level analysis of the microbial community model can provide insights into the metabolic reprogramming in diabetic gut microbiomes, which may be helpful in personalized therapeutics and diet design against T2D.
    DOI:  https://doi.org/10.1038/s41598-024-63718-0
  18. Cell. 2024 Jul 25. pii: S0092-8674(24)00708-6. [Epub ahead of print]187(15): 3821-3823
    Metabolic heterogeneity in humans.
    Heather Christofk, Christian Metallo, Guanghui Liu, Joshua Rabinowitz, Lauren Sparks, David James.
      Recent advancements in technology, especially the emergence of single-cell technologies, genomic sequencing, metabolomics, and artificial intelligence, have enabled us to understand the distinct metabolic changes in different cell types, tissues, genders, disease states, ages, and populations. Six scientists whose work intersects with metabolism in various capacities tell us about their vision for human metabolic heterogeneity.
    DOI:  https://doi.org/10.1016/j.cell.2024.06.033
  19. Nat Commun. 2024 Jul 21. 15(1): 6150
    The AKT2/SIRT5/TFEB pathway as a potential therapeutic target in non-neovascular AMD.
    Sayan Ghosh, Ruchi Sharma, Sridhar Bammidi, Victoria Koontz, Mihir Nemani, Meysam Yazdankhah, Katarzyna M Kedziora, Donna Beer Stolz, Callen T Wallace, Cheng Yu-Wei, Jonathan Franks, Devika Bose, Peng Shang, Helena M Ambrosino, James R Dutton, Zhaohui Geng, Jair Montford, Jiwon Ryu, Dhivyaa Rajasundaram, Stacey Hose, José-Alain Sahel, Rosa Puertollano, Toren Finkel, J Samuel Zigler, Yuri Sergeev, Simon C Watkins, Eric S Goetzman, Deborah A Ferrington, Miguel Flores-Bellver, Kai Kaarniranta, Akrit Sodhi, Kapil Bharti, James T Handa, Debasish Sinha.
      Non-neovascular or dry age-related macular degeneration (AMD) is a multi-factorial disease with degeneration of the aging retinal-pigmented epithelium (RPE). Lysosomes play a crucial role in RPE health via phagocytosis and autophagy, which are regulated by transcription factor EB/E3 (TFEB/E3). Here, we find that increased AKT2 inhibits PGC-1α to downregulate SIRT5, which we identify as an AKT2 binding partner. Crosstalk between SIRT5 and AKT2 facilitates TFEB-dependent lysosomal function in the RPE. AKT2/SIRT5/TFEB pathway inhibition in the RPE induced lysosome/autophagy signaling abnormalities, disrupted mitochondrial function and induced release of debris contributing to drusen. Accordingly, AKT2 overexpression in the RPE caused a dry AMD-like phenotype in aging Akt2 KI mice, as evident from decline in retinal function. Importantly, we show that induced pluripotent stem cell-derived RPE encoding the major risk variant associated with AMD (complement factor H; CFH Y402H) express increased AKT2, impairing TFEB/TFE3-dependent lysosomal function. Collectively, these findings suggest that targeting the AKT2/SIRT5/TFEB pathway may be an effective therapy to delay the progression of dry AMD.
    DOI:  https://doi.org/10.1038/s41467-024-50500-z
  20. Adv Pharmacol. 2024 ;pii: S1054-3589(24)00014-0. [Epub ahead of print]100 157-180
    Therapeutic resurgence of 6-diazo-5-oxo-l-norleucine (DON) through tissue-targeted prodrugs.
    Kateřina Novotná, Lukáš Tenora, Barbara S Slusher, Rana Rais.
      The recognition that rapidly proliferating cancer cells rely heavily on glutamine for their survival and growth has renewed interest in the development of glutamine antagonists for cancer therapy. Glutamine plays a pivotal role as a carbon source for synthesizing lipids and metabolites through the TCA cycle, as well as a nitrogen source for synthesis of amino acid and nucleotides. Numerous studies have explored the significance of glutamine metabolism in cancer, providing a robust rationale for targeting this metabolic pathway in cancer treatment. The glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON) has been explored as an anticancer therapeutic for nearly six decades. Initial investigations revealed remarkable efficacy in preclinical studies and promising outcomes in early clinical trials. However, further advancement of DON was hindered due to dose-limiting gastrointestinal (GI) toxicities as the GI system is highly dependent on glutamine for regulating growth and repair. In an effort to repurpose DON and mitigate gastrointestinal (GI) toxicity concerns, prodrug strategies were utilized. These strategies aimed to enhance the delivery of DON to specific target tissues, such as tumors and the central nervous system (CNS), while sparing DON delivery to normal tissues, particularly the GI tract. When administered at low daily doses, optimized for metabolic inhibition, these prodrugs exhibit remarkable effectiveness without inducing significant toxicity to normal tissues. This approach holds promise for overcoming past challenges associated with DON, offering an avenue for its successful utilization in cancer treatment.
    Keywords:  6-Diazo-5-oxo-L-norleucine (DON); Gastrointestinal; Glutamine addiction; Glutamine antagonist; Metabolic inhibition; Prodrug
    DOI:  https://doi.org/10.1016/bs.apha.2024.04.003
  21. Nat Metab. 2024 Jul 24.
    Complex roles for mitochondrial complexes in microglia.
    Rosa C Paolicelli, Stefano Pluchino.
      
    DOI:  https://doi.org/10.1038/s42255-024-01095-8
  22. Philos Trans R Soc Lond B Biol Sci. 2024 Sep 09. 379(1909): 20230172
    From nets to networks: tools for deciphering phytoplankton metabolic interactions within communities and their global significance.
    Charlotte Nef, Juan José Pierella Karlusich, Chris Bowler.
      Our oceans are populated with a wide diversity of planktonic organisms that form complex dynamic communities at the base of marine trophic networks. Within such communities are phytoplankton, unicellular photosynthetic taxa that provide an estimated half of global primary production and support biogeochemical cycles, along with other essential ecosystem services. One of the major challenges for microbial ecologists has been to try to make sense of this complexity. While phytoplankton distributions can be well explained by abiotic factors such as temperature and nutrient availability, there is increasing evidence that their ecological roles are tightly linked to their metabolic interactions with other plankton members through complex mechanisms (e.g. competition and symbiosis). Therefore, unravelling phytoplankton metabolic interactions is the key for inferring their dependency on, or antagonism with, other taxa and better integrating them into the context of carbon and nutrient fluxes in marine trophic networks. In this review, we attempt to summarize the current knowledge brought by ecophysiology, organismal imaging, in silico predictions and co-occurrence networks using 'omics data, highlighting successful combinations of approaches that may be helpful for future investigations of phytoplankton metabolic interactions within their complex communities.This article is part of the theme issue 'Connected interactions: enriching food web research by spatial and social interactions'.
    Keywords:  Tara oceans; biotic interactions; metagenomics; phytoplankton; symbioses
    DOI:  https://doi.org/10.1098/rstb.2023.0172
  23. Biofactors. 2024 Jul 25.
    Intramuscular administration of fractalkine modulates mitochondrial properties and promotes fast glycolytic phenotype.
    Gourabamani Swalsingh, Punyadhara Pani, Unmod Senapati, Bijayashree Sahu, Sunil Pani, Benudhara Pati, Subhasmita Rout, Naresh C Bal.
      A newly categorized myokine called fractalkine (CX3CL1) has been associated with divergent conditions such as obesity, tissue inflammation, and exercise. CX3CL1 works through specific membrane-bound receptors (CX3CR1) found in various tissues including skeletal muscles. Studies indicate CX3CL1 induces muscles to uptake energy substrates thereby improving glucose utilization and countering diabetes. Here, we tested if the administration of purified CX3CL1 directly into mice skeletal muscles affects its histoarchitecture, mitochondrial activity, and expression of metabolic proteins. We analyzed four muscles: two upper-limb (quadriceps, hamstrings) and two lower-limb (tibialis anterior, gastrocnemius), contralateral leg muscles were taken as controls. The effects of CX3CL1 treatment on histoarchitecture, mitochondrial activity, and expression of metabolic proteins in muscles were characterized. We used histochemical staining succinate dehydrogenase (SDH)/cytochrome c oxidase (COX), myosin ATPase, alkaline phosphatase (ALP) to evaluate the mitochondrial activity, fiber types, and vascularization in the muscles, respectively. Western blotting was used to evaluate the expression of proteins associated with mitochondrial metabolism (OXPHOS), glycolysis, and vascularization. Overall, this study indicates CX3CL1 primarily modulates mitochondrial metabolism and shifts substrate preference toward glucose in the skeletal muscle. Evidence also supports that CX3CL1 stimulates the relative composition of fast fiber types, influencing selection of energy substrates in the skeletal muscle.
    Keywords:  CX3CL1; OXPHOS; fiber types; mitochondria; myokine; skeletal muscle; vascularization
    DOI:  https://doi.org/10.1002/biof.2092
  24. Proc Natl Acad Sci U S A. 2024 Jul 30. 121(31): e2322068121
    Spatial molecular profiling of mixed invasive ductal and lobular breast cancers reveals heterogeneity in intrinsic molecular subtypes, oncogenic signatures, and mutations.
    Osama Shiraz Shah, Azadeh Nasrazadani, Julia Foldi, Jennifer M Atkinson, Celina G Kleer, Priscilla F McAuliffe, Tyler J Johnston, Wayne Stallaert, Edaise M da Silva, Pier Selenica, Higinio Dopeso, Fresia Pareja, Diana Mandelker, Britta Weigelt, Jorge S Reis-Filho, Rohit Bhargava, Peter C Lucas, Adrian V Lee, Steffi Oesterreich.
      Mixed invasive ductal and lobular carcinoma (MDLC) is a rare histologic subtype of breast cancer displaying both E-cadherin positive ductal and E-cadherin negative lobular morphologies within the same tumor, posing challenges with regard to anticipated clinical management. It remains unclear whether these distinct morphologies also have distinct biology and risk of recurrence. Our spatially resolved transcriptomic, genomic, and single-cell profiling revealed clinically significant differences between ductal and lobular tumor regions including distinct intrinsic subtype heterogeneity - e.g., MDLC with triple-negative breast cancer (TNBC) or basal ductal and estrogen receptor positive (ER+) luminal lobular regions, distinct enrichment of cell cycle arrest/senescence and oncogenic (ER and MYC) signatures, genetic and epigenetic CDH1 inactivation in lobular but not ductal regions, and single-cell ductal and lobular subpopulations with unique oncogenic signatures further highlighting intraregional heterogeneity. Altogether, we demonstrated that the intratumoral morphological/histological heterogeneity within MDLC is underpinned by intrinsic subtype and oncogenic heterogeneity which may result in prognostic uncertainty and therapeutic dilemma.
    Keywords:  breast cancer; mixed ductal–lobular carcinoma; single cell omics; spatial transcriptomics; tumor heterogeneity
    DOI:  https://doi.org/10.1073/pnas.2322068121
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