bims-celmim Biomed News
on Cellular and mitochondrial metabolism
Issue of 2024–05–12
twenty-two papers selected by
Marc Segarra Mondejar
  1. Lipid droplets and neurodegeneration.
  2. Giant organelle vesicles to uncover intracellular membrane mechanics and plasticity.
  3. Targeted inhibition of branched-chain amino acid metabolism drives apoptosis of glioblastoma by facilitating ubiquitin degradation of Mfn2 and oxidative stress.
  4. FGFR inhibition blocks NF-ĸB-dependent glucose metabolism and confers metabolic vulnerabilities in cholangiocarcinoma.
  5. Spatial mapping of hepatic ER and mitochondria architecture reveals zonated remodeling in fasting and obesity.
  6. A Pipeline for Dynamic Analysis of Mitochondrial Content in Developing T Cells: Bridging the Gap Between High-Throughput Flow Cytometry and Single-Cell Microscopy Analysis.
  7. Uncovering novel therapeutic targets in glucose, nucleotides and lipids metabolism during cancer and neurological diseases.
  8. An interphase actin wave promotes mitochondrial content mixing and organelle homeostasis.
  9. Glucose starvation causes ferroptosis-mediated lysosomal dysfunction.
  10. Simultaneous targeting of peripheral and brain tumors with a therapeutic nanoparticle to disrupt metabolic adaptability at both sites.
  11. Intermittent fasting influences immunity and metabolism.
  12. Out of the Dark, into the Light: Metabolic Fluorescent Labeling of Nucleic Acids.
  13. Crosstalk between DNA Damage Repair and Metabolic Regulation in Hematopoietic Stem Cells.
  14. A prismatic view of the epigenetic-metabolic regulatory axis in breast cancer therapy resistance.
  15. GLUT1 overexpression enhances CAR T cell metabolic fitness and anti-tumor efficacy.
  16. Characterizing human postprandial metabolic response using multiway data analysis.
  17. The glucose transporter GLUT12, a new actor in obesity and cancer.
  18. Large enrichments in fatty acid 2H/1H ratios distinguish respiration from aerobic fermentation in yeast Saccharomyces cerevisiae.
  19. Golgi defect as a major contributor to lysosomal dysfunction.
  20. Bottom-up parameterization of enzyme rate constants: Reconciling inconsistent data.
  21. Targeting metabolic circuitry to supercharge CD8+ T cell antitumor responses.
  22. Identification of a family of species-selective complex I inhibitors as potential anthelmintics.
  1. Neuroscience. 2024 May 06. pii: S0306-4522(24)00173-8. [Epub ahead of print]
    Lipid droplets and neurodegeneration.
    Keya Mallick, Shuchismita Paul, Sayani Banerjee, Sugato Banerjee.
      Energy metabolism in the brain has been considered one of the critical research areas of neuroscience for ages. One of the most vital parts of brain metabolism cascades is lipid metabolism, and fatty acid plays a crucial role in this process. The fatty acid breakdown process in mitochondria undergoes through a conserved pathway known as β-oxidation where acetyl-CoA and shorter fatty acid chains are produced along with a significant amount of energy molecule. Further, the complete breakdown of fatty acids occurs when they enter the mitochondrial oxidative phosphorylation. Cells store energy as neutral lipids in organelles known as Lipid Droplets (LDs) to prepare for variations in the availability of nutrients. Fatty acids are liberated by lipid droplets and are transported to various cellular compartments for membrane biogenesis or as an energy source. Current research shows that LDs are important in inflammation, metabolic illness, and cellular communication. Lipid droplet biology in peripheral organs like the liver and heart has been well investigated, while the brain's LDs have received less attention. Recently, there has been increased awareness of the existence and role of these dynamic organelles in the central nervous system, mainly connected to neurodegeneration. In this review, we discussed the role of beta-oxidation and lipid droplet formation in the oxidative phosphorylation process, which directly affects neurodegeneration through various pathways.
    Keywords:  Astrocyte; Lipids; Microglia; Mitochondria; Neurodegenerative disorders; Neuron
    DOI:  https://doi.org/10.1016/j.neuroscience.2024.04.014
  2. Nat Commun. 2024 May 04. 15(1): 3767
    Giant organelle vesicles to uncover intracellular membrane mechanics and plasticity.
    Alexandre Santinho, Maxime Carpentier, Julio Lopes Sampaio, Mohyeddine Omrane, Abdou Rachid Thiam.
      Tools for accessing and studying organelles remain underdeveloped. Here, we present a method by which giant organelle vesicles (GOVs) are generated by submitting cells to a hypotonic medium followed by plasma membrane breakage. By this means, GOVs ranging from 3 to over 10 µm become available for micromanipulation. GOVs are made from organelles such as the endoplasmic reticulum, endosomes, lysosomes and mitochondria, or in contact with one another such as giant mitochondria-associated ER membrane vesicles. We measure the mechanical properties of each organelle-derived GOV and find that they have distinct properties. In GOVs procured from Cos7 cells, for example, bending rigidities tend to increase from the endoplasmic reticulum to the plasma membrane. We also found that the mechanical properties of giant endoplasmic reticulum vesicles (GERVs) vary depending on their interactions with other organelles or the metabolic state of the cell. Lastly, we demonstrate GERVs' biochemical activity through their capacity to synthesize triglycerides and assemble lipid droplets. These findings underscore the potential of GOVs as valuable tools for studying the biophysics and biology of organelles.
    DOI:  https://doi.org/10.1038/s41467-024-48086-7
  3. Biochim Biophys Acta Mol Basis Dis. 2024 May 06. pii: S0925-4439(24)00209-6. [Epub ahead of print]1870(5): 167220
    Targeted inhibition of branched-chain amino acid metabolism drives apoptosis of glioblastoma by facilitating ubiquitin degradation of Mfn2 and oxidative stress.
    Zhuo Lu, Gui-Feng Sun, Kai-Yi He, Zhen Zhang, Xin-Hao Han, Xin-Hui Qu, Deng-Feng Wan, Dongyuan Yao, Fang-Fang Tou, Xiao-Jian Han, Tao Wang.
      Glioblastoma is one of the most challenging malignancies with high aggressiveness and invasiveness and its development and progression of glioblastoma highly depends on branched-chain amino acid (BCAA) metabolism. The study aimed to investigate effects of inhibition of BCAA metabolism with cytosolic branched-chain amino acid transaminase (BCATc) Inhibitor 2 on glioblastoma, elucidate its underlying mechanisms, and explore therapeutic potential of targeting BCAA metabolism. The expression of BCATc was upregulated in glioblastoma and BCATc Inhibitor 2 precipitated apoptosis both in vivo and in vitro with the activation of Bax/Bcl2/Caspase-3/Caspase-9 axis. In addition, BCATc Inhibitor 2 promoted K63-linkage ubiquitination of mitofusin 2 (Mfn2), which subsequently caused lysosomal degradation of Mfn2, and then oxidative stress, mitochondrial fission and loss of mitochondrial membrane potential. Furthermore, BCATc Inhibitor 2 treatment resulted in metabolic reprogramming, and significant inhibition of expression of ATP5A, UQCRC2, SDHB and COX II, indicative of suppressed oxidative phosphorylation. Moreover, Mfn2 overexpression or scavenging mitochondria-originated reactive oxygen species (ROS) with mito-TEMPO ameliorated BCATc Inhibitor 2-induced oxidative stress, mitochondrial membrane potential disruption and mitochondrial fission, and abrogated the inhibitory effect of BCATc Inhibitor 2 on glioblastoma cells through PI3K/AKT/mTOR signaling. All of these findings indicate suppression of BCAA metabolism promotes glioblastoma cell apoptosis via disruption of Mfn2-mediated mitochondrial dynamics and inhibition of PI3K/AKT/mTOR pathway, and suggest that BCAA metabolism can be targeted for developing therapeutic agents to treat glioblastoma.
    Keywords:  Apoptosis; BCATc Inhibitor 2; Glioblastoma; Mfn2; Oxidative stress; PI3K/AKT/mTOR signaling
    DOI:  https://doi.org/10.1016/j.bbadis.2024.167220
  4. Nat Commun. 2024 May 07. 15(1): 3805
    FGFR inhibition blocks NF-ĸB-dependent glucose metabolism and confers metabolic vulnerabilities in cholangiocarcinoma.
    Yuanli Zhen, Kai Liu, Lei Shi, Simran Shah, Qin Xu, Haley Ellis, Eranga R Balasooriya, Johannes Kreuzer, Robert Morris, Albert S Baldwin, Dejan Juric, Wilhelm Haas, Nabeel Bardeesy.
      Genomic alterations that activate Fibroblast Growth Factor Receptor 2 (FGFR2) are common in intrahepatic cholangiocarcinoma (ICC) and confer sensitivity to FGFR inhibition. However, the depth and duration of response is often limited. Here, we conduct integrative transcriptomics, metabolomics, and phosphoproteomics analysis of patient-derived models to define pathways downstream of oncogenic FGFR2 signaling that fuel ICC growth and to uncover compensatory mechanisms associated with pathway inhibition. We find that FGFR2-mediated activation of Nuclear factor-κB (NF-κB) maintains a highly glycolytic phenotype. Conversely, FGFR inhibition blocks glucose uptake and glycolysis while inciting adaptive changes, including switching fuel source utilization favoring fatty acid oxidation and increasing mitochondrial fusion and autophagy. Accordingly, FGFR inhibitor efficacy is potentiated by combined mitochondrial targeting, an effect enhanced in xenograft models by intermittent fasting. Thus, we show that oncogenic FGFR2 signaling drives NF-κB-dependent glycolysis in ICC and that metabolic reprogramming in response to FGFR inhibition confers new targetable vulnerabilities.
    DOI:  https://doi.org/10.1038/s41467-024-47514-y
  5. Nat Commun. 2024 May 10. 15(1): 3982
    Spatial mapping of hepatic ER and mitochondria architecture reveals zonated remodeling in fasting and obesity.
    Güneş Parlakgül, Song Pang, Leonardo L Artico, Nina Min, Erika Cagampan, Reyna Villa, Renata L S Goncalves, Grace Yankun Lee, C Shan Xu, Gökhan S Hotamışlıgil, Ana Paula Arruda.
      The hepatocytes within the liver present an immense capacity to adapt to changes in nutrient availability. Here, by using high resolution volume electron microscopy, we map how hepatic subcellular spatial organization is regulated during nutritional fluctuations and as a function of liver zonation. We identify that fasting leads to remodeling of endoplasmic reticulum (ER) architecture in hepatocytes, characterized by the induction of single rough ER sheet around the mitochondria, which becomes larger and flatter. These alterations are enriched in periportal and mid-lobular hepatocytes but not in pericentral hepatocytes. Gain- and loss-of-function in vivo models demonstrate that the Ribosome receptor binding protein1 (RRBP1) is required to enable fasting-induced ER sheet-mitochondria interactions and to regulate hepatic fatty acid oxidation. Endogenous RRBP1 is enriched around periportal and mid-lobular regions of the liver. In obesity, ER-mitochondria interactions are distinct and fasting fails to induce rough ER sheet-mitochondrion interactions. These findings illustrate the importance of a regulated molecular architecture for hepatocyte metabolic flexibility.
    DOI:  https://doi.org/10.1038/s41467-024-48272-7
  6. Methods Mol Biol. 2024 ;2800 167-187
    A Pipeline for Dynamic Analysis of Mitochondrial Content in Developing T Cells: Bridging the Gap Between High-Throughput Flow Cytometry and Single-Cell Microscopy Analysis.
    Vaibhav Dhyani, Anchi S Chann, Lopamudra Giri, Sarah M Russell, Mirren Charnley.
      Analyzing the dynamics of mitochondrial content in developing T cells is crucial for understanding the metabolic state during T cell development. However, monitoring mitochondrial content in real-time needs a balance of cell viability and image resolution. In this chapter, we present experimental protocols for measuring mitochondrial content in developing T cells using three modalities: bulk analysis via flow cytometry, volumetric imaging in laser scanning confocal microscopy, and dynamic live-cell monitoring in spinning disc confocal microscopy. Next, we provide an image segmentation and centroid tracking-based analysis pipeline for automated quantification of a large number of microscopy images. These protocols together offer comprehensive approaches to investigate mitochondrial dynamics in developing T cells, enabling a deeper understanding of their metabolic processes.
    Keywords:  3D imaging; DN3; Density-based spatial clustering of applications with noise (DBSCAN); Image segmentation; MitoView Green; Mitochondria
    DOI:  https://doi.org/10.1007/978-1-0716-3834-7_12
  7. Int J Immunopathol Pharmacol. 2024 Jan-Dec;38:38 3946320241250293
    Uncovering novel therapeutic targets in glucose, nucleotides and lipids metabolism during cancer and neurological diseases.
    Snežana M Jovičić.
       BACKGROUND: Cell metabolism functions without a stop in normal and pathological cells. Different metabolic changes occur in the disease. Cell metabolism influences biochemical and metabolic processes, signaling pathways, and gene regulation. Knowledge regarding disease metabolism is limited.
    OBJECTIVE: The review examines the cell metabolism of glucose, nucleotides, and lipids during homeostatic and pathological conditions of neurotoxicity, neuroimmunological disease, Parkinson's disease, thymoma in myasthenia gravis, and colorectal cancer.
    METHODS: Data collection includes electronic databases, the National Center for Biotechnology Information, and Google Scholar, with several inclusion criteria: cell metabolism, glucose metabolism, nucleotide metabolism, and lipid metabolism in health and disease patients suffering from neurotoxicity, neuroinflammation, Parkinson's disease, thymoma in myasthenia gravis. The initial number of collected and analyzed papers is 250. The final analysis included 150 studies out of 94 selected papers. After the selection process, 62.67% remains useful.
    RESULTS AND CONCLUSION: A literature search shows that signaling molecules are involved in metabolic changes in cells. Differences between cancer and neuroimmunological diseases are present in the result section. Our finding enables insight into novel therapeutic targets and the development of scientific approaches for cancer and neurological disease onset, outcome, progression, and treatment, highlighting the importance of metabolic dysregulation. Current understanding, emerging research technologies and potential therapeutic interventions in metabolic programming is disucussed and highlighted.
    Keywords:  Cell metabolism; Parkinson’s disease; glycose; lipids; neuroinflammation; neurotoxicity; nucleotides; thymoma in myasthenia gravis
    DOI:  https://doi.org/10.1177/03946320241250293
  8. Nat Commun. 2024 May 07. 15(1): 3793
    An interphase actin wave promotes mitochondrial content mixing and organelle homeostasis.
    Stephen M Coscia, Andrew S Moore, Cameron P Thompson, Christian F Tirrito, E Michael Ostap, Erika L F Holzbaur.
      Across the cell cycle, mitochondrial dynamics are regulated by a cycling wave of actin polymerization/depolymerization. In metaphase, this wave induces actin comet tails on mitochondria that propel these organelles to drive spatial mixing, resulting in their equitable inheritance by daughter cells. In contrast, during interphase the cycling actin wave promotes localized mitochondrial fission. Here, we identify the F-actin nucleator/elongator FMNL1 as a positive regulator of the wave. FMNL1-depleted cells exhibit decreased mitochondrial polarization, decreased mitochondrial oxygen consumption, and increased production of reactive oxygen species. Accompanying these changes is a loss of hetero-fusion of wave-fragmented mitochondria. Thus, we propose that the interphase actin wave maintains mitochondrial homeostasis by promoting mitochondrial content mixing. Finally, we investigate the mechanistic basis for the observation that the wave drives mitochondrial motility in metaphase but mitochondrial fission in interphase. Our data indicate that when the force of actin polymerization is resisted by mitochondrial tethering to microtubules, as in interphase, fission results.
    DOI:  https://doi.org/10.1038/s41467-024-48189-1
  9. iScience. 2024 May 17. 27(5): 109735
    Glucose starvation causes ferroptosis-mediated lysosomal dysfunction.
    Kenji Miki, Mikako Yagi, Dongchon Kang, Yuya Kunisaki, Koji Yoshimoto, Takeshi Uchiumi.
      Lysosomes, the hub of metabolic signaling, are associated with various diseases and participate in autophagy by supplying nutrients to cells under nutrient starvation. However, their function and regulation under glucose starvation remain unclear and are studied herein. Under glucose starvation, lysosomal protein expression decreased, leading to the accumulation of damaged lysosomes. Subsequently, cell death occurred via ferroptosis and iron accumulation due to DMT1 degradation. GPX4, a key factor in ferroptosis inhibition located on the outer membrane of lysosomes, accumulated in lysosomes, especially under glucose starvation, to protect cells from ferroptosis. ALDOA, GAPDH, NAMPT, and PGK1 are also located on the outer membrane of lysosomes and participate in lysosomal function. These enzymes did not function effectively under glucose starvation, leading to lysosomal dysfunction and ferroptosis. These findings may facilitate the treatment of lysosomal-related diseases.
    Keywords:  Cell biology; Cellular physiology; Functional aspects of cell biology
    DOI:  https://doi.org/10.1016/j.isci.2024.109735
  10. Proc Natl Acad Sci U S A. 2024 May 14. 121(20): e2318119121
    Simultaneous targeting of peripheral and brain tumors with a therapeutic nanoparticle to disrupt metabolic adaptability at both sites.
    Akash Ashokan, Shrita Sarkar, Mohammad Z Kamran, Bapurao Surnar, Akil A Kalathil, Alexis Spencer, Shanta Dhar.
      Brain metastasis of advanced breast cancer often results in deleterious consequences. Metastases to the brain lead to significant challenges in treatment options, as the blood-brain barrier (BBB) prevents conventional therapy. Thus, we hypothesized that creation of a nanoparticle (NP) that distributes to both primary tumor site and across the BBB for secondary brain tumor can be extremely beneficial. Here, we report a simple targeting strategy to attack both the primary breast and secondary brain tumors utilizing a single NP platform. The nature of these mitochondrion-targeted, BBB-penetrating NPs allow for simultaneous targeting and drug delivery to the hyperpolarized mitochondrial membrane of the extracranial primary tumor site in addition to tumors at the brain. By utilizing a combination of such dual anatomical distributing NPs loaded with therapeutics, we demonstrate a proof-of-concept idea to combat the increased metabolic plasticity of brain metastases by lowering two major energy sources, oxidative phosphorylation (OXPHOS) and glycolysis. By utilizing complementary studies and genomic analyses, we demonstrate the utility of a chemotherapeutic prodrug to decrease OXPHOS and glycolysis by pairing with a NP loaded with pyruvate dehydrogenase kinase 1 inhibitor. Decreasing glycolysis aims to combat the metabolic flexibility of both primary and secondary tumors for therapeutic outcome. We also address the in vivo safety parameters by addressing peripheral neuropathy and neurobehavior outcomes. Our results also demonstrate that this combination therapeutic approach utilizes mitochondrial genome targeting strategy to overcome DNA repair-based chemoresistance mechanisms.
    Keywords:  Sirtuin 3; altered metabolism; chemoresistance; metabolic plasticity
    DOI:  https://doi.org/10.1073/pnas.2318119121
  11. Trends Endocrinol Metab. 2024 May 07. pii: S1043-2760(24)00097-3. [Epub ahead of print]
    Intermittent fasting influences immunity and metabolism.
    Daniel M Marko, Meghan O Conn, Jonathan D Schertzer.
      Intermittent fasting (IF) modifies cell- and tissue-specific immunometabolic responses that dictate metabolic flexibility and inflammation during obesity and type 2 diabetes (T2D). Fasting forces periods of metabolic flexibility and necessitates increased use of different substrates. IF can lower metabolic inflammation and improve glucose metabolism without lowering obesity and can influence time-dependent, compartmentalized changes in immunity. Liver, adipose tissue, skeletal muscle, and immune cells communicate to relay metabolic and immune signals during fasting. Here we review the connections between metabolic and immune cells to explain the divergent effects of IF compared with classic caloric restriction (CR) strategies. We also explore how the immunometabolism of metabolic diseases dictates certain IF outcomes, where the gut microbiota triggers changes in immunity and metabolism during fasting.
    Keywords:  immunity; intermittent fasting; metabolism; obesity
    DOI:  https://doi.org/10.1016/j.tem.2024.04.014
  12. ChemMedChem. 2024 May 07. e202400160
    Out of the Dark, into the Light: Metabolic Fluorescent Labeling of Nucleic Acids.
    Chris Meier, J Iven H Knaack.
      This review outlines recent advances in live-cell imaging techniques for nucleic acids. We describe the evolution of these methods, particularly highlighting the development of metabolic labeling approaches compatible with living systems using fluorescence-based labeling.
    Keywords:  Live Cell Imaging * Metabolic Labeling * Nucleic Acids * iEDDA * Bioorthogonal Labeling
    DOI:  https://doi.org/10.1002/cmdc.202400160
  13. Cells. 2024 Apr 24. pii: 733. [Epub ahead of print]13(9):
    Crosstalk between DNA Damage Repair and Metabolic Regulation in Hematopoietic Stem Cells.
    Jian Xu, Peiwen Fei, Dennis W Simon, Michael J Morowitz, Parinda A Mehta, Wei Du.
      Self-renewal and differentiation are two characteristics of hematopoietic stem cells (HSCs). Under steady physiological conditions, most primitive HSCs remain quiescent in the bone marrow (BM). They respond to different stimuli to refresh the blood system. The transition from quiescence to activation is accompanied by major changes in metabolism, a fundamental cellular process in living organisms that produces or consumes energy. Cellular metabolism is now considered to be a key regulator of HSC maintenance. Interestingly, HSCs possess a distinct metabolic profile with a preference for glycolysis rather than oxidative phosphorylation (OXPHOS) for energy production. Byproducts from the cellular metabolism can also damage DNA. To counteract such insults, mammalian cells have evolved a complex and efficient DNA damage repair (DDR) system to eliminate various DNA lesions and guard genomic stability. Given the enormous regenerative potential coupled with the lifetime persistence of HSCs, tight control of HSC genome stability is essential. The intersection of DDR and the HSC metabolism has recently emerged as an area of intense research interest, unraveling the profound connections between genomic stability and cellular energetics. In this brief review, we delve into the interplay between DDR deficiency and the metabolic reprogramming of HSCs, shedding light on the dynamic relationship that governs the fate and functionality of these remarkable stem cells. Understanding the crosstalk between DDR and the cellular metabolism will open a new avenue of research designed to target these interacting pathways for improving HSC function and treating hematologic disorders.
    Keywords:  DNA damage repair (DDR); Fanconi anemia (FA) pathway; cellular metabolism; hematopoietic stem cells (HSCs)
    DOI:  https://doi.org/10.3390/cells13090733
  14. Oncogene. 2024 May 08.
    A prismatic view of the epigenetic-metabolic regulatory axis in breast cancer therapy resistance.
    Chandrima Das, Apoorva Bhattacharya, Swagata Adhikari, Atanu Mondal, Payel Mondal, Santanu Adhikary, Siddhartha Roy, Kenneth Ramos, Kamlesh K Yadav, John A Tainer, Tej K Pandita.
      Epigenetic regulation established during development to maintain patterns of transcriptional expression and silencing for metabolism and other fundamental cell processes can be reprogrammed in cancer, providing a molecular mechanism for persistent alterations in phenotype. Metabolic deregulation and reprogramming are thus an emerging hallmark of cancer with opportunities for molecular classification as a critical preliminary step for precision therapeutic intervention. Yet, acquisition of therapy resistance against most conventional treatment regimens coupled with tumor relapse, continue to pose unsolved problems for precision healthcare, as exemplified in breast cancer where existing data informs both cancer genotype and phenotype. Furthermore, epigenetic reprograming of the metabolic milieu of cancer cells is among the most crucial determinants of therapeutic resistance and cancer relapse. Importantly, subtype-specific epigenetic-metabolic interplay profoundly affects malignant transformation, resistance to chemotherapy, and response to targeted therapies. In this review, we therefore prismatically dissect interconnected epigenetic and metabolic regulatory pathways and then integrate them into an observable cancer metabolism-therapy-resistance axis that may inform clinical intervention. Optimally coupling genome-wide analysis with an understanding of metabolic elements, epigenetic reprogramming, and their integration by metabolic profiling may decode missing molecular mechanisms at the level of individual tumors. The proposed approach of linking metabolic biochemistry back to genotype, epigenetics, and phenotype for specific tumors and their microenvironment may thus enable successful mechanistic targeting of epigenetic modifiers and oncometabolites despite tumor metabolic heterogeneity.
    DOI:  https://doi.org/10.1038/s41388-024-03054-9
  15. Mol Ther. 2024 May 07. pii: S1525-0016(24)00303-4. [Epub ahead of print]
    GLUT1 overexpression enhances CAR T cell metabolic fitness and anti-tumor efficacy.
    Yuzhe Shi, Ivan S Kotchetkov, Anton Dobrin, Sophie A Hanina, Vinagolu K Rajasekhar, John H Healey, Michel Sadelain.
      The tumor microenvironment presents many obstacles to effective CAR T cell therapy, including glucose competition from tumor and myeloid cells. Using mouse models of acute lymphoblastic leukemia (ALL), renal cell carcinoma (RCC), and glioblastoma (GBM), we show that enforced expression of the glucose transporter GLUT1 enhances anti-tumor efficacy and promotes favorable CAR T cell phenotypes for two clinically relevant CAR designs, 19-28z and IL13Rα2-BBz. In the NALM6 ALL model, 19-28z-GLUT1 promotes Tscm formation and prolongs survival. RNA sequencing of these CAR T cells reveals that overexpression of GLUT1, but not GLUT3, enriches for genes involved in glycolysis, mitochondrial respiration, and memory precursor phenotypes. Extending these data, 19-28z-GLUT1 CAR T cells improve tumor control and response to rechallenge in an RCC patient derived xenograft model. Furthermore, IL13Rα2-BBz CAR T cells overexpressing GLUT1 prolong survival of mice bearing orthotopic GBMs and exhibit decreased exhaustion markers. This novel engineering approach can offer a competitive advantage to CAR T cells in harsh tumor environments where glucose is limiting.
    DOI:  https://doi.org/10.1016/j.ymthe.2024.05.006
  16. Metabolomics. 2024 May 09. 20(3): 50
    Characterizing human postprandial metabolic response using multiway data analysis.
    Shi Yan, Lu Li, David Horner, Parvaneh Ebrahimi, Bo Chawes, Lars O Dragsted, Morten A Rasmussen, Age K Smilde, Evrim Acar.
       INTRODUCTION: Analysis of time-resolved postprandial metabolomics data can improve our understanding of the human metabolism by revealing similarities and differences in postprandial responses of individuals. Traditional data analysis methods often rely on data summaries or univariate approaches focusing on one metabolite at a time.
    OBJECTIVES: Our goal is to provide a comprehensive picture in terms of the changes in the human metabolism in response to a meal challenge test, by revealing static and dynamic markers of phenotypes, i.e., subject stratifications, related clusters of metabolites, and their temporal profiles.
    METHODS: We analyze Nuclear Magnetic Resonance (NMR) spectroscopy measurements of plasma samples collected during a meal challenge test from 299 individuals from the COPSAC2000 cohort using a Nightingale NMR panel at the fasting and postprandial states (15, 30, 60, 90, 120, 150, 240 min). We investigate the postprandial dynamics of the metabolism as reflected in the dynamic behaviour of the measured metabolites. The data is arranged as a three-way array: subjects by metabolites by time. We analyze the fasting state data to reveal static patterns of subject group differences using principal component analysis (PCA), and fasting state-corrected postprandial data using the CANDECOMP/PARAFAC (CP) tensor factorization to reveal dynamic markers of group differences.
    RESULTS: Our analysis reveals dynamic markers consisting of certain metabolite groups and their temporal profiles showing differences among males according to their body mass index (BMI) in response to the meal challenge. We also show that certain lipoproteins relate to the group difference differently in the fasting vs. dynamic state. Furthermore, while similar dynamic patterns are observed in males and females, the BMI-related group difference is observed only in males in the dynamic state.
    CONCLUSION: The CP model is an effective approach to analyze time-resolved postprandial metabolomics data, and provides a compact but a comprehensive summary of the postprandial data revealing replicable and interpretable dynamic markers crucial to advance our understanding of changes in the metabolism in response to a meal challenge.
    Keywords:  CANDECOMP/PARAFAC; Challenge tests; Dynamic metabolomics data; Tensor factorizations
    DOI:  https://doi.org/10.1007/s11306-024-02109-y
  17. J Physiol Biochem. 2024 May 10.
    The glucose transporter GLUT12, a new actor in obesity and cancer.
    Miguel Burgos, Eva Gil-Iturbe, Adrián Idoate-Bayón, Rosa Castilla-Madrigal, Maria J Moreno-Aliaga, M Pilar Lostao.
      Obesity constitutes a global health epidemic which worsens the main leading death causes such as type 2 diabetes, cardiovascular diseases, and cancer. Changes in the metabolism in patients with obesity frequently lead to insulin resistance, along with hyperglycemia, dyslipidemia and low-grade inflammation, favoring a more aggressive tumor microenvironment. One of the hallmarks of cancer is the reprogramming of the energy metabolism, in which tumor cells change oxidative phosphorylation to aerobic glycolysis or "Warburg effect". Aerobic glycolysis is faster than oxidative phosphorylation, but less efficient in terms of ATP production. To obtain sufficient ATP, tumor cells increase glucose uptake by the glucose transporters of the GLUT/SLC2 family. The human glucose transporter GLUT12 was isolated from the breast cancer cell line MCF7. It is expressed in adipose tissue, skeletal muscle and small intestine, where insulin promotes its translocation to the plasma membrane. Moreover, GLUT12 over-expression in mice increases the whole-body insulin sensitivity. Thus, GLUT12 has been proposed as a second insulin-responsive glucose transporter. In obesity, GLUT12 is downregulated and does not respond to insulin. In contrast, GLUT12 is overexpressed in human solid tumors such as breast, prostate, gastric, liver and colon. High glucose concentration, insulin, and hypoxia upregulate GLUT12 both in adipocytes and tumor cells. Inhibition of GLUT12 mediated Warburg effect suppresses proliferation, migration, and invasion of cancer cells and xenografted tumors. This review summarizes the up-to-date information about GLUT12 physiological role and its implication in obesity and cancer, opening new perspectives to consider this transporter as a therapeutic target.
    Keywords:  Cancer; GLUT12; Obesity; Warburg effect
    DOI:  https://doi.org/10.1007/s13105-024-01028-9
  18. Proc Natl Acad Sci U S A. 2024 May 14. 121(20): e2310771121
    Large enrichments in fatty acid 2H/1H ratios distinguish respiration from aerobic fermentation in yeast Saccharomyces cerevisiae.
    Ashley E Maloney, Sebastian H Kopf, Zhaoyue Zhang, Jamie McFarlin, Daniel B Nelson, Andrew L Masterson, Xinning Zhang.
      Shifts in the hydrogen stable isotopic composition (2H/1H ratio) of lipids relative to water (lipid/water 2H-fractionation) at natural abundances reflect different sources of the central cellular reductant, NADPH, in bacteria. Here, we demonstrate that lipid/water 2H-fractionation (2εfattyacid/water) can also constrain the relative importance of key NADPH pathways in eukaryotes. We used the metabolically flexible yeast Saccharomyces cerevisiae, a microbial model for respiratory and fermentative metabolism in industry and medicine, to investigate 2εfattyacid/water. In chemostats, fatty acids from glycerol-respiring cells were >550‰ 2H-enriched compared to those from cells aerobically fermenting sugars via overflow metabolism, a hallmark feature in cancer. Faster growth decreased 2H/1H ratios, particularly in glycerol-respiring cells by 200‰. Variations in the activities and kinetic isotope effects among NADP+-reducing enzymes indicate cytosolic NADPH supply as the primary control on 2εfattyacid/water. Contributions of cytosolic isocitrate dehydrogenase (cIDH) to NAPDH production drive large 2H-enrichments with substrate metabolism (cIDH is absent during fermentation but contributes up to 20 percent NAPDH during respiration) and slower growth on glycerol (11 percent more NADPH from cIDH). Shifts in NADPH demand associated with cellular lipid abundance explain smaller 2εfattyacid/water variations (<30‰) with growth rate during fermentation. Consistent with these results, tests of murine liver cells had 2H-enriched lipids from slower-growing, healthy respiring cells relative to fast-growing, fermenting hepatocellular carcinoma. Our findings point to the broad potential of lipid 2H/1H ratios as a passive natural tracker of eukaryotic metabolism with applications to distinguish health and disease, complementing studies that rely on complex isotope-tracer addition methods.
    Keywords:  NADPH; fractionation; hydrogen isotope; lipids; yeast
    DOI:  https://doi.org/10.1073/pnas.2310771121
  19. Front Cell Dev Biol. 2024 ;12 1386149
    Golgi defect as a major contributor to lysosomal dysfunction.
    Sarah R Akaaboune, Yanzhuang Wang.
      The Golgi apparatus plays a crucial role in lysosome biogenesis and the delivery of lysosomal enzymes, essential for maintaining cellular homeostasis and ensuring cell survival. Deficiencies in Golgi structure and function can profoundly impact lysosomal homeostasis, leading to various lysosomal storage diseases and neurodegenerative disorders. In this review, we highlight the role of the Golgi Reassembly Stacking Proteins (GRASPs) in the formation and function of the Golgi apparatus, emphasizing the current understanding of the association between the Golgi apparatus, lysosomes, and lysosomal storage diseases. Additionally, we discuss how Golgi dysfunction leads to the secretion of lysosomal enzymes. This review aims to serve as a concise resource, offering insights into Golgi structure, function, disease-related defects, and their consequential effects on lysosomal biogenesis and function. By highlighting Golgi defects as an underappreciated contributor to lysosomal dysfunction across various diseases, we aim to enhance comprehension of these intricate cellular processes.
    Keywords:  GRASP55; GRASP65; Golgi; HexA; lysosomal storage diseases; lysosome; neurodegenerative diseases; secretion
    DOI:  https://doi.org/10.3389/fcell.2024.1386149
  20. Metab Eng Commun. 2024 Jun;18 e00234
    Bottom-up parameterization of enzyme rate constants: Reconciling inconsistent data.
    Daniel C Zielinski, Marta R A Matos, James E de Bree, Kevin Glass, Nikolaus Sonnenschein, Bernhard O Palsson.
      Kinetic models of metabolism are promising platforms for studying complex metabolic systems and designing production strains. Given the availability of enzyme kinetic data from historical experiments and machine learning estimation tools, a straightforward modeling approach is to assemble kinetic data enzyme by enzyme until a desired scale is reached. However, this type of 'bottom up' parameterization of kinetic models has been difficult due to a number of issues including gaps in kinetic parameters, the complexity of enzyme mechanisms, inconsistencies between parameters obtained from different sources, and in vitro-in vivo differences. Here, we present a computational workflow for the robust estimation of kinetic parameters for detailed mass action enzyme models while taking into account parameter uncertainty. The resulting software package, termed MASSef (the Mass Action Stoichiometry Simulation Enzyme Fitting package), can handle standard 'macroscopic' kinetic parameters, including Km, kcat, Ki, Keq, and nh, as well as diverse reaction mechanisms defined in terms of mass action reactions and 'microscopic' rate constants. We provide three enzyme case studies demonstrating that this approach can identify and reconcile inconsistent data either within in vitro experiments or between in vitro and in vivo enzyme function. We further demonstrate how parameterized enzyme modules can be used to assemble pathway-scale kinetic models consistent with in vivo behavior. This work builds on the legacy of knowledge on kinetic behavior of enzymes by enabling robust parameterization of enzyme kinetic models at scale utilizing the abundance of historical literature data and machine learning parameter estimates.
    DOI:  https://doi.org/10.1016/j.mec.2024.e00234
  21. Cell Metab. 2024 May 07. pii: S1550-4131(24)00127-X. [Epub ahead of print]36(5): 884-886
    Targeting metabolic circuitry to supercharge CD8+ T cell antitumor responses.
    Qiang Cai, Yihao Tian, Quazi T H Shubhra.
      Tumors compromise T cell functionality through various mechanisms, including the induction of a nutrient-scarce microenvironment, leading to lipid accumulation and metabolic reprogramming. Hunt et al. elucidate acetyl-CoA carboxylase's crucial role in regulating lipid metabolism in CD8+ T cells, uncovering a novel metabolic strategy to potentiate antitumor immune responses.
    DOI:  https://doi.org/10.1016/j.cmet.2024.04.007
  22. Nat Commun. 2024 May 08. 15(1): 3367
    Identification of a family of species-selective complex I inhibitors as potential anthelmintics.
    Taylor Davie, Xènia Serrat, Lea Imhof, Jamie Snider, Igor Štagljar, Jennifer Keiser, Hiroyuki Hirano, Nobumoto Watanabe, Hiroyuki Osada, Andrew G Fraser.
      Soil-transmitted helminths (STHs) are major pathogens infecting over a billion people. There are few classes of anthelmintics and there is an urgent need for new drugs. Many STHs use an unusual form of anaerobic metabolism to survive the hypoxic conditions of the host gut. This requires rhodoquinone (RQ), a quinone electron carrier. RQ is not made or used by vertebrate hosts making it an excellent therapeutic target. Here we screen 480 structural families of natural products to find compounds that kill Caenorhabditis elegans specifically when they require RQ-dependent metabolism. We identify several classes of compounds including a family of species-selective inhibitors of mitochondrial respiratory complex I. These identified complex I inhibitors have a benzimidazole core and we determine key structural requirements for activity by screening 1,280 related compounds. Finally, we show several of these compounds kill adult STHs. We suggest these species-selective complex I inhibitors are potential anthelmintics.
    DOI:  https://doi.org/10.1038/s41467-024-47331-3
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