bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2024–02–25
53 papers selected by
Christian Frezza, Universität zu Köln
  1. Monocarboxylate transporters facilitate succinate uptake into brown adipocytes.
  2. Identification of MIMAS, a multifunctional mega-assembly integrating metabolic and respiratory biogenesis factors of mitochondria.
  3. A SPLICS reporter reveals [Formula: see text]-synuclein regulation of lysosome-mitochondria contacts which affects TFEB nuclear translocation.
  4. MCT1 helps brown fat suck up succinate.
  5. mTORC1 activity oscillates throughout the cell cycle promoting mitotic entry and differentially influencing autophagy induction.
  6. MIMAS is a new giant multifunctional player in the mitochondrial megacomplex playground.
  7. Enhanced Branched-Chain Amino Acid Metabolism Improves Age-Related Reproduction in C. elegans.
  8. Genome-wide screens identify SEL1L as an intracellular rheostat controlling collagen turnover.
  9. Mitochondrial quinone redox states as a marker of mitochondrial metabolism.
  10. Exposure of the inner mitochondrial membrane triggers apoptotic mitophagy.
  11. Proteome allocation and the evolution of metabolic cross-feeding.
  12. Role of the small protein Mco6 in the mitochondrial sorting and assembly machinery.
  13. ER remodeling via lipid metabolism.
  14. Lysosomal channels sensing forces.
  15. Transport activity regulates mitochondrial bioenergetics and biogenesis in renal tubules.
  16. Recurrent evolutionary switches of mitochondrial cytochrome c maturation systems in Archaeplastida.
  17. An engineered biosensor enables dynamic aspartate measurements in living cells.
  18. IL-10 constrains sphingolipid metabolism to limit inflammation.
  19. Metabolic regulation of chemoresistance and immuno-surveillance in AML by SHP-1.
  20. αKG-mediated carnitine synthesis promotes homologous recombination via histone acetylation.
  21. Calcium oscillations optimize the energetic efficiency of mitochondrial metabolism.
  22. Hyperacetylated histone H4 is a source of carbon contributing to lipid synthesis.
  23. Judith Campisi (1948-2024), cell biologist who explored how cells age.
  24. Reciprocal activity of AgRP and POMC neurons governs coordinated control of feeding and metabolism.
  25. Chromosome evolution screens recapitulate tissue-specific tumor aneuploidy patterns.
  26. Untargeted Pixel-by-Pixel Imaging of Metabolite Ratio Pairs as a Novel Tool for Biomedical Discovery in Mass Spectrometry Imaging.
  27. Dietary methionine restriction in cancer development and antitumor immunity.
  28. A new era of cysteine proteomics - Technological advances in thiol biology.
  29. Inhibiting centrosome clustering reduces cystogenesis and improves kidney function in autosomal dominant polycystic kidney disease.
  30. Stalled translation by mitochondrial stress upregulates a CNOT4-ZNF598 ribosomal quality control pathway important for tissue homeostasis.
  31. Metabolic basis of cardiac dysfunction in cancer patients.
  32. GATOR1 Mutations Impair PI3 Kinase-Dependent Growth Factor Signaling Regulation of mTORC1.
  33. Metabolic engineering for optimized CAR-T cell therapy.
  34. Bacteria employ lysine acetylation of transcriptional regulators to adapt gene expression to cellular metabolism.
  35. Comparative genomics incorporating translocation renal cell carcinoma mouse model reveals molecular mechanisms of tumorigenesis.
  36. An optimized protocol for the extraction and quantification of cytosolic DNA in mammalian cells.
  37. Ageing-dependent thiol oxidation reveals early oxidation of proteins with core proteostasis functions.
  38. Regulation of stress granule formation in human oligodendrocytes.
  39. METTL17 coordinates ferroptosis and tumorigenesis by regulating mitochondrial translation in colorectal cancer.
  40. FLVCR1a Controls Cellular Cholesterol Levels through the Regulation of Heme Biosynthesis and Tricarboxylic Acid Cycle Flux in Endothelial Cells.
  41. Methionine secreted by tumor-associated pericytes supports cancer stem cells in clear cell renal carcinoma.
  42. PRMT1 sustains de novo fatty acid synthesis by methylating PHGDH to drive chemoresistance in triple-negative breast cancer.
  43. Proteogenomic characterization of primary colorectal cancer and metastatic progression identifies proteome-based subtypes and signatures.
  44. Why are we nice? Altruism's origins are put to the test.
  45. M2 macrophages independently promote beige adipogenesis via blocking adipocyte Ets1.
  46. Oncogenic c-Myc induces replication stress by increasing cohesins chromatin occupancy in a CTCF-dependent manner.
  47. Targeting nuclear receptor corepressors for reversible male contraception.
  48. YAP mediates apoptosis through failed integrin adhesion reinforcement.
  49. UDP-glucose dehydrogenase supports autophagy-deficient PDAC growth via increasing hyaluronic acid biosynthesis.
  50. Developmental regulation of cellular metabolism is required for intestinal elongation and rotation.
  51. An immunogenetic basis for lung cancer risk.
  52. Lysine lactylation in the regulation of tumor biology.
  53. Driving factors of neuronal ferroptosis.
  1. Nat Metab. 2024 Feb 20.
    Monocarboxylate transporters facilitate succinate uptake into brown adipocytes.
    Anita Reddy, Sally Winther, Nhien Tran, Haopeng Xiao, Josefine Jakob, Ryan Garrity, Arianne Smith, Martha Ordonez, Dina Laznik-Bogoslavski, Jeffrey D Rothstein, Evanna L Mills, Edward T Chouchani.
      Uptake of circulating succinate by brown adipose tissue (BAT) and beige fat elevates whole-body energy expenditure, counteracts obesity and antagonizes systemic tissue inflammation in mice. The plasma membrane transporters that facilitate succinate uptake in these adipocytes remain undefined. Here we elucidate a mechanism underlying succinate import into BAT via monocarboxylate transporters (MCTs). We show that succinate transport is strongly dependent on the proportion that is present in the monocarboxylate form. MCTs facilitate monocarboxylate succinate uptake, which is promoted by alkalinization of the cytosol driven by adrenoreceptor stimulation. In brown adipocytes, we show that MCT1 primarily facilitates succinate import. In male mice, we show that both acute pharmacological inhibition of MCT1 and congenital depletion of MCT1 decrease succinate uptake into BAT and consequent catabolism. In sum, we define a mechanism of succinate uptake in BAT that underlies its protective activity in mouse models of metabolic disease.
    DOI:  https://doi.org/10.1038/s42255-024-00981-5
  2. Cell Rep. 2024 Feb 21. pii: S2211-1247(24)00100-1. [Epub ahead of print]43(3): 113772
    Identification of MIMAS, a multifunctional mega-assembly integrating metabolic and respiratory biogenesis factors of mitochondria.
    Patrick Horten, Kuo Song, Joshua Garlich, Robert Hardt, Lilia Colina-Tenorio, Susanne E Horvath, Uwe Schulte, Bernd Fakler, Martin van der Laan, Thomas Becker, Rosemary A Stuart, Nikolaus Pfanner, Heike Rampelt.
      The mitochondrial inner membrane plays central roles in bioenergetics and metabolism and contains several established membrane protein complexes. Here, we report the identification of a mega-complex of the inner membrane, termed mitochondrial multifunctional assembly (MIMAS). Its large size of 3 MDa explains why MIMAS has escaped detection in the analysis of mitochondria so far. MIMAS combines proteins of diverse functions from respiratory chain assembly to metabolite transport, dehydrogenases, and lipid biosynthesis but not the large established supercomplexes of the respiratory chain, ATP synthase, or prohibitin scaffold. MIMAS integrity depends on the non-bilayer phospholipid phosphatidylethanolamine, in contrast to respiratory supercomplexes whose stability depends on cardiolipin. Our findings suggest that MIMAS forms a protein-lipid mega-assembly in the mitochondrial inner membrane that integrates respiratory biogenesis and metabolic processes in a multifunctional platform.
    Keywords:  CP: Metabolism; CP: Molecular biology; membrane protein complex; metabolism; metabolite carriers; mitochondria; phosphatidylethanolamine; phospholipids; protein assembly; respiratory chain
    DOI:  https://doi.org/10.1016/j.celrep.2024.113772
  3. Nat Commun. 2024 Feb 19. 15(1): 1516
    A SPLICS reporter reveals [Formula: see text]-synuclein regulation of lysosome-mitochondria contacts which affects TFEB nuclear translocation.
    Flavia Giamogante, Lucia Barazzuol, Francesca Maiorca, Elena Poggio, Alessandra Esposito, Anna Masato, Gennaro Napolitano, Alessio Vagnoni, Tito Calì, Marisa Brini.
      Mitochondrial and lysosomal activities are crucial to maintain cellular homeostasis: optimal coordination is achieved at their membrane contact sites where distinct protein machineries regulate organelle network dynamics, ions and metabolites exchange. Here we describe a genetically encoded SPLICS reporter for short- and long- juxtapositions between mitochondria and lysosomes. We report the existence of narrow and wide lysosome-mitochondria contacts differently modulated by mitophagy, autophagy and genetic manipulation of tethering factors. The overexpression of α-synuclein (α-syn) reduces the apposition of mitochondria/lysosomes membranes and affects their privileged Ca2+ transfer, impinging on TFEB nuclear translocation. We observe enhanced TFEB nuclear translocation in α-syn-overexpressing cells. We propose that α-syn, by interfering with mitochondria/lysosomes tethering impacts on local Ca2+ regulated pathways, among which TFEB mediated signaling, and in turn mitochondrial and lysosomal function. Defects in mitochondria and lysosome represent a common hallmark of neurodegenerative diseases: targeting their communication could open therapeutic avenues.
    DOI:  https://doi.org/10.1038/s41467-024-46007-2
  4. Nat Metab. 2024 Feb 20.
    MCT1 helps brown fat suck up succinate.
    Jens Lund, Marie Sophie Isidor, Zachary Gerhart-Hines.
      
    DOI:  https://doi.org/10.1038/s42255-024-00979-z
  5. bioRxiv. 2024 Feb 07. pii: 2024.02.06.579216. [Epub ahead of print]
    mTORC1 activity oscillates throughout the cell cycle promoting mitotic entry and differentially influencing autophagy induction.
    Jay N Joshi, Ariel D Lerner, Frank Scallo, Alexandra N Grumet, Paul Matteson, James H Millonig, Alexander J Valvezan.
      Mechanistic Target of Rapamycin Complex 1 (mTORC1) is a master metabolic regulator that stimulates anabolic cell growth while suppressing catabolic processes such as autophagy. mTORC1 is active in most, if not all, proliferating eukaryotic cells. However, it remains unclear whether and how mTORC1 activity changes from one cell cycle phase to another. Here we tracked mTORC1 activity through the complete cell cycle and uncover oscillations in its activity. We find that mTORC1 activity peaks in S and G2, and is lowest in mitosis and G1. We further demonstrate that multiple mechanisms are involved in controlling this oscillation. The interphase oscillation is mediated through the TSC complex, an upstream negative regulator of mTORC1, but is independent of major known regulatory inputs to the TSC complex, including Akt, Mek/Erk, and CDK4/6 signaling. By contrast, suppression of mTORC1 activity in mitosis does not require the TSC complex, and instead involves CDK1-dependent control of the subcellular localization of mTORC1 itself. Functionally, we find that in addition to its well-established role in promoting progression through G1, mTORC1 also promotes progression through S and G2, and is important for satisfying the Wee1- and Chk1-dependent G2/M checkpoint to allow entry into mitosis. We also find that low mTORC1 activity in G1 sensitizes cells to autophagy induction in response to partial mTORC1 inhibition or reduced nutrient levels. Together these findings demonstrate that mTORC1 is differentially regulated throughout the cell cycle, with important phase-specific functional consequences in proliferating cells.
    DOI:  https://doi.org/10.1101/2024.02.06.579216
  6. Cell Rep. 2024 Feb 21. pii: S2211-1247(24)00202-X. [Epub ahead of print]43(3): 113874
    MIMAS is a new giant multifunctional player in the mitochondrial megacomplex playground.
    Kostas Tokatlidis.
      Mitochondria are rich in multi-protein assemblies that are usually dedicated to one function. In this issue of Cell Reports, Horten et al.1 describe a 3-nanometer megacomplex in the mitochondrial inner membrane, which serves multiple functions integrating mitochondria biogenesis and metabolism.
    DOI:  https://doi.org/10.1016/j.celrep.2024.113874
  7. bioRxiv. 2024 Feb 09. pii: 2023.02.09.527915. [Epub ahead of print]
    Enhanced Branched-Chain Amino Acid Metabolism Improves Age-Related Reproduction in C. elegans.
    Chen Lesnik, Rachel Kaletsky, Jasmine M Ashraf, Salman Sohrabi, Vanessa Cota, Titas Sengupta, William Keyes, Shijing Luo, Coleen T Murphy.
      Reproductive aging is one of the earliest human aging phenotypes, and mitochondrial dysfunction has been linked to oocyte quality decline. However, it is not known which mitochondrial metabolic processes are critical for oocyte quality maintenance with age. To understand how mitochondrial processes contribute to C. elegans oocyte quality, we characterized the mitochondrial proteomes of young and aged wild-type and long-reproductive daf-2 mutants. Here we show that the mitochondrial proteomic profiles of young wild-type and daf-2 worms are similar and share upregulation of branched-chain amino acid (BCAA) metabolism pathway enzymes. Reduction of the BCAA catabolism enzyme BCAT-1 shortens reproduction, elevates mitochondrial reactive oxygen species levels, and shifts mitochondrial localization. Moreover, bcat-1 knockdown decreases oocyte quality in daf-2 worms and reduces reproductive capability, indicating the role of this pathway in the maintenance of oocyte quality with age. Importantly, oocyte quality deterioration can be delayed, and reproduction can be extended in wild-type animals both by bcat-1 overexpression and by supplementing with Vitamin B1, a cofactor needed for BCAA metabolism.
    DOI:  https://doi.org/10.1101/2023.02.09.527915
  8. Nat Commun. 2024 Feb 20. 15(1): 1531
    Genome-wide screens identify SEL1L as an intracellular rheostat controlling collagen turnover.
    Michael J Podolsky, Benjamin Kheyfets, Monika Pandey, Afaq H Beigh, Christopher D Yang, Carlos O Lizama, Ritwik Datta, Liangguang L Lin, Zhihong Wang, Paul J Wolters, Michael T McManus, Ling Qi, Kamran Atabai.
      Accumulating evidence has implicated impaired extracellular matrix (ECM) clearance as a key factor in fibrotic disease. Despite decades of research elucidating the effectors of ECM clearance, relatively little is understood regarding the upstream regulation of this process. Collagen is the most abundant constituent of normal and fibrotic ECM in mammalian tissues. Its catabolism occurs through extracellular proteolysis and cell-mediated uptake of collagen fragments for intracellular degradation. Given the paucity of information regarding the regulation of this latter process, here we execute unbiased genome-wide screens to understand the molecular underpinnings of cell-mediated collagen clearance. Using this approach, we discover a mechanism through which collagen biosynthesis is sensed by cells internally and directly regulates clearance of extracellular collagen. The sensing mechanism appears to be dependent on endoplasmic reticulum-resident protein SEL1L and occurs via a noncanonical function of this protein. This pathway functions as a homeostatic negative feedback loop that limits collagen accumulation in tissues. In human fibrotic lung disease, the induction of this collagen clearance pathway by collagen synthesis is impaired, thereby contributing to the pathological accumulation of collagen in lung tissue. Thus, we describe cell-autonomous, rheostatic collagen clearance as an important pathway of tissue homeostasis.
    DOI:  https://doi.org/10.1038/s41467-024-45817-8
  9. Biochim Biophys Acta Bioenerg. 2024 Feb 16. pii: S0005-2728(24)00003-3. [Epub ahead of print] 149033
    Mitochondrial quinone redox states as a marker of mitochondrial metabolism.
    M Martins Pinto, S Ransac, J P Mazat, L Schwartz, M Rigoulet, S Arbault, P Paumard, A Devin.
      Mitochondrial and thus cellular energetics are highly regulated both thermodynamically and kinetically. Cellular energetics is of prime importance in the regulation of cellular functions since it provides ATP for their accomplishment. However, cellular energetics is not only about ATP production but also about the ability to re-oxidize reduced coenzymes at a proper rate, such that the cellular redox potential remains at a level compatible with enzymatic reactions. However, this parameter is not only difficult to assess due to its dual compartmentation (mitochondrial and cytosolic) but also because it is well known that most NADH in the cells is bound to the enzymes. In this paper, we investigated the potential relevance of mitochondrial quinones redox state as a marker of mitochondrial metabolism and more particularly mitochondrial redox state. We were able to show that Q2 is an appropriate redox mediator to assess the mitochondrial quinone redox states. On isolated mitochondria, the mitochondrial quinone redox states depend on the mitochondrial substrate and the mitochondrial energetic state (phosphorylating or not phosphorylating). Last but not least, we show that the quinones redox state response allows to better understand the Krebs cycle functioning and respiratory substrates oxidation. Taken together, our results suggest that the quinones redox state is an excellent marker of mitochondrial metabolism.
    Keywords:  Bioenergetics; Mitochondria respiratory chain; Quinones; Redox state
    DOI:  https://doi.org/10.1016/j.bbabio.2024.149033
  10. Cell Death Differ. 2024 Feb 23.
    Exposure of the inner mitochondrial membrane triggers apoptotic mitophagy.
    Tahnee L Saunders, Simon P Windley, Gediminas Gervinskas, Katherine R Balka, Caitlin Rowe, Rachael Lane, Maximilien Tailler, Thanh Ngoc Nguyen, Georg Ramm, Michael Lazarou, Dominic De Nardo, Benjamin T Kile, Kate McArthur.
      During apoptosis mediated by the intrinsic pathway, BAX/BAK triggers mitochondrial permeabilization and the release of cytochrome-c, followed by a dramatic remodelling of the mitochondrial network that results in mitochondrial herniation and the subsequent release of pro-inflammatory mitochondrial components. Here, we show that mitochondrial herniation and subsequent exposure of the inner mitochondrial membrane (IMM) to the cytoplasm, initiates a unique form of mitophagy to deliver these damaged organelles to lysosomes. IMM-induced mitophagy occurs independently of canonical PINK1/Parkin signalling and is driven by ubiquitination of the IMM. Our data suggest IMM-induced mitophagy is an additional safety mechanism that cells can deploy to contain damaged mitochondria. It may have particular relevance in situations where caspase activation is incomplete or inhibited, and in contexts where PINK1/Parkin-mitophagy is impaired or overwhelmed.
    DOI:  https://doi.org/10.1038/s41418-024-01260-2
  11. Evolution. 2024 Feb 20. pii: qpae008. [Epub ahead of print]
    Proteome allocation and the evolution of metabolic cross-feeding.
    Florian J F Labourel, Vincent Daubin, Frédéric Menu, Etienne Rajon.
      In a common instance of metabolic cross-feeding (MCF), an organism incompletely meta- bolises nutrients and releases metabolites that are used by another to produce energy or building blocks. Why would the former waste edible food, and why does this prefer- entially occur at specific locations in a metabolic pathway have challenged evolutionary theory for decades. To address these questions, we combine adaptive dynamics with an explicit model of cell metabolism, including enzyme-driven catalysis of metabolic reactions and the cellular constraints acting on the proteome that may incur a cost to expressing all enzymes along a pathway. After pointing out that cells should in principle prioritise upstream reactions when metabolites are restrained inside the cell, we show that the oc- currence of permeability-driven MCF is rare and requires that an intermediate metabolite be extremely diffusive. Indeed, only at very high levels of membrane permeability (consist- ent with those of acetate and glycerol, for instance) and under distinctive sets of paramet- ers should the population diversify and MCF evolve. These results help understand the origins of simple microbial communities, such as those that readily evolve in short-term evolutionary experiments, and may later be extended to investigate how evolution has progressively built up today's extremely diverse ecosystems.
    Keywords:  Division of labour; Gene expression; Metabolism; Proteome optimisation; Specialisation
    DOI:  https://doi.org/10.1093/evolut/qpae008
  12. Cell Rep. 2024 Feb 19. pii: S2211-1247(24)00133-5. [Epub ahead of print]43(3): 113805
    Role of the small protein Mco6 in the mitochondrial sorting and assembly machinery.
    Jon V Busto, Iniyan Ganesan, Hannah Mathar, Conny Steiert, Eva F Schneider, Sebastian P Straub, Lars Ellenrieder, Jiyao Song, Sebastian B Stiller, Philipp Lübbert, Ritwika Chatterjee, Jana Elsaesser, Laura Melchionda, Christina Schug, Fabian den Brave, Uwe Schulte, Till Klecker, Claudine Kraft, Bernd Fakler, Thomas Becker, Nils Wiedemann.
      The majority of mitochondrial precursor proteins are imported through the Tom40 β-barrel channel of the translocase of the outer membrane (TOM). The sorting and assembly machinery (SAM) is essential for β-barrel membrane protein insertion into the outer membrane and thus required for the assembly of the TOM complex. Here, we demonstrate that the α-helical outer membrane protein Mco6 co-assembles with the mitochondrial distribution and morphology protein Mdm10 as part of the SAM machinery. MCO6 and MDM10 display a negative genetic interaction, and a mco6-mdm10 yeast double mutant displays reduced levels of the TOM complex. Cells lacking Mco6 affect the levels of Mdm10 and show assembly defects of the TOM complex. Thus, this work uncovers a role of the SAMMco6 complex for the biogenesis of the mitochondrial outer membrane.
    Keywords:  CP: Cell biology; ERMES complex; Mdm10; SAM complex; TOM complex; mitochondria; outer membrane; protein import; protein translocation; β-barrel protein
    DOI:  https://doi.org/10.1016/j.celrep.2024.113805
  13. Trends Cell Biol. 2024 Feb 22. pii: S0962-8924(24)00023-0. [Epub ahead of print]
    ER remodeling via lipid metabolism.
    Wonyul Jang, Volker Haucke.
      Unlike most other organelles found in multiple copies, the endoplasmic reticulum (ER) is a unique singular organelle within eukaryotic cells. Despite its continuous membrane structure, encompassing more than half of the cellular endomembrane system, the ER is subdivided into specialized sub-compartments, including morphological, membrane contact site (MCS), and de novo organelle biogenesis domains. In this review, we discuss recent emerging evidence indicating that, in response to nutrient stress, cells undergo a reorganization of these sub-compartmental ER domains through two main mechanisms: non-destructive remodeling of morphological ER domains via regulation of MCS and organelle hitchhiking, and destructive remodeling of specialized domains by ER-phagy. We further highlight and propose a critical role of membrane lipid metabolism in this ER remodeling during starvation.
    Keywords:  endoplasmic reticulum; hitchhiking; lipids; membrane contact sites; membrane remodeling; metabolism; nutrient stress
    DOI:  https://doi.org/10.1016/j.tcb.2024.01.011
  14. Nat Cell Biol. 2024 Feb 22.
    Lysosomal channels sensing forces.
    Erika Riederer, Dejian Ren.
      
    DOI:  https://doi.org/10.1038/s41556-024-01347-5
  15. bioRxiv. 2024 Feb 08. pii: 2024.02.04.578838. [Epub ahead of print]
    Transport activity regulates mitochondrial bioenergetics and biogenesis in renal tubules.
    Chih-Jen Cheng, Jonathan M Nizar, Dao-Fu Dai, Chou-Long Huang.
      Renal tubules are featured with copious mitochondria and robust transport activity. Mutations in mitochondrial genes cause congenital renal tubulopathies, and changes in transport activity affect mitochondrial morphology, suggesting mitochondrial function and transport activity are tightly coupled. Current methods of using bulk kidney tissues or cultured cells to study mitochondrial bioenergetics are limited. Here, we optimized an extracellular flux analysis (EFA) to study mitochondrial respiration and energy metabolism using microdissected mouse renal tubule segments. EFA detects mitochondrial respiration and glycolysis by measuring oxygen consumption and extracellular acidification rates, respectively. We show that both measurements positively correlate with sample sizes of a few centimeter-length renal tubules. The thick ascending limbs (TALs) and distal convoluted tubules (DCTs) predominantly utilize glucose/pyruvate as energy substrates, whereas proximal tubules (PTs) are significantly much less so. Acute inhibition of TALs' transport activity by ouabain treatment reduces basal and ATP-linked mitochondrial respiration. Chronic inhibition of transport activity by 2-week furosemide treatment or deletion of with-no-lysine kinase 4 (Wnk4) decreases maximal mitochondrial capacity. In addition, chronic inhibition downregulates mitochondrial DNA mass and mitochondrial length/density in TALs and DCTs. Conversely, gain-of-function Wnk4 mutation increases maximal mitochondrial capacity and mitochondrial length/density without increasing mitochondrial DNA mass. In conclusion, EFA is a sensitive and reliable method to investigate mitochondrial functions in isolated renal tubules. Transport activity tightly regulates mitochondrial bioenergetics and biogenesis to meet the energy demand in renal tubules. The system allows future investigation into whether and how mitochondria contribute to tubular remodeling adapted to changes in transport activity.
    Key points: A positive correlation between salt reabsorption and oxygen consumption in mammalian kidneys hints at a potential interaction between transport activity and mitochondrial respiration in renal tubules.Renal tubules are heterogeneous in transport activity and mitochondrial metabolism, and traditional assays using bulk kidney tissues cannot provide segment-specific information.Here, we applied an extracellular flux analysis to investigate mitochondrial respiration and energy metabolism in isolated renal tubules. This assay is sensitive in detecting oxygen consumption and acid production in centimeter-length renal tubules and reliably recapitulates segment-specific metabolic features.Acute inhibition of transport activity reduces basal and ATP-linked mitochondrial respirations without changing maximal mitochondrial respiratory capacity. Chronic alterations of transport activity further adjust maximal mitochondrial respiratory capacity via regulating mitochondrial biogenesis or non-transcriptional mechanisms.Our findings support the concept that renal tubular cells finely adjust mitochondrial bioenergetics and biogenesis to match the new steady state of transport activity.
    DOI:  https://doi.org/10.1101/2024.02.04.578838
  16. Nat Commun. 2024 Feb 20. 15(1): 1548
    Recurrent evolutionary switches of mitochondrial cytochrome c maturation systems in Archaeplastida.
    Huang Li, Soujanya Akella, Carina Engstler, Joy J Omini, Moira Rodriguez, Toshihiro Obata, Chris Carrie, Heriberto Cerutti, Jeffrey P Mower.
      Mitochondrial cytochrome c maturation (CCM) requires heme attachment via distinct pathways termed systems I and III. The mosaic distribution of these systems in Archaeplastida raises questions about the genetic mechanisms and evolutionary forces promoting repeated evolution. Here, we show a recurrent shift from ancestral system I to the eukaryotic-specific holocytochrome c synthase (HCCS) of system III in 11 archaeplastid lineages. Archaeplastid HCCS is sufficient to rescue mutants of yeast system III and Arabidopsis system I. Algal HCCS mutants exhibit impaired growth and respiration, and altered biochemical and metabolic profiles, likely resulting from deficient CCM and reduced cytochrome c-dependent respiratory activity. Our findings demonstrate that archaeplastid HCCS homologs function as system III components in the absence of system I. These results elucidate the evolutionary trajectory and functional divergence of CCM pathways in Archaeplastida, providing insight into the causes, mechanisms, and consequences of repeated cooption of an entire biological pathway.
    DOI:  https://doi.org/10.1038/s41467-024-45813-y
  17. Elife. 2024 Feb 23. pii: RP90024. [Epub ahead of print]12
    An engineered biosensor enables dynamic aspartate measurements in living cells.
    Kristian Davidsen, Jonathan S Marvin, Abhi Aggarwal, Timothy A Brown, Lucas B Sullivan.
      Intracellular levels of the amino acid aspartate are responsive to changes in metabolism in mammalian cells and can correspondingly alter cell function, highlighting the need for robust tools to measure aspartate abundance. However, comprehensive understanding of aspartate metabolism has been limited by the throughput, cost, and static nature of the mass spectrometry (MS)-based measurements that are typically employed to measure aspartate levels. To address these issues, we have developed a green fluorescent protein (GFP)-based sensor of aspartate (jAspSnFR3), where the fluorescence intensity corresponds to aspartate concentration. As a purified protein, the sensor has a 20-fold increase in fluorescence upon aspartate saturation, with dose-dependent fluorescence changes covering a physiologically relevant aspartate concentration range and no significant off target binding. Expressed in mammalian cell lines, sensor intensity correlated with aspartate levels measured by MS and could resolve temporal changes in intracellular aspartate from genetic, pharmacological, and nutritional manipulations. These data demonstrate the utility of jAspSnFR3 and highlight the opportunities it provides for temporally resolved and high-throughput applications of variables that affect aspartate levels.
    Keywords:  aspartate; biochemistry; biosensor; cell biology; chemical biology; glutamine; human; metabolism; mitochondria; protein engineering
    DOI:  https://doi.org/10.7554/eLife.90024
  18. Nature. 2024 Feb 21.
    IL-10 constrains sphingolipid metabolism to limit inflammation.
    Autumn G York, Mathias H Skadow, Joonseok Oh, Rihao Qu, Quan D Zhou, Wei-Yuan Hsieh, Walter K Mowel, J Richard Brewer, Eleanna Kaffe, Kevin J Williams, Yuval Kluger, Stephen T Smale, Jason M Crawford, Steven J Bensinger, Richard A Flavell.
      Interleukin-10 (IL-10) is a key anti-inflammatory cytokine that can limit immune cell activation and cytokine production in innate immune cell types1. Loss of IL-10 signalling results in life-threatening inflammatory bowel disease in humans and mice-however, the exact mechanism by which IL-10 signalling subdues inflammation remains unclear2-5. Here we find that increased saturated very long chain (VLC) ceramides are critical for the heightened inflammatory gene expression that is a hallmark of IL-10 deficiency. Accordingly, genetic deletion of ceramide synthase 2 (encoded by Cers2), the enzyme responsible for VLC ceramide production, limited the exacerbated inflammatory gene expression programme associated with IL-10 deficiency both in vitro and in vivo. The accumulation of saturated VLC ceramides was regulated by a decrease in metabolic flux through the de novo mono-unsaturated fatty acid synthesis pathway. Restoring mono-unsaturated fatty acid availability to cells deficient in IL-10 signalling limited saturated VLC ceramide production and the associated inflammation. Mechanistically, we find that persistent inflammation mediated by VLC ceramides is largely dependent on sustained activity of REL, an immuno-modulatory transcription factor. Together, these data indicate that an IL-10-driven fatty acid desaturation programme rewires VLC ceramide accumulation and aberrant activation of REL. These studies support the idea that fatty acid homeostasis in innate immune cells serves as a key regulatory node to control pathologic inflammation and suggests that 'metabolic correction' of VLC homeostasis could be an important strategy to normalize dysregulated inflammation caused by the absence of IL-10.
    DOI:  https://doi.org/10.1038/s41586-024-07098-5
  19. Nat Cell Biol. 2024 Feb 23.
    Metabolic regulation of chemoresistance and immuno-surveillance in AML by SHP-1.
      
    DOI:  https://doi.org/10.1038/s41556-024-01350-w
  20. bioRxiv. 2024 Feb 11. pii: 2024.02.06.578742. [Epub ahead of print]
    αKG-mediated carnitine synthesis promotes homologous recombination via histone acetylation.
    Apoorva Uboveja, Zhentai Huang, Raquel Buj, Amandine Amalric, Hui Wang, Naveen Kumar Tangudu, Aidan R Cole, Emily Megill, Daniel Kantner, Adam Chatoff, Hafsah Ahmad, Mariola M Marcinkiewicz, Julie A Disharoon, Sarah Graff, Erika S Dahl, Nadine Hempel, Wayne Stallaert, Simone Sidoli, Benjamin G Bitler, David T Long, Nathaniel W Snyder, Katherine M Aird.
      Homologous recombination (HR) deficiency enhances sensitivity to DNA damaging agents commonly used to treat cancer. In HR-proficient cancers, metabolic mechanisms driving response or resistance to DNA damaging agents remain unclear. Here we identified that depletion of alpha-ketoglutarate (αKG) sensitizes HR-proficient cells to DNA damaging agents by metabolic regulation of histone acetylation. αKG is required for the activity of αKG-dependent dioxygenases (αKGDDs), and prior work has shown that changes in αKGDD affect demethylases. Using a targeted CRISPR knockout library consisting of 64 αKGDDs, we discovered that Trimethyllysine Hydroxylase Epsilon (TMLHE), the first and rate-limiting enzyme in de novo carnitine synthesis, is necessary for proliferation of HR-proficient cells in the presence of DNA damaging agents. Unexpectedly, αKG-mediated TMLHE-dependent carnitine synthesis was required for histone acetylation, while histone methylation was affected but dispensable. The increase in histone acetylation via αKG-dependent carnitine synthesis promoted HR-mediated DNA repair through site- and substrate-specific histone acetylation. These data demonstrate for the first time that HR-proficiency is mediated through αKG directly influencing histone acetylation via carnitine synthesis and provide a metabolic avenue to induce HR-deficiency and sensitivity to DNA damaging agents.
    DOI:  https://doi.org/10.1101/2024.02.06.578742
  21. iScience. 2024 Mar 15. 27(3): 109078
    Calcium oscillations optimize the energetic efficiency of mitochondrial metabolism.
    Valérie Voorsluijs, Francesco Avanzini, Gianmaria Falasco, Massimiliano Esposito, Alexander Skupin.
      Energy transduction is central to living organisms, but the impact of enzyme regulation and signaling on its thermodynamic efficiency is generally overlooked. Here, we analyze the efficiency of ATP production by the tricarboxylic acid cycle and oxidative phosphorylation, which generate most of the chemical energy in eukaryotes. Calcium signaling regulates this pathway and can affect its energetic output, but the concrete energetic impact of this cross-talk remains elusive. Calcium enhances ATP production by activating key enzymes of the tricarboxylic acid cycle while calcium homeostasis is ATP-dependent. We propose a detailed kinetic model describing the calcium-mitochondria cross-talk and analyze it using nonequilibrium thermodynamics: after identifying the effective reactions driving mitochondrial metabolism out of equilibrium, we quantify the mitochondrial thermodynamic efficiency for different conditions. Calcium oscillations, triggered by extracellular stimulation or energy deficiency, boost the thermodynamic efficiency of mitochondrial metabolism, suggesting a compensatory role of calcium signaling in mitochondrial bioenergetics.
    Keywords:  Biological sciences; Human metabolism; Molecular biology; Natural sciences
    DOI:  https://doi.org/10.1016/j.isci.2024.109078
  22. EMBO J. 2024 Feb 21.
    Hyperacetylated histone H4 is a source of carbon contributing to lipid synthesis.
    Evelina Charidemou, Roberta Noberini, Chiara Ghirardi, Polymnia Georgiou, Panayiota Marcou, Andria Theophanous, Katerina Strati, Hector Keun, Volker Behrends, Tiziana Bonaldi, Antonis Kirmizis.
      Histone modifications commonly integrate environmental cues with cellular metabolic outputs by affecting gene expression. However, chromatin modifications such as acetylation do not always correlate with transcription, pointing towards an alternative role of histone modifications in cellular metabolism. Using an approach that integrates mass spectrometry-based histone modification mapping and metabolomics with stable isotope tracers, we demonstrate that elevated lipids in acetyltransferase-depleted hepatocytes result from carbon atoms derived from deacetylation of hyperacetylated histone H4 flowing towards fatty acids. Consistently, enhanced lipid synthesis in acetyltransferase-depleted hepatocytes is dependent on histone deacetylases and acetyl-CoA synthetase ACSS2, but not on the substrate specificity of the acetyltransferases. Furthermore, we show that during diet-induced lipid synthesis the levels of hyperacetylated histone H4 decrease in hepatocytes and in mouse liver. In addition, overexpression of acetyltransferases can reverse diet-induced lipogenesis by blocking lipid droplet accumulation and maintaining the levels of hyperacetylated histone H4. Overall, these findings highlight hyperacetylated histones as a metabolite reservoir that can directly contribute carbon to lipid synthesis, constituting a novel function of chromatin in cellular metabolism.
    Keywords:  Acetylation; Epigenetics; Histone Reservoirs; Lipid Metabolism
    DOI:  https://doi.org/10.1038/s44318-024-00053-0
  23. Nature. 2024 Feb 21.
    Judith Campisi (1948-2024), cell biologist who explored how cells age.
    Jan Vijg, Jan Hoeijmakers.
      
    Keywords:  Cancer; Cell biology; Medical research
    DOI:  https://doi.org/10.1038/d41586-024-00538-2
  24. Nat Metab. 2024 Feb 20.
    Reciprocal activity of AgRP and POMC neurons governs coordinated control of feeding and metabolism.
    Alain J De Solis, Almudena Del Río-Martín, Jan Radermacher, Weiyi Chen, Lukas Steuernagel, Corinna A Bauder, Fynn R Eggersmann, Donald A Morgan, Anna-Lena Cremer, Michael Sué, Maximilian Germer, Christian Kukat, Stefan Vollmar, Heiko Backes, Kamal Rahmouni, Peter Kloppenburg, Jens C Brüning.
      Agouti-related peptide (AgRP)-expressing and proopiomelanocortin (POMC)-expressing neurons reciprocally regulate food intake. Here, we combine non-interacting recombinases to simultaneously express functionally opposing chemogenetic receptors in AgRP and POMC neurons for comparing metabolic responses in male and female mice with simultaneous activation of AgRP and inhibition of POMC neurons with isolated activation of AgRP neurons or isolated inhibition of POMC neurons. We show that food intake is regulated by the additive effect of AgRP neuron activation and POMC neuron inhibition, while systemic insulin sensitivity and gluconeogenesis are differentially modulated by isolated-versus-simultaneous regulation of AgRP and POMC neurons. We identify a neurocircuit engaging Npy1R-expressing neurons in the paraventricular nucleus of the hypothalamus, where activated AgRP neurons and inhibited POMC neurons cooperate to promote food consumption and activate Th+ neurons in the nucleus tractus solitarii. Collectively, these results unveil how food intake is precisely regulated by the simultaneous bidirectional interplay between AgRP and POMC neurocircuits.
    DOI:  https://doi.org/10.1038/s42255-024-00987-z
  25. Nat Genet. 2024 Feb 22.
    Chromosome evolution screens recapitulate tissue-specific tumor aneuploidy patterns.
    Emma V Watson, Jake June-Koo Lee, Doga C Gulhan, Giorgio E M Melloni, Sergey V Venev, Rayna Y Magesh, Abdulrazak Frederick, Kunitoshi Chiba, Eric C Wooten, Kamila Naxerova, Job Dekker, Peter J Park, Stephen J Elledge.
      Whole chromosome and arm-level copy number alterations occur at high frequencies in tumors, but their selective advantages, if any, are poorly understood. Here, utilizing unbiased whole chromosome genetic screens combined with in vitro evolution to generate arm- and subarm-level events, we iteratively selected the fittest karyotypes from aneuploidized human renal and mammary epithelial cells. Proliferation-based karyotype selection in these epithelial lines modeled tissue-specific tumor aneuploidy patterns in patient cohorts in the absence of driver mutations. Hi-C-based translocation mapping revealed that arm-level events usually emerged in multiples of two via centromeric translocations and occurred more frequently in tetraploids than diploids, contributing to the increased diversity in evolving tetraploid populations. Isogenic clonal lineages enabled elucidation of pro-tumorigenic mechanisms associated with common copy number alterations, revealing Notch signaling potentiation as a driver of 1q gain in breast cancer. We propose that intrinsic, tissue-specific proliferative effects underlie tumor copy number patterns in cancer.
    DOI:  https://doi.org/10.1038/s41588-024-01665-2
  26. bioRxiv. 2024 Feb 07. pii: 2024.01.10.575105. [Epub ahead of print]
    Untargeted Pixel-by-Pixel Imaging of Metabolite Ratio Pairs as a Novel Tool for Biomedical Discovery in Mass Spectrometry Imaging.
    Huiyong Cheng, Dawson Miller, Nneka Southwell, Joshua L Fischer, Isobel Taylor, J Michael Salbaum, Claudia Kappen, Fenghua Hu, Cha Yang, Steven S Gross, Marilena D'Aurelio, Qiuying Chen.
      Mass spectrometry imaging (MSI) is a powerful technology used to define the spatial distribution and relative abundance of structurally identified and yet-undefined metabolites across tissue cryosections. While numerous software packages enable pixel-by-pixel imaging of individual metabolites, the research community lacks a discovery tool that images all metabolite abundance ratio pairs. Importantly, recognition of correlated metabolite pairs informs discovery of unanticipated molecules contributing to shared metabolic pathways, uncovers hidden metabolic heterogeneity across cells and tissue subregions, and indicates single-timepoint flux through pathways of interest. Here, we describe the development and implementation of an untargeted R package workflow for pixel-by-pixel ratio imaging of all metabolites detected in an MSI experiment. Considering untargeted MSI studies of murine brain and embryogenesis, we demonstrate that ratio imaging minimizes systematic data variation introduced by sample handling and instrument drift, markedly enhances spatial image resolution, and reveals previously unrecognized metabotype-distinct tissue regions. Furthermore, ratio imaging facilitates identification of novel regional biomarkers and provides anatomical information regarding spatial distribution of metabolite-linked biochemical pathways. The algorithm described herein is applicable to any MSI dataset containing spatial information for metabolites, peptides or proteins, offering a potent tool to enhance knowledge obtained from current spatial metabolite profiling technologies.
    DOI:  https://doi.org/10.1101/2024.01.10.575105
  27. Trends Endocrinol Metab. 2024 Feb 20. pii: S1043-2760(24)00023-7. [Epub ahead of print]
    Dietary methionine restriction in cancer development and antitumor immunity.
    Ming Ji, Qing Xu, Xiaoling Li.
      Methionine restriction (MR) has been shown to suppress tumor growth and improve the responses to various anticancer therapies. However, methionine itself is required for the proliferation, activation, and differentiation of T cells that are crucial for antitumor immunity. The dual impact of methionine, that influences both tumor and immune cells, has generated concerns regarding the potential consequences of MR on T cell immunity and its possible role in promoting cancer. In this review we systemically examine current literature on the interactions between dietary methionine, cancer cells, and immune cells. Based on recent findings on MR in immunocompetent animals, we further discuss how tumor stage-specific methionine dependence of immune cells and cancer cells in the tumor microenvironment could ultimately dictate the response of tumors to MR.
    Keywords:  antitumor immunity; gut microbiota; methylation; redox homeostasis; sulfur metabolism
    DOI:  https://doi.org/10.1016/j.tem.2024.01.009
  28. Curr Opin Chem Biol. 2024 Feb 20. pii: S1367-5931(24)00011-5. [Epub ahead of print]79 102435
    A new era of cysteine proteomics - Technological advances in thiol biology.
    Nils Burger, Edward T Chouchani.
      Cysteines are amenable to a diverse set of modifications that exhibit critical regulatory functions over the proteome and thereby control a wide range of cellular processes. Proteomic technologies have emerged as a powerful strategy to interrogate cysteine modifications across the proteome. Recent advancements in enrichment strategies, multiplexing capabilities and increased analytical sensitivity have enabled deeper quantitative cysteine profiling, capturing a substantial proportion of the cysteine proteome. This is complemented by a rapidly growing repertoire of analytical strategies illuminating the diverse landscape of cysteine modifications. Cysteine chemoproteomics technologies have evolved into a powerful strategy to facilitate the development of covalent drugs, opening unprecedented opportunities to target the extensive undrugged proteome. Herein we review recent technological and scientific advances that shape the cysteine proteomics field.
    DOI:  https://doi.org/10.1016/j.cbpa.2024.102435
  29. JCI Insight. 2024 Feb 22. pii: e172047. [Epub ahead of print]9(4):
    Inhibiting centrosome clustering reduces cystogenesis and improves kidney function in autosomal dominant polycystic kidney disease.
    Tao Cheng, Aruljothi Mariappan, Ewa Langner, Kyuhwan Shim, Jay Gopalakrishnan, Moe R Mahjoub.
      Autosomal dominant polycystic kidney disease (ADPKD) is a monogenic disorder accounting for approximately 5% of patients with renal failure, yet therapeutics for the treatment of ADPKD remain limited. ADPKD tissues display abnormalities in the biogenesis of the centrosome, a defect that can cause genome instability, aberrant ciliary signaling, and secretion of pro-inflammatory factors. Cystic cells form excess centrosomes via a process termed centrosome amplification (CA), which causes abnormal multipolar spindle configurations, mitotic catastrophe, and reduced cell viability. However, cells with CA can suppress multipolarity via "centrosome clustering," a key mechanism by which cells circumvent apoptosis. Here, we demonstrate that inhibiting centrosome clustering can counteract the proliferation of renal cystic cells with high incidences of CA. Using ADPKD human cells and mouse models, we show that preventing centrosome clustering with 2 inhibitors, CCB02 and PJ34, blocks cyst initiation and growth in vitro and in vivo. Inhibiting centrosome clustering activates a p53-mediated surveillance mechanism leading to apoptosis, reduced cyst expansion, decreased interstitial fibrosis, and improved kidney function. Transcriptional analysis of kidneys from treated mice identified pro-inflammatory signaling pathways implicated in CA-mediated cystogenesis and fibrosis. Our results demonstrate that centrosome clustering is a cyst-selective target for the improvement of renal morphology and function in ADPKD.
    Keywords:  Cell Biology; Cytoskeleton; Nephrology
    DOI:  https://doi.org/10.1172/jci.insight.172047
  30. Nat Commun. 2024 Feb 22. 15(1): 1637
    Stalled translation by mitochondrial stress upregulates a CNOT4-ZNF598 ribosomal quality control pathway important for tissue homeostasis.
    Ji Geng, Shuangxi Li, Yu Li, Zhihao Wu, Sunil Bhurtel, Suman Rimal, Danish Khan, Rani Ohja, Onn Brandman, Bingwei Lu.
      Translational control exerts immediate effect on the composition, abundance, and integrity of the proteome. Ribosome-associated quality control (RQC) handles ribosomes stalled at the elongation and termination steps of translation, with ZNF598 in mammals and Hel2 in yeast serving as key sensors of translation stalling and coordinators of downstream resolution of collided ribosomes, termination of stalled translation, and removal of faulty translation products. The physiological regulation of RQC in general and ZNF598 in particular in multicellular settings is underexplored. Here we show that ZNF598 undergoes regulatory K63-linked ubiquitination in a CNOT4-dependent manner and is upregulated upon mitochondrial stresses in mammalian cells and Drosophila. ZNF598 promotes resolution of stalled ribosomes and protects against mitochondrial stress in a ubiquitination-dependent fashion. In Drosophila models of neurodegenerative diseases and patient cells, ZNF598 overexpression aborts stalled translation of mitochondrial outer membrane-associated mRNAs, removes faulty translation products causal of disease, and improves mitochondrial and tissue health. These results shed lights on the regulation of ZNF598 and its functional role in mitochondrial and tissue homeostasis.
    DOI:  https://doi.org/10.1038/s41467-024-45525-3
  31. Curr Opin Cardiol. 2024 Feb 22.
    Metabolic basis of cardiac dysfunction in cancer patients.
    Jane C Figueiredo, Neil Adri Bhowmick, Anja Karlstaedt.
       PURPOSE OF REVIEW: The relationship between metabolism and cardiovascular diseases is complex and bidirectional. Cardiac cells must adapt metabolic pathways to meet biosynthetic demands and energy requirements to maintain contractile function. During cancer, this homeostasis is challenged by the increased metabolic demands of proliferating cancer cells.
    RECENT FINDINGS: Tumors have a systemic metabolic impact that extends beyond the tumor microenvironment. Lipid metabolism is critical to cancer cell proliferation, metabolic adaptation, and increased cardiovascular risk. Metabolites serve as signals which provide insights for diagnosis and prognosis in cardio-oncology patients.
    SUMMARY: Metabolic processes demonstrate a complex relationship between cancer cell states and cardiovascular remodeling with potential for therapeutic interventions.
    DOI:  https://doi.org/10.1097/HCO.0000000000001118
  32. Int J Mol Sci. 2024 Feb 08. pii: 2068. [Epub ahead of print]25(4):
    GATOR1 Mutations Impair PI3 Kinase-Dependent Growth Factor Signaling Regulation of mTORC1.
    Maéline Muller, Jasmine Bélanger, Imane Hadj-Aissa, Conghao Zhang, Chantelle F Sephton, Paul A Dutchak.
      GATOR1 (GAP Activity TOward Rag 1) is an evolutionarily conserved GTPase-activating protein complex that controls the activity of mTORC1 (mammalian Target Of Rapamycin Complex 1) in response to amino acid availability in cells. Genetic mutations in the GATOR1 subunits, NPRL2 (nitrogen permease regulator-like 2), NPRL3 (nitrogen permease regulator-like 3), and DEPDC5 (DEP domain containing 5), have been associated with epilepsy in humans; however, the specific effects of these mutations on GATOR1 function and mTORC1 regulation are not well understood. Herein, we report that epilepsy-linked mutations in the NPRL2 subunit of GATOR1, NPRL2-L105P, -T110S, and -D214H, increase basal mTORC1 signal transduction in cells. Notably, we show that NPRL2-L105P is a loss-of-function mutation that disrupts protein interactions with NPRL3 and DEPDC5, impairing GATOR1 complex assembly and resulting in high mTORC1 activity even under conditions of amino acid deprivation. Furthermore, our studies reveal that the GATOR1 complex is necessary for the rapid and robust inhibition of mTORC1 in response to growth factor withdrawal or pharmacological inhibition of phosphatidylinositol-3 kinase (PI3K). In the absence of the GATOR1 complex, cells are refractory to PI3K-dependent inhibition of mTORC1, permitting sustained translation and restricting the nuclear localization of TFEB, a transcription factor regulated by mTORC1. Collectively, our results show that epilepsy-linked mutations in NPRL2 can block GATOR1 complex assembly and restrict the appropriate regulation of mTORC1 by canonical PI3K-dependent growth factor signaling in the presence or absence of amino acids.
    Keywords:  GATOR1; NPRL2; NPRL3; PI3 kinase; amino acids; epilepsy; growth factor signaling; mTORC1; metabolism; transcription; translation
    DOI:  https://doi.org/10.3390/ijms25042068
  33. Nat Metab. 2024 Feb 22.
    Metabolic engineering for optimized CAR-T cell therapy.
    Sarah J McPhedran, Gillian A Carleton, Julian J Lum.
      The broad effectiveness of T cell-based therapy for treating solid tumour cancers remains limited. This is partly due to the growing appreciation that immune cells must inhabit and traverse a metabolically demanding tumour environment. Accordingly, recent efforts have centred on using genome-editing technologies to augment T cell-mediated cytotoxicity by manipulating specific metabolic genes. However, solid tumours exhibit numerous characteristics restricting immune cell-mediated cytotoxicity, implying a need for metabolic engineering at the pathway level rather than single gene targets. This emerging concept has yet to be put into clinical practice as many questions concerning the complex interplay between metabolic networks and T cell function remain unsolved. This Perspective will highlight key foundational studies that examine the relevant metabolic pathways required for effective T cell cytotoxicity and persistence in the human tumour microenvironment, feasible strategies for metabolic engineering to increase the efficiency of chimeric antigen receptor T cell-based approaches, and the challenges lying ahead for clinical implementation.
    DOI:  https://doi.org/10.1038/s42255-024-00976-2
  34. Nat Commun. 2024 Feb 23. 15(1): 1674
    Bacteria employ lysine acetylation of transcriptional regulators to adapt gene expression to cellular metabolism.
    Magdalena Kremer, Sabrina Schulze, Nadja Eisenbruch, Felix Nagel, Robert Vogt, Leona Berndt, Babett Dörre, Gottfried J Palm, Jens Hoppen, Britta Girbardt, Dirk Albrecht, Susanne Sievers, Mihaela Delcea, Ulrich Baumann, Karin Schnetz, Michael Lammers.
      The Escherichia coli TetR-related transcriptional regulator RutR is involved in the coordination of pyrimidine and purine metabolism. Here we report that lysine acetylation modulates RutR function. Applying the genetic code expansion concept, we produced site-specifically lysine-acetylated RutR proteins. The crystal structure of lysine-acetylated RutR reveals how acetylation switches off RutR-DNA-binding. We apply the genetic code expansion concept in E. coli in vivo revealing the consequences of RutR acetylation on the transcriptional level. We propose a model in which RutR acetylation follows different kinetic profiles either reacting non-enzymatically with acetyl-phosphate or enzymatically catalysed by the lysine acetyltransferases PatZ/YfiQ and YiaC. The NAD+-dependent sirtuin deacetylase CobB reverses enzymatic and non-enzymatic acetylation of RutR playing a dual regulatory and detoxifying role. By detecting cellular acetyl-CoA, NAD+ and acetyl-phosphate, bacteria apply lysine acetylation of transcriptional regulators to sense the cellular metabolic state directly adjusting gene expression to changing environmental conditions.
    DOI:  https://doi.org/10.1038/s41467-024-46039-8
  35. J Clin Invest. 2024 Feb 22. pii: e170559. [Epub ahead of print]
    Comparative genomics incorporating translocation renal cell carcinoma mouse model reveals molecular mechanisms of tumorigenesis.
    Gopinath Prakasam, Akhilesh Mishra, Alana Christie, Jeffrey Miyata, Deyssy Carrillo, Vanina T Tcheuyap, Hui Ye, Quyen N Do, Yunguan Wang, Oscar Reig Torras, Ramesh Butti, Hua Zhong, Jeffrey Gagan, Kevin B Jones, Thomas J Carroll, Zora Modrusan, Steffen Durinck, Mai-Carmen Requena-Komuro, Noelle S Williams, Ivan Pedrosa, Tao Wang, Dinesh Rakheja, Payal Kapur, James Brugarolas.
      Translocation Renal Cell Carcinoma (tRCC) most commonly involves an ASPSCR1-TFE3 fusion, but molecular mechanisms remain elusive and animal models are lacking. Here, we show that human ASPSCR1-TFE3 driven by Pax8-Cre (a credentialed ccRCC driver) disrupted nephrogenesis and glomerular development causing neonatal death, whilst the ccRCC failed driver, Sglt2-Cre, induced aggressive tRCC (as well as ASPS) with complete penetrance and short latency. However, in both contexts, ASPSCR1-TFE3 led to characteristic morphological cellular changes, loss of epithelial markers, and an EMT program. Electron microscopy of tRCC tumors showed lysosome expansion and functional studies revealed simultaneous activation of autophagy and mTORC1 pathways. Comparative genomic analyses encompassing an institutional human tRCC cohort (including a hitherto unreported SFPQ-TFEB fusion) and a variety of tumorgraft models (ASPSCR1-TFE3, PRCC-TFE3, SFPQ-TFE3, RBM10-TFE3, and MALAT1-TFEB) disclosed significant convergence in canonical (cell cycle, lysosome and mTORC1) and less established pathways such as Myc, E2F and inflammation (IL6/JAK/STAT3, interferon-γ, TLR signaling, systemic lupus, etc). Therapeutic trials (adjusted for human drug exposures) showed anti-tumor activity of cabozantinib. Overall, this study provides insight into MiT/TFE-driven tumorigenesis including the cell of origin and characterizes diverse mouse models available for research.
    Keywords:  Cancer; Cell biology; Molecular genetics; Mouse models; Oncology
    DOI:  https://doi.org/10.1172/JCI170559
  36. STAR Protoc. 2024 Feb 22. pii: S2666-1667(24)00078-9. [Epub ahead of print]5(1): 102913
    An optimized protocol for the extraction and quantification of cytosolic DNA in mammalian cells.
    Aminu S Jahun, Frederic Sorgeloos, Ian G Goodfellow.
      Leakage of mitochondrial or nuclear DNA into the cytosol can occur following viral infections, radiation damage, and some cancers. Here, we present an optimized protocol for isolating and quantifying cytosolic DNA from mammalian cells. We describe steps for collecting cytosolic fractions from cells, extracting DNA using columns, and quantifying extracted DNA using qPCR. This straightforward protocol can be completed in as little as 5 hours, and allows for the identification of the source of DNA. For complete details on the use and execution of this protocol, please refer to Jahun et al.1.
    Keywords:  Cancer; Cell Biology; Cell separation/fractionation; Cell-based Assays; Immunology; Molecular Biology
    DOI:  https://doi.org/10.1016/j.xpro.2024.102913
  37. Life Sci Alliance. 2024 May;pii: e202302300. [Epub ahead of print]7(5):
    Ageing-dependent thiol oxidation reveals early oxidation of proteins with core proteostasis functions.
    Katarzyna Jonak, Ida Suppanz, Julian Bender, Agnieszka Chacinska, Bettina Warscheid, Ulrike Topf.
      Oxidative post-translational modifications of protein thiols are well recognized as a readily occurring alteration of proteins, which can modify their function and thus control cellular processes. The development of techniques enabling the site-specific assessment of protein thiol oxidation on a proteome-wide scale significantly expanded the number of known oxidation-sensitive protein thiols. However, lacking behind are large-scale data on the redox state of proteins during ageing, a physiological process accompanied by increased levels of endogenous oxidants. Here, we present the landscape of protein thiol oxidation in chronologically aged wild-type Saccharomyces cerevisiae in a time-dependent manner. Our data determine early-oxidation targets in key biological processes governing the de novo production of proteins, protein folding, and degradation, and indicate a hierarchy of cellular responses affected by a reversible redox modification. Comparison with existing datasets in yeast, nematode, fruit fly, and mouse reveals the evolutionary conservation of these oxidation targets. To facilitate accessibility, we integrated the cross-species comparison into the newly developed OxiAge Database.
    DOI:  https://doi.org/10.26508/lsa.202302300
  38. Nat Commun. 2024 Feb 19. 15(1): 1524
    Regulation of stress granule formation in human oligodendrocytes.
    Florian Pernin, Qiao-Ling Cui, Abdulshakour Mohammadnia, Milton G F Fernandes, Jeffery A Hall, Myriam Srour, Roy W R Dudley, Stephanie E J Zandee, Wendy Klement, Alexandre Prat, Hannah E Salapa, Michael C Levin, G R Wayne Moore, Timothy E Kennedy, Christine Vande Velde, Jack P Antel.
      Oligodendrocyte (OL) injury and subsequent loss is a pathologic hallmark of multiple sclerosis (MS). Stress granules (SGs) are membrane-less organelles containing mRNAs stalled in translation and considered as participants of the cellular response to stress. Here we show SGs in OLs in active and inactive areas of MS lesions as well as in normal-appearing white matter. In cultures of primary human adult brain derived OLs, metabolic stress conditions induce transient SG formation in these cells. Combining pro-inflammatory cytokines, which alone do not induce SG formation, with metabolic stress results in persistence of SGs. Unlike sodium arsenite, metabolic stress induced SG formation is not blocked by the integrated stress response inhibitor. Glycolytic inhibition also induces persistent SGs indicating the dependence of SG formation and disassembly on the energetic glycolytic properties of human OLs. We conclude that SG persistence in OLs in MS reflects their response to a combination of metabolic stress and pro-inflammatory conditions.
    DOI:  https://doi.org/10.1038/s41467-024-45746-6
  39. Redox Biol. 2024 Feb 13. pii: S2213-2317(24)00063-6. [Epub ahead of print]71 103087
    METTL17 coordinates ferroptosis and tumorigenesis by regulating mitochondrial translation in colorectal cancer.
    Hao Li, Kailun Yu, Huilong Hu, Xiandan Zhang, Siyu Zeng, Jiawen Li, Xiaoning Dong, Xusheng Deng, Jianhui Zhang, Yongyou Zhang.
      Ferroptosis, an iron-dependent lipid peroxidation-induced form of regulated cell death, shows great promise as a cancer therapy strategy. Despite the critical role of mitochondria in ferroptosis regulation, the underlying mechanisms remain elusive. This study reveals that the mitochondrial protein METTL17 governs mitochondrial function in colorectal cancer (CRC) cells through epigenetic modulation. Bioinformatic analysis establishes that METTL17 expression positively correlates with ferroptosis resistance in cancer cells and is up-regulated in CRC. Depletion of METTL17 sensitizes CRC cells to ferroptosis, impairs cell proliferation, migration, invasion, xenograft tumor growth, and AOM/DSS-induced CRC tumorigenesis. Furthermore, suppression of METTL17 disrupts mitochondrial function, energy metabolism, and enhances intracellular and mitochondrial lipid peroxidation and ROS levels during ferroptotic stress. Mechanistically, METTL17 inhibition significantly reduces mitochondrial RNA methylation, including m4C, m5C, m3C, m7G, and m6A, leading to impaired translation of mitochondrial protein-coding genes. Additionally, the interacting proteins associated with METTL17 are essential for mitochondrial gene expression, and their knockdown sensitizes CRC cells to ferroptosis and inhibits cell proliferation. Notably, combined targeting of METTL17 and ferroptosis in a therapeutic approach effectively suppresses CRC xenograft growth in vivo. This study uncovers the METTL17-mediated defense mechanism for cell survival and ferroptosis in mitochondria, highlighting METTL17 as a potential therapeutic target for CRC.
    Keywords:  Colorectal cancer (CRC); Ferroptosis; METTL17; Mitochondrial RNA methylation
    DOI:  https://doi.org/10.1016/j.redox.2024.103087
  40. Biomolecules. 2024 Jan 26. pii: 149. [Epub ahead of print]14(2):
    FLVCR1a Controls Cellular Cholesterol Levels through the Regulation of Heme Biosynthesis and Tricarboxylic Acid Cycle Flux in Endothelial Cells.
    Marta Manco, Giorgia Ammirata, Sara Petrillo, Francesco De Giorgio, Simona Fontana, Chiara Riganti, Paolo Provero, Sharmila Fagoonee, Fiorella Altruda, Emanuela Tolosano.
      Feline leukemia virus C receptor 1a (FLVCR1a), initially identified as a retroviral receptor and localized on the plasma membrane, has emerged as a crucial regulator of heme homeostasis. Functioning as a positive regulator of δ-aminolevulinic acid synthase 1 (ALAS1), the rate-limiting enzyme in the heme biosynthetic pathway, FLVCR1a influences TCA cycle cataplerosis, thus impacting TCA flux and interconnected metabolic pathways. This study reveals an unexplored link between FLVCR1a, heme synthesis, and cholesterol production in endothelial cells. Using cellular models with manipulated FLVCR1a expression and inducible endothelial-specific Flvcr1a-null mice, we demonstrate that FLVCR1a-mediated control of heme synthesis regulates citrate availability for cholesterol synthesis, thereby influencing cellular cholesterol levels. Moreover, alterations in FLVCR1a expression affect membrane cholesterol content and fluidity, supporting a role for FLVCR1a in the intricate regulation of processes crucial for vascular development and endothelial function. Our results underscore FLVCR1a as a positive regulator of heme synthesis, emphasizing its integration with metabolic pathways involved in cellular energy metabolism. Furthermore, this study suggests that the dysregulation of heme metabolism may have implications for modulating lipid metabolism. We discuss these findings in the context of FLVCR1a's potential heme-independent function as a choline importer, introducing additional complexity to the interplay between heme and lipid metabolism.
    Keywords:  ALAS1; FLVCR1; FLVCR1a; cholesterol; endothelial cell; heme; heme synthesis
    DOI:  https://doi.org/10.3390/biom14020149
  41. Cell Metab. 2024 Feb 13. pii: S1550-4131(24)00018-4. [Epub ahead of print]
    Methionine secreted by tumor-associated pericytes supports cancer stem cells in clear cell renal carcinoma.
    ChuanJie Zhang, ZunGuo Du, Yi Gao, Kiat Shenq Lim, WenJie Zhou, Hai Huang, HongChao He, Jun Xiao, DanFeng Xu, QingQuan Li.
      Here, we identify a subset of vascular pericytes, defined by expression of platelet-derived growth factor receptor beta (PDGFR-β) and G-protein-coupled receptor 91 (GPR91), that promote tumorigenesis and tyrosine kinase inhibitors (TKIs) resistance by functioning as the primary methionine source for cancer stem cells (CSCs) in clear cell renal cell carcinoma (ccRCC). Tumor-cell-derived succinate binds to GPR91 on pericyte to activate autophagy for methionine production. CSCs use methionine to create stabilizing N6-methyladenosine in ATPase-family-AAA-domain-containing 2 (ATAD2) mRNA, and the resulting ATAD2 protein complexes with SRY-box transcription factor 9 to assemble super enhancers and thereby dictate its target genes that feature prominently in CSCs. Targeting PDGFR-β+GPR91+ pericytes with specific GRP91 antagonists reduce intratumoral methionine level, eliminate CSCs, and enhance TKIs sensitivity. These results unraveled the mechanisms by which PDGFR-β+GPR91+ pericytes provide supportive niche for CSCs and could be used to develop targets for treating ccRCC.
    Keywords:  GPR91; autophagy; cancer stem cell; clear cell renal cell carcinoma; methionine; pericytes
    DOI:  https://doi.org/10.1016/j.cmet.2024.01.018
  42. Cancer Res. 2024 Feb 22.
    PRMT1 sustains de novo fatty acid synthesis by methylating PHGDH to drive chemoresistance in triple-negative breast cancer.
    Takehiro Yamamoto, Tetsu Hayashida, Yohei Masugi, Kiyotaka Oshikawa, Noriyo Hayakawa, Mai Itoh, Chiyoko Nishime, Masami Suzuki, Aiko Nagayama, Yuko Kawai, Takako Hishiki, Tomomi Matsuura, Yoshiko Naito, Akiko Kubo, Arisa Yamamoto, Yujiro Yoshioka, Tomokazu Kurahori, Misa Nagasaka, Minako Takizawa, Naoharu Takano, Koji Kawakami, Michiie Sakamoto, Masatoshi Wakui, Takushi Yamamoto, Yuko Kitagawa, Yasuaki Kabe, Kenichi Horisawa, Atsushi Suzuki, Masaki Matsumoto, Makoto Suematsu.
      Triple-negative breast cancer (TNBC) chemoresistance hampers the ability to effectively treat patients. Identification of mechanisms driving chemoresistance can lead to strategies to improve treatment. Here, we revealed that protein arginine methyltransferase-1 (PRMT1) simultaneously methylates D-3-phosphoglycerate dehydrogenase (PHGDH), a critical enzyme in serine synthesis, and the glycolytic enzymes PFKFB3 and PKM2 in TNBC cells. 13C metabolic flux analyses showed that PRMT1 methylation of these three enzymes diverts glucose toward intermediates in the serine-synthesizing and serine/glycine cleavage pathways, thereby accelerating the production of methyl donors in TNBC cells. Mechanistically, PRMT1-dependent methylation of PHGDH at R54 or R20 activated its enzymatic activity by stabilizing 3-phosphoglycerate binding and suppressing polyubiquitination. PRMT1-mediated PHGDH methylation drove chemoresistance independently of glutathione synthesis. Rather, activation of the serine synthesis pathway supplied α-ketoglutarate and citrate to increase palmitate levels through activation of fatty acid synthase (FASN). Increased palmitate induced protein S-palmitoylation of PHGDH and FASN to further enhance fatty acid synthesis in a PRMT1-dependent manner. Loss of PRMT1 or pharmacological inhibition of FASN or protein S-palmitoyltransferase reversed chemoresistance in TNBC. Furthermore, immunohistochemistry coupled with imaging mass spectrometry in clinical TNBC specimens substantiated that PRMT1-mediated methylation of PHGDH, PFKFB3, and PKM2 correlates with chemoresistance and that metabolites required for methylation and fatty acid synthesis are enriched in TNBC. Together, these results suggest that enhanced de novo fatty acid synthesis mediated by coordinated protein arginine methylation and protein S-palmitoylation is a therapeutic target for overcoming chemoresistance in TNBC.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-23-2266
  43. Cell Rep. 2024 Feb 19. pii: S2211-1247(24)00138-4. [Epub ahead of print]43(2): 113810
    Proteogenomic characterization of primary colorectal cancer and metastatic progression identifies proteome-based subtypes and signatures.
    Atsushi Tanaka, Makiko Ogawa, Yihua Zhou, Kei Namba, Ronald C Hendrickson, Matthew M Miele, Zhuoning Li, David S Klimstra, Patrick G Buckley, Jeffrey Gulcher, Julia Y Wang, Michael H A Roehrl.
      Metastatic progression of colorectal adenocarcinoma (CRC) remains poorly understood and poses significant challenges for treatment. To overcome these challenges, we performed multiomics analyses of primary CRC and liver metastases. Genomic alterations, such as structural variants or copy number alterations, were enriched in oncogenes and tumor suppressor genes and increased in metastases. Unsupervised mass spectrometry-based proteomics of 135 primary and 123 metastatic CRCs uncovered distinct proteomic subtypes, three each for primary and metastatic CRCs, respectively. Integrated analyses revealed that hypoxia, stemness, and immune signatures characterize these 6 subtypes. Hypoxic CRC harbors high epithelial-to-mesenchymal transition features and metabolic adaptation. CRC with a stemness signature shows high oncogenic pathway activation and alternative telomere lengthening (ALT) phenotype, especially in metastatic lesions. Tumor microenvironment analysis shows immune evasion via modulation of major histocompatibility complex (MHC) class I/II and antigen processing pathways. This study characterizes both primary and metastatic CRCs and provides a large proteogenomics dataset of metastatic progression.
    Keywords:  CP: Cancer; biomarkers; colorectal cancer; hypoxia; mass spectrometry; metastasis; molecular signature; proteomics; stemness; subtyping; tumor immune microenvironment
    DOI:  https://doi.org/10.1016/j.celrep.2024.113810
  44. Nature. 2024 Feb 21.
    Why are we nice? Altruism's origins are put to the test.
    Benjamin Thompson, Nick Petrić Howe.
      
    Keywords:  Evolution; Human behaviour; Optics and photonics
    DOI:  https://doi.org/10.1038/d41586-024-00539-1
  45. Nat Commun. 2024 Feb 22. 15(1): 1646
    M2 macrophages independently promote beige adipogenesis via blocking adipocyte Ets1.
    Suyang Wu, Chen Qiu, Jiahao Ni, Wenli Guo, Jiyuan Song, Xingyin Yang, Yulin Sun, Yanjun Chen, Yunxia Zhu, Xiaoai Chang, Peng Sun, Chunxia Wang, Kai Li, Xiao Han.
      Adipose tissue macrophages can promote beige adipose thermogenesis by altering local sympathetic activity. Here, we perform sympathectomy in mice and further eradicate subcutaneous adipose macrophages and discover that these macrophages have a direct beige-promoting function that is independent of sympathetic system. We further identify adipocyte Ets1 as a vital mediator in this process. The anti-inflammatory M2 macrophages suppress Ets1 expression in adipocytes, transcriptionally activate mitochondrial biogenesis, as well as suppress mitochondrial clearance, thereby increasing the mitochondrial numbers and promoting the beiging process. Male adipocyte Ets1 knock-in mice are completely cold intolerant, whereas male mice lacking Ets1 in adipocytes show enhanced energy expenditure and are resistant to metabolic disorders caused by high-fat-diet. Our findings elucidate a direct communication between M2 macrophages and adipocytes, and uncover a function for Ets1 in responding to macrophages and negatively governing mitochondrial content and beige adipocyte formation.
    DOI:  https://doi.org/10.1038/s41467-024-45899-4
  46. Nat Commun. 2024 Feb 21. 15(1): 1579
    Oncogenic c-Myc induces replication stress by increasing cohesins chromatin occupancy in a CTCF-dependent manner.
    Silvia Peripolli, Leticia Meneguello, Chiara Perrod, Tanya Singh, Harshil Patel, Sazia T Rahman, Koshiro Kiso, Peter Thorpe, Vincenzo Calvanese, Cosetta Bertoli, Robertus A M de Bruin.
      Oncogene-induced replication stress is a crucial driver of genomic instability and one of the key events contributing to the onset and evolution of cancer. Despite its critical role in cancer, the mechanisms that generate oncogene-induced replication stress remain not fully understood. Here, we report that an oncogenic c-Myc-dependent increase in cohesins on DNA contributes to the induction of replication stress. Accumulation of cohesins on chromatin is not sufficient to cause replication stress, but also requires cohesins to accumulate at specific sites in a CTCF-dependent manner. We propose that the increased accumulation of cohesins at CTCF site interferes with the progression of replication forks, contributing to oncogene-induced replication stress. This is different from, and independent of, previously suggested mechanisms of oncogene-induced replication stress. This, together with the reported protective role of cohesins in preventing replication stress-induced DNA damage, supports a double-edge involvement of cohesins in causing and tolerating oncogene-induced replication stress.
    DOI:  https://doi.org/10.1038/s41467-024-45955-z
  47. Proc Natl Acad Sci U S A. 2024 Feb 27. 121(9): e2320129121
    Targeting nuclear receptor corepressors for reversible male contraception.
    Suk-Hyun Hong, Glenda Castro, Dan Wang, Russell Nofsinger, Maureen Kane, Alexandra Folias, Annette R Atkins, Ruth T Yu, Joseph L Napoli, Paolo Sassone-Corsi, Dirk G de Rooij, Christopher Liddle, Michael Downes, Ronald M Evans.
      Despite numerous female contraceptive options, nearly half of all pregnancies are unintended. Family planning choices for men are currently limited to unreliable condoms and invasive vasectomies with questionable reversibility. Here, we report the development of an oral contraceptive approach based on transcriptional disruption of cyclical gene expression patterns during spermatogenesis. Spermatogenesis involves a continuous series of self-renewal and differentiation programs of spermatogonial stem cells (SSCs) that is regulated by retinoic acid (RA)-dependent activation of receptors (RARs), which control target gene expression through association with corepressor proteins. We have found that the interaction between RAR and the corepressor silencing mediator of retinoid and thyroid hormone receptors (SMRT) is essential for spermatogenesis. In a genetically engineered mouse model that negates SMRT-RAR binding (SMRTmRID mice), the synchronized, cyclic expression of RAR-dependent genes along the seminiferous tubules is disrupted. Notably, the presence of an RA-resistant SSC population that survives RAR de-repression suggests that the infertility attributed to the loss of SMRT-mediated repression is reversible. Supporting this notion, we show that inhibiting the action of the SMRT complex with chronic, low-dose oral administration of a histone deacetylase inhibitor reversibly blocks spermatogenesis and fertility without affecting libido. This demonstration validates pharmacologic targeting of the SMRT repressor complex for non-hormonal male contraception.
    Keywords:  retinoic acid signaling; spermatogenesis; transcriptional corepression
    DOI:  https://doi.org/10.1073/pnas.2320129121
  48. Cell Rep. 2024 Feb 21. pii: S2211-1247(24)00139-6. [Epub ahead of print]43(3): 113811
    YAP mediates apoptosis through failed integrin adhesion reinforcement.
    Lidan Shi, Elisabeth Nadjar-Boger, Hamidreza Jafarinia, Aurélie Carlier, Haguy Wolfenson.
      Extracellular matrix (ECM) rigidity is a major effector of cell fate decisions. Whereas cell proliferation on stiff matrices, wherein Yes-associated protein (YAP) plays a pivotal role, is well documented, activation of apoptosis in response to soft matrices is poorly understood. Here, we show that YAP drives the apoptotic decision as well. We find that in cells on soft matrices, YAP is recruited to small adhesions, phosphorylated at the Y357 residue, and translocated into the nucleus, ultimately leading to apoptosis. In contrast, Y357 phosphorylation levels are dramatically low in large adhesions on stiff matrices. Furthermore, mild attenuation of actomyosin contractility allows adhesion growth on soft matrices, leading to reduced Y357 phosphorylation levels and resulting in cell growth. These findings indicate that failed adhesion reinforcement drives rigidity-dependent apoptosis through YAP and that this decision is not determined solely by ECM rigidity but rather by the balance between cellular forces and ECM rigidity.
    Keywords:  CP: Cell biology; Src; YAP; actomyosin; anchorage-independence; apoptosis; c-Abl; mechanosensing; pYAP-Y357; rigidity sensing
    DOI:  https://doi.org/10.1016/j.celrep.2024.113811
  49. Cell Rep. 2024 Feb 16. pii: S2211-1247(24)00136-0. [Epub ahead of print]43(2): 113808
    UDP-glucose dehydrogenase supports autophagy-deficient PDAC growth via increasing hyaluronic acid biosynthesis.
    Minghe Fan, Sihan Huo, Yuyao Guo, Ruoxuan Wang, Wenqin Hao, Ziyang Zhang, Lina Wang, Ying Zhao.
      Autophagy is an essential degradation and recycling process that maintains cellular homeostasis during stress or nutrient deprivation. However, certain types of tumors such as pancreatic cancers can circumvent autophagy inhibition to sustain growth. The mechanism that autophagy-deficient pancreatic ductal adenocarcinoma (PDAC) uses to grow under nutrient deprivation is poorly understood. Our data show that nutrient deprivation in PDAC results in UDP-glucose dehydrogenase (UGDH) degradation, which is dependent on autophagic cargo receptor sequestosome 1 (p62). Moreover, we demonstrate that accumulated UGDH is indispensable for autophagy-deficient PDAC cells proliferation by promoting hyaluronic acid (HA) synthesis upon energy deprivation. Using an orthotopic mouse model of PDAC, we find that inhibition of HA synthesis by targeting UGDH in PDAC reduces tumor weight. Thus, the combined inhibition of HA and autophagy might be an attractive strategy for PDAC treatment.
    Keywords:  CP: Cancer; CP: Metabolism; HA; PDAC; UDP-glucose dehydrogenase; UGDH; autophagy; hyaluronic acid; p62; pancreatic ductal adenocarcinoma; sequestosome 1
    DOI:  https://doi.org/10.1016/j.celrep.2024.113808
  50. Development. 2024 Feb 15. pii: dev202020. [Epub ahead of print]151(4):
    Developmental regulation of cellular metabolism is required for intestinal elongation and rotation.
    Julia K Grzymkowski, Yu-Chun Chiu, Dereje D Jima, Brent H Wyatt, Sudhish Jayachandran, Whitney L Stutts, Nanette M Nascone-Yoder.
      Malrotation of the intestine is a prevalent birth anomaly, the etiology of which remains poorly understood. Here, we show that late-stage exposure of Xenopus embryos to atrazine, a widely used herbicide that targets electron transport chain (ETC) reactions, elicits intestinal malrotation at high frequency. Interestingly, atrazine specifically inhibits the cellular morphogenetic events required for gut tube elongation, including cell rearrangement, differentiation and proliferation; insufficient gut lengthening consequently reorients the direction of intestine rotation. Transcriptome analyses of atrazine-exposed intestines reveal misexpression of genes associated with glycolysis and oxidative stress, and metabolomics shows that atrazine depletes key glycolytic and tricarboxylic acid cycle metabolites. Moreover, cellular bioenergetics assays indicate that atrazine blocks a crucial developmental transition from glycolytic ATP production toward oxidative phosphorylation. Atrazine-induced defects are phenocopied by rotenone, a known ETC Complex I inhibitor, accompanied by elevated reactive oxygen species, and rescued by antioxidant supplementation, suggesting that malrotation may be at least partly attributable to redox imbalance. These studies reveal roles for metabolism in gut morphogenesis and implicate defective gut tube elongation and/or metabolic perturbations in the etiology of intestinal malrotation.
    Keywords:   Xenopus ; Atrazine; Electron transport chain; Elongation; Intestine; Metabolism; Rotation
    DOI:  https://doi.org/10.1242/dev.202020
  51. Science. 2024 Feb 23. 383(6685): eadi3808
    An immunogenetic basis for lung cancer risk.
    FinnGen§
      Cancer risk is influenced by inherited mutations, DNA replication errors, and environmental factors. However, the influence of genetic variation in immunosurveillance on cancer risk is not well understood. Leveraging population-level data from the UK Biobank and FinnGen, we show that heterozygosity at the human leukocyte antigen (HLA)-II loci is associated with reduced lung cancer risk in smokers. Fine-mapping implicated amino acid heterozygosity in the HLA-II peptide binding groove in reduced lung cancer risk, and single-cell analyses showed that smoking drives enrichment of proinflammatory lung macrophages and HLA-II+ epithelial cells. In lung cancer, widespread loss of HLA-II heterozygosity (LOH) favored loss of alleles with larger neopeptide repertoires. Thus, our findings nominate genetic variation in immunosurveillance as a critical risk factor for lung cancer.
    DOI:  https://doi.org/10.1126/science.adi3808
  52. Trends Endocrinol Metab. 2024 Feb 22. pii: S1043-2760(24)00025-0. [Epub ahead of print]
    Lysine lactylation in the regulation of tumor biology.
    Zijian Yang, Yingqi Zheng, Qiang Gao.
      Lysine lactylation (Kla), a newly discovered post-translational modification (PTM) of lysine residues, is progressively revealing its crucial role in tumor biology. A growing body of evidence supports its capacity of transcriptional regulation through histone modification and modulation of non-histone protein function. It intricately participates in a myriad of events in the tumor microenvironment (TME) by orchestrating the transitions of immune states and augmenting tumor malignancy. Its preferential modification of metabolic proteins underscores its specific regulatory influence on metabolism. This review focuses on the effect and the probable mechanisms of Kla-mediated regulation of tumor metabolism, the upstream factors that determine Kla intensity, and its potential implications for the clinical diagnosis and treatment of tumors.
    Keywords:  lysine lactylation; post-translational modification; precision medicine; tumor metabolism; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.tem.2024.01.011
  53. Trends Cell Biol. 2024 Feb 22. pii: S0962-8924(24)00022-9. [Epub ahead of print]
    Driving factors of neuronal ferroptosis.
    Julie Jacquemyn, Isha Ralhan, Maria S Ioannou.
      Ferroptosis is an oxidative form of iron-dependent cell death characterized by the accumulation of lipid peroxides on membranes. Iron and lipids containing polyunsaturated fatty acids are essential for this process. Ferroptosis is central to several neurological diseases and underlies the importance of balanced iron and polyunsaturated fatty acid metabolism in the brain, particularly in neurons. Here, we reflect on the potential links between neuronal physiology and the accumulation of iron and peroxidated lipids, the mechanisms neurons use to protect themselves from ferroptosis, and the relationship between pathogenic protein deposition and ferroptosis in neurodegenerative disease. We propose that the unique physiology of neurons makes them especially vulnerable to ferroptosis.
    Keywords:  ferroptosis; iron; lipid peroxidation; neurodegenerative disease; neuron; unsaturated fatty acid
    DOI:  https://doi.org/10.1016/j.tcb.2024.01.010
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