bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2024–11–24
48 papers selected by
Christian Frezza, Universität zu Köln
  1. An alternative route for β-hydroxybutyrate metabolism supports fatty acid synthesis in cancer cells.
  2. Nutrient control of growth and metabolism through mTORC1 regulation of mRNA splicing.
  3. Textbook oxidative phosphorylation needs to be rewritten.
  4. Endogenous mitochondrial NAD(P)H fluorescence can predict lifespan.
  5. A mitochondrial redox switch licenses the onset of morphogenesis in animals.
  6. AMPK: Balancing mitochondrial quality and quantity through opposite regulation of mitophagy pathways.
  7. Human genetics identify convergent signals in mitochondrial LACTB-mediated lipid metabolism in cardiovascular-kidney-metabolic syndrome.
  8. Brown Fat and Metabolic Health: The Diverse Functions of Dietary Components.
  9. Impaired branched chain amino acid (BCAA) catabolism during adipocyte differentiation decreases glycolytic flux.
  10. Multiomics reveals age-dependent metabolic reprogramming of macrophages by wound bed niche secreted signals.
  11. Spatially restricted immune and microbiota-driven adaptation of the gut.
  12. Mapping the Temporal Landscape of Breast Cancer Using Epigenetic Entropy.
  13. Gliocidin is a nicotinamide-mimetic prodrug that targets glioblastoma.
  14. ACBP orchestrates the metabolic phenotype in Cushing's syndrome.
  15. Tumor cell-derived spermidine promotes a pro-tumorigenic immune microenvironment in glioblastoma via CD8+ T cell inhibition.
  16. DFCP1 is a Regulator of Starvation-driven ATGL-mediated Lipid Droplet Lipolysis.
  17. Mitochondrial NADK2-dependent NADPH controls Tau oligomer uptake in human neurons.
  18. Interaction with the cysteine-free protein HAX1 expands the substrate specificity and function of MIA40 beyond protein oxidation.
  19. The commitment of the human cell atlas to humanity.
  20. Evolving cell states and oncogenic drivers during the progression of IDH-mutant gliomas.
  21. An expanded view of cell competition.
  22. TET3 regulates terminal cell differentiation at the metabolic level.
  23. Cancer cachexia: multilevel metabolic dysfunction.
  24. ZBTB7A is a modulator of KDM5-driven transcriptional networks in basal breast cancer.
  25. Human HDAC6 senses valine abundancy to regulate DNA damage.
  26. mTORC1, the maestro of cell metabolism and growth.
  27. Metabolic complementation between cells drives the evolution of tissues and organs.
  28. Proteomic insights into circadian transcription regulation: novel E-box interactors revealed by proximity labeling.
  29. Liver X receptor unlinks intestinal regeneration and tumorigenesis.
  30. Regulation of mitochondrial oxidative phosphorylation through tight control of cytochrome c oxidase in health and disease - Implications for ischemia/reperfusion injury, inflammatory diseases, diabetes, and cancer.
  31. Single-cell integration reveals metaplasia in inflammatory gut diseases.
  32. Molecular and genetic insights into human ovarian aging from single-nuclei multi-omics analyses.
  33. Social state alters vision using three circuit mechanisms in Drosophila.
  34. Adipose tissue retains an epigenetic memory of obesity after weight loss.
  35. Coordinated translational control of multiple immune checkpoints by the integrated stress response pathway in lung cancer.
  36. Methylglyoxal is an antibacterial effector produced by macrophages during infection.
  37. Macrophage modulation of tumor immunity.
  38. Pathogenic PDE12 variants impair mitochondrial RNA processing causing neonatal mitochondrial disease.
  39. Cutaneous T cell lymphoma atlas reveals malignant TH2 cells supported by a B cell-rich tumor microenvironment.
  40. Sticky enzymes: increased metabolic efficiency via substrate-dependent enzyme clustering.
  41. Role of Arginine and its Metabolism in TGF-β-Induced Activation of Lung Fibroblasts.
  42. Human metabolic chambers reveal a coordinated metabolic-physiologic response to nutrition.
  43. Acid-exposed and hypoxic cancer cells do not overlap but are interdependent for unsaturated fatty acid resources.
  44. The critical role of endoplasmic reticulum stress and the stimulator of interferon genes (STING) pathway in kidney fibrosis.
  45. H 2 S remodels mitochondrial ultrastructure and destabilizes respiratory supercomplexes.
  46. The DNA demethylase TET1 modifies the impact of maternal folic acid status on embryonic brain development.
  47. Morphological diversity in SDH-deficient renal carcinomas: a three-case exploration of variant features and dedifferentiation.
  48. Lysosomal catabolic activity promotes the exit of murine totipotent 2-cell state by silencing early-embryonic retrotransposons.
  1. bioRxiv. 2024 Nov 03. pii: 2024.10.31.621317. [Epub ahead of print]
    An alternative route for β-hydroxybutyrate metabolism supports fatty acid synthesis in cancer cells.
    Faith C Kaluba, Thomas J Rogers, Yu-Jin Jeong, Althea Waldhart, Kelly H Sokol, Cameron J Lee, Samuel R Daniels, Joseph Longo, Amy Johnson, Ryan D Sheldon, Russell G Jones, Evan C Lien.
      Cancer cells are exposed to diverse metabolites in the tumor microenvironment that are used to support the synthesis of nucleotides, amino acids, and lipids needed for rapid cell proliferation 1-3 . Recent work has shown that ketone bodies such as β-hydroxybutyrate (β-OHB), which are elevated in circulation under fasting conditions or low glycemic diets, can serve as an alternative fuel that is metabolized in the mitochondria to provide acetyl-CoA for the tricarboxylic acid (TCA) cycle in some tumors 4-7 . Here, we discover a non-canonical route for β-OHB metabolism, in which β-OHB can bypass the TCA cycle to generate cytosolic acetyl-CoA for de novo fatty acid synthesis in cancer cells. We show that β-OHB-derived acetoacetate in the mitochondria can be shunted into the cytosol, where acetoacetyl-CoA synthetase (AACS) and thiolase convert it into acetyl-CoA for fatty acid synthesis. This alternative metabolic routing of β-OHB allows it to avoid oxidation in the mitochondria and net contribute to anabolic biosynthetic processes. In cancer cells, β-OHB is used for fatty acid synthesis to support cell proliferation under lipid-limited conditions in vitro and contributes to tumor growth under lipid-limited conditions induced by a calorie-restricted diet in vivo . Together, these data demonstrate that β-OHB is preferentially used for fatty acid synthesis in cancer cells to support tumor growth.
    DOI:  https://doi.org/10.1101/2024.10.31.621317
  2. Mol Cell. 2024 Nov 15. pii: S1097-2765(24)00877-3. [Epub ahead of print]
    Nutrient control of growth and metabolism through mTORC1 regulation of mRNA splicing.
    Takafumi Ogawa, Meltem Isik, Ziyun Wu, Kiran Kurmi, Jin Meng, Sungyun Cho, Gina Lee, L Paulette Fernandez-Cardenas, Masaki Mizunuma, John Blenis, Marcia C Haigis, T Keith Blackwell.
      Cellular growth and organismal development are remarkably complex processes that require the nutrient-responsive kinase mechanistic target of rapamycin complex 1 (mTORC1). Anticipating that important mTORC1 functions remained to be identified, we employed genetic and bioinformatic screening in C. elegans to uncover mechanisms of mTORC1 action. Here, we show that during larval growth, nutrients induce an extensive reprogramming of gene expression and alternative mRNA splicing by acting through mTORC1. mTORC1 regulates mRNA splicing and the production of protein-coding mRNA isoforms largely independently of its target p70 S6 kinase (S6K) by increasing the activity of the serine/arginine-rich (SR) protein RSP-6 (SRSF3/7) and other splicing factors. mTORC1-mediated mRNA splicing regulation is critical for growth; mediates nutrient control of mechanisms that include energy, nucleotide, amino acid, and other metabolic pathways; and may be conserved in humans. Although mTORC1 inhibition delays aging, mTORC1-induced mRNA splicing promotes longevity, suggesting that when mTORC1 is inhibited, enhancement of this splicing might provide additional anti-aging benefits.
    Keywords:  C. elegans; SR proteins; development; gene expression; growth; human cell growth; longevity; mRNA splicing; mTORC1; metabolism; nutrient response
    DOI:  https://doi.org/10.1016/j.molcel.2024.10.037
  3. Trends Biochem Sci. 2024 Nov 21. pii: S0968-0004(24)00254-8. [Epub ahead of print]
    Textbook oxidative phosphorylation needs to be rewritten.
    Alicia J Kowaltowski, Fernando Abdulkader.
      Oxidative phosphorylation (OxPhos) is the energy-transfer process that generates most of our ATP, fueled by proton and electrical gradients across the inner mitochondrial membrane. A new surprising finding by Hernansanz-Agustín et al. demonstrates that between one-third and half of this gradient is attributable to Na+, transported in exchange for protons within complex I.
    Keywords:  complex I; ion transport; mitochondria; oxidative phosphorylation; sodium–proton exchange
    DOI:  https://doi.org/10.1016/j.tibs.2024.11.002
  4. Commun Biol. 2024 Nov 21. 7(1): 1551
    Endogenous mitochondrial NAD(P)H fluorescence can predict lifespan.
    Christopher S Morrow, Pallas Yao, Carlos A Vergani-Junior, Praju Vikas Anekal, Paula Montero Llopis, Jeffrey W Miller, Bérénice A Benayoun, William B Mair.
      Many aging clocks have recently been developed to predict health outcomes and deconvolve heterogeneity in aging. However, existing clocks are limited by technical constraints, such as low spatial resolution, long processing time, sample destruction, and a bias towards specific aging phenotypes. Therefore, here we present a non-destructive, label-free and subcellular resolution approach for quantifying aging through optically resolving age-dependent changes to the biophysical properties of NAD(P)H in mitochondria through fluorescence lifetime imaging (FLIM) of endogenous NAD(P)H fluorescence. We uncover age-dependent changes to mitochondrial NAD(P)H across tissues in C. elegans that are associated with a decline in physiological function and construct non-destructive, label-free and cellular resolution models for prediction of age, which we refer to as "mito-NAD(P)H age clocks." Mito-NAD(P)H age clocks can resolve heterogeneity in the rate of aging across individuals and predict remaining lifespan. Moreover, we spatiotemporally resolve age-dependent changes to mitochondria across and within tissues, revealing multiple modes of asynchrony in aging and show that longevity is associated with a ubiquitous attenuation of these changes. Our data present a high-resolution view of mitochondrial NAD(P)H across aging, providing insights that broaden our understanding of how mitochondria change during aging and approaches which expand the toolkit to quantify aging.
    DOI:  https://doi.org/10.1038/s42003-024-07243-w
  5. bioRxiv. 2024 Oct 29. pii: 2024.10.28.620733. [Epub ahead of print]
    A mitochondrial redox switch licenses the onset of morphogenesis in animals.
    Updip Kahlon, Francesco Dalla Ricca, Saraswathi J Pillai, Marine Olivetta, Kevin M Tharp, Li-En Jao, Omaya Dudin, Kent McDonald, Mustafa G Aydogan.
      Embryos undergo pre-gastrulation cleavage cycles to generate a critical cell mass before transitioning to morphogenesis. The molecular underpinnings of this transition have traditionally centered on zygotic chromatin remodeling and genome activation1,2, as their repression can prevent downstream processes of differentiation and organogenesis. Despite precedents that oxygen depletion can similarly suspend development in early embryos3-6, hinting at a pivotal role for oxygen metabolism in this transition, whether there is a bona fide chemical switch that licenses the onset of morphogenesis remains unknown. Here we discover that a mitochondrial oxidant acts as a metabolic switch to license the onset of animal morphogenesis. Concomitant with the instatement of mitochondrial membrane potential, we found a burst-like accumulation of mitochondrial superoxide (O2 -) during fly blastoderm formation. In vivo chemistry experiments revealed that an electron leak from site IIIQo at ETC Complex III is responsible for O2 - production. Importantly, depleting mitochondrial O2 - fully mimics anoxic conditions and, like anoxia, induces suspended animation prior to morphogenesis, but not after. Specifically, H2O2, and not ONOO-, NO, or HO•, can single-handedly account for this mtROS-based response. We demonstrate that depleting mitochondrial O2 - similarly prevents the onset of morphogenetic events in vertebrate embryos and ichthyosporea, close relatives of animals. We postulate that such redox-based metabolic licensing of morphogenesis is an ancient trait of holozoans that couples the availability of oxygen to development, conserved from early-diverging animal relatives to vertebrates.
    DOI:  https://doi.org/10.1101/2024.10.28.620733
  6. Mol Cell. 2024 Nov 21. pii: S1097-2765(24)00880-3. [Epub ahead of print]84(22): 4261-4263
    AMPK: Balancing mitochondrial quality and quantity through opposite regulation of mitophagy pathways.
    Hui Jiang.
      In this issue of Molecular Cell, Longo et al.1 reveal that AMPK, a regulatory kinase activated by metabolic stress, inhibits NIX/BNIP3-dependent mitophagy to preserve mitochondrial quantity and activates PINK1/Parkin-dependent mitophagy to ensure mitochondrial quality.
    DOI:  https://doi.org/10.1016/j.molcel.2024.10.040
  7. Cell Metab. 2024 Nov 14. pii: S1550-4131(24)00403-0. [Epub ahead of print]
    Human genetics identify convergent signals in mitochondrial LACTB-mediated lipid metabolism in cardiovascular-kidney-metabolic syndrome.
    Shen Li, Hongbo Liu, Hailong Hu, Eunji Ha, Praveena Prasad, Brenita C Jenkins, Ujjalkumar Subhash Das, Sarmistha Mukherjee, Kyosuke Shishikura, Renming Hu, Daniel J Rader, Liming Pei, Joseph A Baur, Megan L Matthews, Garret A FitzGerald, Melanie R McReynolds, Katalin Susztak.
      The understanding of cardiovascular-kidney-metabolic syndrome remains difficult despite recently performed large scale genome-wide association studies. Here, we identified beta-lactamase (LACTB), a novel gene whose expression is targeted by genetic variations causing kidney dysfunction and hyperlipidemia. Mice with LACTB deletion developed impaired glucose tolerance, elevated lipid levels, and increased sensitivity to kidney disease, while mice with tubule-specific overexpression of LACTB were protected from kidney injury. We show that LACTB is a novel mitochondrial protease cleaving and activating phospholipase A2 group VI (PLA2G6), a kidney-metabolic risk gene itself. Genetic deletion of PLA2G6 in tubule-specific LACTB-overexpressing mice abolished the protective function of LACTB. Via mouse and human lipidomic studies, we show that LACTB and downstream PLA2G6 convert oxidized phosphatidylethanolamine to lyso-phosphatidylethanolamine and thereby regulate mitochondrial function and ferroptosis. In summary, we identify a novel gene and a core targetable pathway for kidney-metabolic disorders.
    Keywords:  GWAS; cardiovascular-kidney-metabolic syndrome; ferroptosis; genetics; kidney disease; mitochondria; phospholipase; phospholipid; serine protease
    DOI:  https://doi.org/10.1016/j.cmet.2024.10.007
  8. Endocrinol Metab (Seoul). 2024 Nov 20.
    Brown Fat and Metabolic Health: The Diverse Functions of Dietary Components.
    Zachary Brown, Takeshi Yoneshiro.
      Brown and beige adipocytes utilize a variety of substrates for cold-induced thermogenesis, contributing to the clearance of metabolites in circulation and, consequently, metabolic health. Food-derived compounds that exhibit agonistic activity at temperature-sensitive transient receptor potential channels may serve as cold mimics to elicit thermogenesis and substrate utilization in brown adipose tissue (BAT). In addition to fatty acids and glucose, branched-chain amino acids (BCAAs), which are essential amino acids obtained from foods, are actively catabolized in BAT through mitochondrial BCAA carrier (MBC). The relative contribution of BCAAs to fueling the tricarboxylic acid cycle as a substrate (i.e., anaplerosis) is estimated to be relatively small, yet BCAA catabolism in BAT exerts a critical role in systemic insulin sensitivity. The nature of this apparent tension remained unclear until the recent discovery that active BCAA catabolism in BAT through MBC is critical for the synthesis of metabolites such as glutathione, which is delivered to the liver to improve hepatic insulin sensitivity through redox homeostasis. Novel mechanistic insights into the control of BAT function and systemic metabolism reveal the therapeutic potential of food-derived compounds for improving metabolic flexibility and insulin sensitivity.
    Keywords:  Branched-chain amino acids; Food ingredients; Glucose homeostasis; Nitrogen flux; Thermogenesis; Transporter
    DOI:  https://doi.org/10.3803/EnM.2024.2121
  9. J Biol Chem. 2024 Nov 15. pii: S0021-9258(24)02506-7. [Epub ahead of print] 108004
    Impaired branched chain amino acid (BCAA) catabolism during adipocyte differentiation decreases glycolytic flux.
    Courtney R Green, Lynn M Alaeddine, Karl A Wessendorf-Rodriguez, Rory Turner, Merve Elmastas, Justin D Hover, Anne N Murphy, Mikael Ryden, Niklas Mejhert, Christian M Metallo, Martina Wallace.
      Dysregulated branched chain amino acid (BCAA) metabolism has emerged as a key metabolic feature associated with the obese insulin resistant state, and adipose BCAA catabolism is decreased in this context. BCAA catabolism is upregulated early in adipogenesis, but the impact of suppressing this pathway on the broader metabolic functions of the resultant adipocyte remains unclear. Here, we use CRISPR/Cas9 to decrease BCKDHA in 3T3-L1 and human pre-adipocytes, and ACAD8 in 3T3-L1 pre-adipocytes to induce a deficiency in BCAA catabolism through differentiation. We characterize the transcriptional and metabolic phenotype of 3T1-L1 cells using RNAseq and 13C metabolic flux analysis within a network spanning glycolysis, tricarboxylic acid (TCA) metabolism, BCAA catabolism, and fatty acid synthesis. While lipid droplet accumulation is maintained in Bckdha-deficient adipocytes, they display a more fibroblast-like transcriptional signature. In contrast, Acad8 deficiency minimally impacts gene expression. Decreased glycolytic flux emerges as the most distinct metabolic feature of 3T3-L1 Bckdha-deficient cells, accompanied by a ∼40% decrease in lactate secretion, yet pyruvate oxidation and utilization for de novo lipogenesis are increased to compensate for loss of BCAA carbon. Deletion of BCKDHA in human adipocyte progenitors also led to a decrease in glucose uptake and lactate secretion, however these cells did not upregulate pyruvate utilisation and lipid droplet accumulation and expression of adipocyte differentiation markers was decreased in BCKDH knockout cells. Overall our data suggest that human adipocyte differentiation may be more sensitive to the impact of decreased BCKDH activity than 3T3-L1 cells, and that both metabolic and regulatory cross-talk exists between BCAA catabolism and glycolysis in adipocytes. Suppression of BCAA catabolism associated with metabolic syndrome may result in a metabolically compromised adipocyte.
    Keywords:  adipogenesis; adipose; branched chain amino acids; glycolysis; metabolic flux
    DOI:  https://doi.org/10.1016/j.jbc.2024.108004
  10. bioRxiv. 2024 Nov 03. pii: 2024.10.30.621159. [Epub ahead of print]
    Multiomics reveals age-dependent metabolic reprogramming of macrophages by wound bed niche secreted signals.
    Maria Fernanda Forni, Gabriela A Pizzurro, Will Krause, Amanda F Alexander, Kate Bridges, Yiting Xu, Olivia Justynski, Anthony Gabry, Niels Olsen Saraiva Camara, Kathryn Miller-Jensen, Valerie Horsley.
      The cellular metabolism of macrophages depends on tissue niches and can control macrophage inflammatory or resolving phenotypes. Yet, the identity of signals within tissue niches that control macrophage metabolism is not well understood. Here, using single-cell RNA sequencing of macrophages in early mouse wounds, we find that, rather than gene expression of canonical inflammatory or resolving polarization markers, metabolic gene expression defines distinct populations of early wound macrophages. Single-cell secretomics and transcriptomics identify inflammatory and resolving cytokines expressed by early wound macrophages, and we show that these signals drive metabolic inputs and mitochondrial metabolism in an age-dependent manner. We show that aging alters the metabolome of early wound macrophages and rewires their metabolism from mitochondria to glycolysis. We further show that macrophage-derived Chi3l3 and IGF-1 can induce metabolic inputs and mitochondrial mass/metabolism in aged and bone marrow-derived macrophages. Together, these findings reveal that macrophage-derived signals drive the mitochondrial metabolism of macrophages within early wounds in an age-dependent manner and have implications for inflammatory diseases, chronic injuries, and age-related inflammatory diseases.
    In Brief: This study reveals that macrophage subsets in early inflammatory stages of skin wound healing are defined by their metabolic profiles rather than polarization phenotype. Using single-cell secretomics, we establish key macrophage cytokines that comprise the in vivo wound niche and drive mitochondrial-based metabolism. Aging significantly alters macrophage heterogeneity and increases glycolytic metabolism, which can be restored to OxPHOS-based metabolism with young niche cytokines. These findings highlight the importance of the tissue niche in driving macrophage phenotypes, with implications for aging-related impairments in wound healing.
    Highlights: Single cell transcriptional analysis reveals that reveals that metabolic gene expression identifies distinct macrophage populations in early skin wounds.Single-cell secretomic data show that young macrophages contribute to the wound bed niche by secreting molecules such as IGF-1 and Chi3l3.Old wound macrophages display altered metabolomics, elevated glycolytic metabolism and glucose uptake, and reduced lipid uptake and mitochondrial mass/metabolism.Chi3l3 but not IGF-1 secretion is altered in macrophages in an age dependent manner.Chi3l3 can restore mitochondrial mass/metabolism in aged macrophages.
    DOI:  https://doi.org/10.1101/2024.10.30.621159
  11. Nature. 2024 Nov 20.
    Spatially restricted immune and microbiota-driven adaptation of the gut.
    Toufic Mayassi, Chenhao Li, Åsa Segerstolpe, Eric M Brown, Rebecca Weisberg, Toru Nakata, Hiroshi Yano, Paula Herbst, David Artis, Daniel B Graham, Ramnik J Xavier.
      The intestine is characterized by an environment in which host requirements for nutrient and water absorption are consequently paired with the requirements to establish tolerance to the outside environment. To better understand how the intestine functions in health and disease, large efforts have been made to characterize the identity and composition of cells from different intestinal regions1-8. However, the robustness, nature of adaptability and extent of resilience of the transcriptional landscape and cellular underpinning of the intestine in space are still poorly understood. Here we generated an integrated resource of the spatial and cellular landscape of the murine intestine in the steady and perturbed states. Leveraging these data, we demonstrated that the spatial landscape of the intestine was robust to the influence of the microbiota and was adaptable in a spatially restricted manner. Deploying a model of spatiotemporal acute inflammation, we demonstrated that both robust and adaptable features of the landscape were resilient. Moreover, highlighting the physiological relevance and value of our dataset, we identified a region of the middle colon characterized by an immune-driven multicellular spatial adaptation of structural cells to the microbiota. Our results demonstrate that intestinal regionalization is characterized by robust and resilient structural cell states and that the intestine can adapt to environmental stress in a spatially controlled manner through the crosstalk between immunity and structural cell homeostasis.
    DOI:  https://doi.org/10.1038/s41586-024-08216-z
  12. Res Sq. 2024 Oct 28. pii: rs.3.rs-5119308. [Epub ahead of print]
    Mapping the Temporal Landscape of Breast Cancer Using Epigenetic Entropy.
    Darryl Shibata, Daniel Monyak, Shannon Holloway, Graham Gumbert, Lars Grimm, Shelley Hwang, Jeffrey Marks, Marc Ryser.
      Although generally unknown, the age of a newly diagnosed tumor encodes valuable etiologic and prognostic information. Here, we estimate the age of breast cancers, defined as the time from the start of growth to detection, using a measure of epigenetic entropy derived from genome-wide methylation arrays. Based on an ensemble of neutrally fluctuating CpG (fCpG) sites, this stochastic epigenetic clock differs from conventional clocks that measure age-related increases in methylation. We show that younger tumors exhibit hallmarks of aggressiveness, such as increased proliferation and genomic instability, whereas older tumors are characterized by elevated immune infiltration, indicative of enhanced immune surveillance. These findings suggest that the clock captures a tumor's effective growth rate resulting from the evolutionary-ecological competition between intrinsic growth potential and external systemic pressures. Because of the clock's ability to delineate old and stable from young and aggressive tumors, it has potential applications in risk stratification of early-stage breast cancers and guiding early detection efforts.
    DOI:  https://doi.org/10.21203/rs.3.rs-5119308/v1
  13. Nature. 2024 Nov 20.
    Gliocidin is a nicotinamide-mimetic prodrug that targets glioblastoma.
    Yu-Jung Chen, Swathi V Iyer, David Chun-Cheng Hsieh, Buren Li, Harold K Elias, Tao Wang, Jing Li, Mungunsarnai Ganbold, Michelle C Lien, Yu-Chun Peng, Xuanhua P Xie, Chenura D Jayewickreme, Marcel R M van den Brink, Sean F Brady, S Kyun Lim, Luis F Parada.
      Glioblastoma is incurable and in urgent need of improved therapeutics1. Here we identify a small compound, gliocidin, that kills glioblastoma cells while sparing non-tumour replicative cells. Gliocidin activity targets a de novo purine synthesis vulnerability in glioblastoma through indirect inhibition of inosine monophosphate dehydrogenase 2 (IMPDH2). IMPDH2 blockade reduces intracellular guanine nucleotide levels, causing nucleotide imbalance, replication stress and tumour cell death2. Gliocidin is a prodrug that is anabolized into its tumoricidal metabolite, gliocidin-adenine dinucleotide (GAD), by the enzyme nicotinamide nucleotide adenylyltransferase 1 (NMNAT1) of the NAD+ salvage pathway. The cryo-electron microscopy structure of GAD together with IMPDH2 demonstrates its entry, deformation and blockade of the NAD+ pocket3. In vivo, gliocidin penetrates the blood-brain barrier and extends the survival of mice with orthotopic glioblastoma. The DNA alkylating agent temozolomide induces Nmnat1 expression, causing synergistic tumour cell killing and additional survival benefit in orthotopic patient-derived xenograft models. This study brings gliocidin to light as a prodrug with the potential to improve the survival of patients with glioblastoma.
    DOI:  https://doi.org/10.1038/s41586-024-08224-z
  14. Nat Metab. 2024 Nov 22.
    ACBP orchestrates the metabolic phenotype in Cushing's syndrome.
    Mhairi Paul, Mark Nixon.
      
    DOI:  https://doi.org/10.1038/s42255-024-01169-7
  15. J Clin Invest. 2024 Nov 19. pii: e177824. [Epub ahead of print]
    Tumor cell-derived spermidine promotes a pro-tumorigenic immune microenvironment in glioblastoma via CD8+ T cell inhibition.
    Kristen E Kay, Juyeun Lee, Ellen S Hong, Julia Beilis, Sahil Dayal, Emily R Wesley, Sofia Mitchell, Sabrina Z Wang, Daniel J Silver, Josephine Volovetz, Sarah Johnson, Mary McGraw, Matthew Grabowski, Tianyao Lu, Lutz Freytag, Vinod K Narayana, Saskia Freytag, Sarah A Best, James R Whittle, Zeneng Wang, Ofer Reizes, Jennifer S Yu, Stanley L Hazen, J Mark Brown, Defne Bayik, Justin Lathia.
      The glioblastoma (GBM) microenvironment is enriched in immunosuppressive factors that potently interfere with the function of cytotoxic T lymphocytes. Cancer cells can directly impact the immune system, but the mechanisms driving these interactions are not completely clear. Here we demonstrate that the polyamine metabolite spermidine (SPD) is elevated in the GBM tumor microenvironment. Exogenous administration of SPD drives tumor aggressiveness in an immune-dependent manner in pre-clinical mouse models via reduction of CD8+ T cell frequency and reduced cytotoxic function. Knockdown of ornithine decarboxylase, the rate-limiting enzyme in spermidine synthesis, did not impact cancer cell growth in vitro but did result in extended survival. Furthermore, glioblastoma patients with a more favorable outcome had a significant reduction in spermidine compared to patients with a poor prognosis. Our results demonstrate that spermidine functions as a cancer cell-derived metabolite that drives tumor progression by reducing CD8+ T cell number and function.
    Keywords:  Adaptive immunity; Brain cancer; Immunology; Oncology; Polyamines
    DOI:  https://doi.org/10.1172/JCI177824
  16. J Lipid Res. 2024 Nov 18. pii: S0022-2275(24)00205-0. [Epub ahead of print] 100700
    DFCP1 is a Regulator of Starvation-driven ATGL-mediated Lipid Droplet Lipolysis.
    V A Ismail, M N Harvey, Zak Baker, J Castillo-Badillo, T Naismith, D J Pagliarini, D J Kast.
      Lipid droplets (LDs) are transient lipid storage organelles that can be readily tapped to resupply cells with energy or lipid building blocks, and therefore play a central role in cellular metabolism. Double FYVE Domain Containing Protein 1 (DFCP1/ZFYV1) has emerged as a key regulator of LD metabolism, where the nucleotide-dependent accumulation of DFCP1 on LDs influences their size, number, and dynamics. Here we show that DFCP1 regulates lipid metabolism by directly modulating the activity of Adipose Triglyceride Lipase (ATGL/PNPLA2), the rate-limiting lipase driving the catabolism of LDs. We show through pharmacological inhibition of key enzymes associated with LD metabolism that DFCP1 specifically regulates lipolysis and, to a lesser extent, lipophagy. Consistent with this observation, DFCP1 interacts with and recruits ATGL to LDs in starved cells, irrespective of other known regulatory factors of ATGL. We further establish that this interaction prevents dynamic disassociation of ATGL from LDs and thereby impedes the rate of LD lipolysis. Collectively, our findings indicate that DFCP1 is a nutrient-sensitive regulator of LD catabolism.
    Keywords:  ABHD5; ATGL; CGI-58; DFCP1; FRAP; PLPL2; ZFYVE1; diglycerides; fatty acids; lipid droplets; triglycerides
    DOI:  https://doi.org/10.1016/j.jlr.2024.100700
  17. bioRxiv. 2024 Nov 01. pii: 2024.10.31.621392. [Epub ahead of print]
    Mitochondrial NADK2-dependent NADPH controls Tau oligomer uptake in human neurons.
    Evelyn Pardo, Taylor Kim, Horst Wallrabe, Kristine E Zengeler, Vijay Kumar Sagar, Garnett Mingledorff, Xuehan Sun, Ammasi Periasamy, John R Lukens, George S Bloom, Andrés Norambuena.
      Alterations in NADH and NADPH metabolism are associated with aging, cancer, and Alzheimer's Disease. Using 2P-FLIM imaging of the mitochondrial NAD(P)H in live human neurons and PS19 mouse brains, we show that tau oligomers (TauO) upregulate the mitochondrial de novo NADPH synthesis through NADK2. This process controls LRP1-mediated internalization of TauO, setting a vicious cycle for further TauO internalization. Thus, mitochondrial NADK2-dependent NADPH controls a key step in TauO toxicity.
    DOI:  https://doi.org/10.1101/2024.10.31.621392
  18. FEBS J. 2024 Nov 20.
    Interaction with the cysteine-free protein HAX1 expands the substrate specificity and function of MIA40 beyond protein oxidation.
    Robin Alexander Rothemann, Dylan Stobbe, Michaela Nicole Hoehne-Wiechmann, Lena Maria Murschall, Esra Peker, Lara Katharina Knaup, Julia Racho, Markus Habich, Sarah Gerlich, Kim Jasmin Lapacz, Kathrin Ulrich, Jan Riemer.
      The mitochondrial disulphide relay machinery is essential for the import and oxidative folding of many proteins in the mitochondrial intermembrane space. Its core component, the import receptor MIA40 (also CHCHD4), serves as an oxidoreductase but also as a chaperone holdase, which initially interacts with its substrates non-covalently before introducing disulphide bonds for folding and retaining proteins in the intermembrane space. Interactome studies have identified diverse substrates of MIA40, among them the intrinsically disordered HCLS1-associated protein X-1 (HAX1). Interestingly, this protein does not contain cysteines, raising the question of how and to what end HAX1 can interact with MIA40. Here, we demonstrate that MIA40 non-covalently interacts with HAX1 independent of its redox-active cysteines. While HAX1 import is driven by its weak mitochondrial targeting sequence, its subsequent transient interaction with MIA40 stabilizes the protein in the intermembrane space. HAX1 solely depends on the holdase activity of MIA40, and the absence of MIA40 results in the aggregation, degradation and loss of HAX1. Collectively, our study introduces HAX1 as the first endogenous MIA40 substrate without cysteines and demonstrates the diverse functions of this highly conserved oxidoreductase and import receptor.
    Keywords:  HAX1; IMS; MIA40; mitochondria; mitochondrial disulphide relay
    DOI:  https://doi.org/10.1111/febs.17328
  19. Nat Commun. 2024 Nov 20. 15(1): 10019
    The commitment of the human cell atlas to humanity.
    Ido Amit, Kristin Ardlie, Fabiana Arzuaga, Gordon Awandare, Gary Bader, Alexander Bernier, Piero Carninci, Stacey Donnelly, Roland Eils, Alistair R R Forrest, Henry T Greely, Roderic Guigo, Nir Hacohen, Muzlifah Haniffa, Emily Sarah Kirby, Bartha Maria Knoppers, Arnold Kriegstein, Ed S Lein, Sten Linnarsson, Partha P Majumder, Miriam Merad, Kerstin Meyer, Musa M Mhlanga, Garry Nolan, Ntobeko A B Ntusi, Dana Pe'er, Shyam Prabhakar, Maili Raven-Adams, Aviv Regev, Orit Rozenblatt-Rosen, Senjuti Saha, Andrea Saltzman, Alex K Shalek, Jay W Shin, Henk Stunnenberg, Sarah A Teichmann, Timothy Tickle, Alexandra-Chloe Villani, Christine Wells, Barbara Wold, Huanming Yang, Xiaowei Zhuang.
      The Human Cell Atlas (HCA) is a global partnership "to create comprehensive reference maps of all human cells-the fundamental units of life - as a basis for both understanding human health and diagnosing, monitoring, and treating disease." ( https://www.humancellatlas.org/ ) The atlas shall characterize cells from diverse individuals across the globe to better understand human biology. HCA proactively considers the priorities of, and benefits accrued to, contributing communities. Here, we lay out principles and action items that have been adopted to affirm HCA's commitment to equity so that the atlas is beneficial to all of humanity.
    DOI:  https://doi.org/10.1038/s41467-024-54306-x
  20. Nat Cancer. 2024 Nov 21.
    Evolving cell states and oncogenic drivers during the progression of IDH-mutant gliomas.
    Jingyi Wu, L Nicolas Gonzalez Castro, Sofia Battaglia, Chadi A El Farran, Joshua P D'Antonio, Tyler E Miller, Mario L Suvà, Bradley E Bernstein.
      Isocitrate dehydrogenase (IDH) mutants define a class of gliomas that are initially slow-growing but inevitably progress to fatal disease. To characterize their malignant cell hierarchy, we profiled chromatin accessibility and gene expression across single cells from low-grade and high-grade IDH-mutant gliomas and ascertained their developmental states through a comparison to normal brain cells. We provide evidence that these tumors are initially fueled by slow-cycling oligodendrocyte progenitor cell-like cells. During progression, a more proliferative neural progenitor cell-like population expands, potentially through partial reprogramming of 'permissive' chromatin in progenitors. This transition is accompanied by a switch from methylation-based drivers to genetic ones. In low-grade IDH-mutant tumors or organoids, DNA hypermethylation appears to suppress interferon (IFN) signaling, which is induced by IDH or DNA methyltransferase 1 inhibitors. High-grade tumors frequently lose this hypermethylation and instead acquire genetic alterations that disrupt IFN and other tumor-suppressive programs. Our findings explain how these slow-growing tumors may progress to lethal malignancies and have implications for therapies that target their epigenetic underpinnings.
    DOI:  https://doi.org/10.1038/s43018-024-00865-3
  21. Development. 2024 Nov 15. pii: dev204212. [Epub ahead of print]151(22):
    An expanded view of cell competition.
    Ameya Khandekar, Stephanie J Ellis.
      Cell competition arises in heterogeneous tissues when neighbouring cells sense their relative fitness and undergo selection. It has been a challenge to define contexts in which cell competition is a physiologically relevant phenomenon and to understand the cellular features that underlie fitness and fitness sensing. Drawing on examples across a range of contexts and length scales, we illuminate molecular and cellular features that could underlie fitness in diverse tissue types and processes to promote and reinforce long-term maintenance of tissue function. We propose that by broadening the scope of how fitness is defined and the circumstances in which cell competition can occur, the field can unlock the potential of cell competition as a lens through which heterogeneity and its role in the fundamental principles of complex tissue organisation can be understood.
    Keywords:  Cell competition; Cell selection; Cellular fitness sensing; Complex tissue organization; Heterogeneity; Tissue robustness
    DOI:  https://doi.org/10.1242/dev.204212
  22. Nat Commun. 2024 Nov 18. 15(1): 9749
    TET3 regulates terminal cell differentiation at the metabolic level.
    Isabel Mulet, Carmen Grueso-Cortina, Mireia Cortés-Cano, Daniela Gerovska, Guangming Wu, Stefania Alexandra Iakab, Daniel Jimenez-Blasco, Andrea Curtabbi, Pablo Hernansanz-Agustín, Harmony Ketchum, Israel Manjarrés-Raza, F Thomas Wunderlich, Juan Pedro Bolaños, Meelad M Dawlaty, Carsten Hopf, José Antonio Enríquez, Marcos J Araúzo-Bravo, Natalia Tapia.
      TET-family members play a critical role in cell fate commitment. Indeed, TET3 is essential to postnatal development due to yet unknown reasons. To define TET3 function in cell differentiation, we have profiled the intestinal epithelium at single-cell level from wild-type and Tet3 knockout mice. We have found that Tet3 is mostly expressed in differentiated enterocytes. In the absence of TET3, enterocytes exhibit an aberrant differentiation trajectory and do not acquire a physiological cell identity due to an impairment in oxidative phosphorylation, specifically due to an ATP synthase assembly deficiency. Moreover, spatial metabolomics analysis has revealed that Tet3 knockout enterocytes exhibit an unphysiological metabolic profile when compared with their wild-type counterparts. In contrast, no metabolic differences have been observed between both genotypes in the stem cell compartment where Tet3 is mainly not expressed. Collectively, our findings suggest a mechanism by which TET3 regulates mitochondrial function and, thus, terminal cell differentiation at the metabolic level.
    DOI:  https://doi.org/10.1038/s41467-024-54044-0
  23. Nat Metab. 2024 Nov 22.
    Cancer cachexia: multilevel metabolic dysfunction.
    Mauricio Berriel Diaz, Maria Rohm, Stephan Herzig.
      Cancer cachexia is a complex metabolic disorder marked by unintentional body weight loss or 'wasting' of body mass, driven by multiple aetiological factors operating at various levels. It is associated with many malignancies and significantly contributes to cancer-related morbidity and mortality. With emerging recognition of cancer as a systemic disease, there is increasing awareness that understanding and treatment of cancer cachexia may represent a crucial cornerstone for improved management of cancer. Here, we describe the metabolic changes contributing to body wasting in cachexia and explain how the entangled action of both tumour-derived and host-amplified processes induces these metabolic changes. We discuss energy homeostasis and possible ways that the presence of a tumour interferes with or hijacks physiological energy conservation pathways. In that context, we highlight the role played by metabolic cross-talk mechanisms in cachexia pathogenesis. Lastly, we elaborate on the challenges and opportunities in the treatment of this devastating paraneoplastic phenomenon that arise from the complex and multifaceted metabolic cross-talk mechanisms and provide a status on current and emerging therapeutic approaches.
    DOI:  https://doi.org/10.1038/s42255-024-01167-9
  24. Cell Rep. 2024 Nov 20. pii: S2211-1247(24)01342-1. [Epub ahead of print]43(12): 114991
    ZBTB7A is a modulator of KDM5-driven transcriptional networks in basal breast cancer.
    Benedetto DiCiaccio, Marco Seehawer, Zheqi Li, Andriana Patmanidis, Triet Bui, Pierre Foidart, Jun Nishida, Clive S D'Santos, Evangelia K Papachristou, Malvina Papanastasiou, Andrew H Reiter, Xintao Qiu, Rong Li, Yijia Jiang, Xiao-Yun Huang, Anton Simeonov, Stephen C Kales, Ganesha Rai, Madhu Lal-Nag, Ajit Jadhav, Myles Brown, Jason S Carroll, Henry W Long, Kornelia Polyak.
      We previously described that the KDM5B histone H3 lysine 4 demethylase is an oncogene in estrogen-receptor-positive breast cancer. Here, we report that KDM5A is amplified and overexpressed in basal breast tumors, and KDM5 inhibition (KDM5i) suppresses the growth of KDM5-amplified breast cancer cell lines. Using CRISPR knockout screens in a basal breast cancer cell line with or without KDM5i, we found that deletion of the ZBTB7A transcription factor and core SAGA complex sensitizes cells to KDM5i, whereas deletion of RHO-GTPases leads to resistance. Chromatin immunoprecipitation sequencing (ChIP-seq) and RNA sequencing (RNA-seq) revealed co-localization of ZBTB7A and KDM5A/B at promoters with high histone H3K4me3 and dependence of KDM5A chromatin binding on ZBTB7A. ZBTB7A knockout altered the transcriptional response to KDM5i at NF-κB targets and mitochondrion-related pathways. High expression of ZBTB7A in triple-negative breast cancer is significantly associated with poor response to neoadjuvant chemotherapy. Our work furthers the understanding of KDM5-mediated gene regulation and identifies mediators of sensitivity to KDM5i.
    Keywords:  CP: Cancer; CRISPR screen; breast cancer; histone demethylase; mitochondrial signaling
    DOI:  https://doi.org/10.1016/j.celrep.2024.114991
  25. Nature. 2024 Nov 20.
    Human HDAC6 senses valine abundancy to regulate DNA damage.
    Jiali Jin, Tong Meng, Yuanyuan Yu, Shuheng Wu, Chen-Chen Jiao, Sihui Song, Ya-Xu Li, Yu Zhang, Yuan-Yuan Zhao, Xinran Li, Zixin Wang, Yu-Fan Liu, Runzhi Huang, Jieling Qin, Yihua Chen, Hao Cao, Xiao Tan, Xin Ge, Cong Jiang, Jianhuang Xue, Jian Yuan, Dianqing Wu, Wei Wu, Ci-Zhong Jiang, Ping Wang.
      As an essential branched amino acid, valine is pivotal for protein synthesis, neurological behaviour, haematopoiesis and leukaemia progression1-3. However, the mechanism by which cellular valine abundancy is sensed for subsequent cellular functions remains undefined. Here we identify that human histone deacetylase 6 (HDAC6) serves as a valine sensor by directly binding valine through a primate-specific SE14 repeat domain. The nucleus and cytoplasm shuttling of human, but not mouse, HDAC6 is tightly controlled by the intracellular levels of valine. Valine deprivation leads to HDAC6 retention in the nucleus and induces DNA damage. Mechanistically, nuclear-localized HDAC6 binds and deacetylates ten-eleven translocation 2 (TET2) to initiate active DNA demethylation, which promotes DNA damage through thymine DNA glycosylase-driven excision. Dietary valine restriction inhibits tumour growth in xenograft and patient-derived xenograft models, and enhances the therapeutic efficacy of PARP inhibitors. Collectively, our study identifies human HDAC6 as a valine sensor that mediates active DNA demethylation and DNA damage in response to valine deprivation, and highlights the potential of dietary valine restriction for cancer treatment.
    DOI:  https://doi.org/10.1038/s41586-024-08248-5
  26. Genes Dev. 2024 Nov 21.
    mTORC1, the maestro of cell metabolism and growth.
    Long He, Sungyun Cho, John Blenis.
      The mechanistic target of rapamycin (mTOR) pathway senses and integrates various environmental and intracellular cues to regulate cell growth and proliferation. As a key conductor of the balance between anabolic and catabolic processes, mTOR complex 1 (mTORC1) orchestrates the symphonic regulation of glycolysis, nucleic acid and lipid metabolism, protein translation and degradation, and gene expression. Dysregulation of the mTOR pathway is linked to numerous human diseases, including cancer, neurodegenerative disorders, obesity, diabetes, and aging. This review provides an in-depth understanding of how nutrients and growth signals are coordinated to influence mTOR signaling and the extensive metabolic rewiring under its command. Additionally, we discuss the use of mTORC1 inhibitors in various aging-associated metabolic diseases and the current and future potential for targeting mTOR in clinical settings. By deciphering the complex landscape of mTORC1 signaling, this review aims to inform novel therapeutic strategies and provide a road map for future research endeavors in this dynamic and rapidly evolving field.
    Keywords:  cancer; cellular signaling; mT; mTOR complex 1; mTORC1
    DOI:  https://doi.org/10.1101/gad.352084.124
  27. Biol Lett. 2024 Nov;20(11): 20240490
    Metabolic complementation between cells drives the evolution of tissues and organs.
    Mihaela Pavlicev, J DiFrisco, Alan C Love, Günter P Wagner.
      Although evolutionary transitions of individuality have been extensively theorized, little attention has been paid to the origin of levels of organization within organisms. How and why do specialized cells become organized into specialized tissues or organs? What spurs a transition in organizational level in cases where the function is already present in constituent cell types? We propose a hypothesis for this kind of evolutionary transition based on two features of cellular metabolism: metabolic constraints on functional performance and the capacity for metabolic complementation between parenchymal and supporting cells. These features suggest a scenario whereby pre-existing specialized cell types are integrated into tissues when changes to the internal or external environment favour offloading metabolic burdens from a primary specialized cell type onto supporting cells. We illustrate this process of 'supra-functionalization' using the nervous system and pancreas.
    Keywords:  levels of organization; metabolic complementation; metabolic constraint; self-maintenance; tissue origin
    DOI:  https://doi.org/10.1098/rsbl.2024.0490
  28. Genes Dev. 2024 Nov 19.
    Proteomic insights into circadian transcription regulation: novel E-box interactors revealed by proximity labeling.
    Manon Torres, Marieluise Kirchner, Caroline G Marks, Philipp Mertins, Achim Kramer.
      Circadian clocks (∼24 h) are responsible for daily physiological, metabolic, and behavioral changes. Central to these oscillations is the regulation of gene transcription. Previous research has identified clock protein complexes that interact with the transcriptional machinery to orchestrate circadian transcription, but technological constraints have limited the identification of de novo proteins. Here we use a novel genomic locus-specific quantitative proteomics approach to provide a new perspective on time of day-dependent protein binding at a critical chromatin locus involved in circadian transcription: the E-box. Using proximity labeling proteomics at the E-box of the clock-controlled Dbp gene in mouse fibroblasts, we identified 69 proteins at this locus at the time of BMAL1 binding. This method successfully enriched BMAL1 as well as HDAC3 and HISTONE H2A.V/Z, known circadian regulators. New E-box proteins include the MINK1 kinase and the transporters XPO7 and APPL1, whose depletion in human U-2 OS cells results in disrupted circadian rhythms, suggesting a role in the circadian transcriptional machinery. Overall, our approach uncovers novel circadian modulators and provides a new strategy to obtain a complete temporal picture of circadian transcriptional regulation.
    Keywords:  DNA–protein proximity labeling; circadian clock; circadian transcription; enhancer–enhancer interactions; protein–protein interactions; proteomics
    DOI:  https://doi.org/10.1101/gad.351836.124
  29. Nature. 2024 Nov 20.
    Liver X receptor unlinks intestinal regeneration and tumorigenesis.
    Srustidhar Das, S Martina Parigi, Xinxin Luo, Jennifer Fransson, Bianca C Kern, Ali Okhovat, Oscar E Diaz, Chiara Sorini, Paulo Czarnewski, Anna T Webb, Rodrigo A Morales, Sacha Lebon, Gustavo Monasterio, Francisca Castillo, Kumar P Tripathi, Ning He, Penelope Pelczar, Nicola Schaltenberg, Marjorie De la Fuente, Francisco López-Köstner, Susanne Nylén, Hjalte List Larsen, Raoul Kuiper, Per Antonson, Marcela A Hermoso, Samuel Huber, Moshe Biton, Sandra Scharaw, Jan-Åke Gustafsson, Pekka Katajisto, Eduardo J Villablanca.
      Uncontrolled regeneration leads to neoplastic transformation1-3. The intestinal epithelium requires precise regulation during continuous homeostatic and damage-induced tissue renewal to prevent neoplastic transformation, suggesting that pathways unlinking tumour growth from regenerative processes must exist. Here, by mining RNA-sequencing datasets from two intestinal damage models4,5 and using pharmacological, transcriptomics and genetic tools, we identified liver X receptor (LXR) pathway activation as a tissue adaptation to damage that reciprocally regulates intestinal regeneration and tumorigenesis. Using single-cell RNA sequencing, intestinal organoids, and gain- and loss-of-function experiments, we demonstrate that LXR activation in intestinal epithelial cells induces amphiregulin (Areg), enhancing regenerative responses. This response is coordinated by the LXR-ligand-producing enzyme CYP27A1, which was upregulated in damaged intestinal crypt niches. Deletion of Cyp27a1 impaired intestinal regeneration, which was rescued by exogenous LXR agonists. Notably, in tumour models, Cyp27a1 deficiency led to increased tumour growth, whereas LXR activation elicited anti-tumour responses dependent on adaptive immunity. Consistently, human colorectal cancer specimens exhibited reduced levels of CYP27A1, LXR target genes, and B and CD8 T cell gene signatures. We therefore identify an epithelial adaptation mechanism to damage, whereby LXR functions as a rheostat, promoting tissue repair while limiting tumorigenesis.
    DOI:  https://doi.org/10.1038/s41586-024-08247-6
  30. Redox Biol. 2024 Nov 10. pii: S2213-2317(24)00404-X. [Epub ahead of print]78 103426
    Regulation of mitochondrial oxidative phosphorylation through tight control of cytochrome c oxidase in health and disease - Implications for ischemia/reperfusion injury, inflammatory diseases, diabetes, and cancer.
    Lucynda Pham, Tasnim Arroum, Junmei Wan, Lauren Pavelich, Jamie Bell, Paul T Morse, Icksoo Lee, Lawrence I Grossman, Thomas H Sanderson, Moh H Malek, Maik Hüttemann.
      Mitochondria are essential to cellular function as they generate the majority of cellular ATP, mediated through oxidative phosphorylation, which couples proton pumping of the electron transport chain (ETC) to ATP production. The ETC generates an electrochemical gradient, known as the proton motive force, consisting of the mitochondrial membrane potential (ΔΨm, the major component in mammals) and ΔpH across the inner mitochondrial membrane. Both ATP production and reactive oxygen species (ROS) are linked to ΔΨm, and it has been shown that an imbalance in ΔΨm beyond the physiological optimal intermediate range results in excessive ROS production. The reaction of cytochrome c oxidase (COX) of the ETC with its small electron donor cytochrome c (Cytc) is the proposed rate-limiting step in mammals under physiological conditions. The rate at which this redox reaction occurs controls ΔΨm and thus ATP and ROS production. Multiple mechanisms are in place that regulate this reaction to meet the cell's energy demand and respond to acute stress. COX and Cytc have been shown to be regulated by all three main mechanisms, which we discuss in detail: allosteric regulation, tissue-specific isoforms, and post-translational modifications for which we provide a comprehensive catalog and discussion of their functional role with 55 and 50 identified phosphorylation and acetylation sites on COX, respectively. Disruption of these regulatory mechanisms has been found in several common human diseases, including stroke and myocardial infarction, inflammation including sepsis, and diabetes, where changes in COX or Cytc phosphorylation lead to mitochondrial dysfunction contributing to disease pathophysiology. Identification and subsequent targeting of the underlying signaling pathways holds clear promise for future interventions to improve human health. An example intervention is the recently discovered noninvasive COX-inhibitory infrared light therapy that holds promise to transform the current standard of clinical care in disease conditions where COX regulation has gone awry.
    DOI:  https://doi.org/10.1016/j.redox.2024.103426
  31. Nature. 2024 Nov;635(8039): 699-707
    Single-cell integration reveals metaplasia in inflammatory gut diseases.
    Amanda J Oliver, Ni Huang, Raquel Bartolome-Casado, Ruoyan Li, Simon Koplev, Hogne R Nilsen, Madelyn Moy, Batuhan Cakir, Krzysztof Polanski, Victoria Gudiño, Elisa Melón-Ardanaz, Dinithi Sumanaweera, Daniel Dimitrov, Lisa Marie Milchsack, Michael E B FitzPatrick, Nicholas M Provine, Jacqueline M Boccacino, Emma Dann, Alexander V Predeus, Ken To, Martin Prete, Jonathan A Chapman, Andrea C Masi, Emily Stephenson, Justin Engelbert, Sebastian Lobentanzer, Shani Perera, Laura Richardson, Rakeshlal Kapuge, Anna Wilbrey-Clark, Claudia I Semprich, Sophie Ellams, Catherine Tudor, Philomeena Joseph, Alba Garrido-Trigo, Ana M Corraliza, Thomas R W Oliver, C Elizabeth Hook, Kylie R James, Krishnaa T Mahbubani, Kourosh Saeb-Parsy, Matthias Zilbauer, Julio Saez-Rodriguez, Marte Lie Høivik, Espen S Bækkevold, Christopher J Stewart, Janet E Berrington, Kerstin B Meyer, Paul Klenerman, Azucena Salas, Muzlifah Haniffa, Frode L Jahnsen, Rasa Elmentaite, Sarah A Teichmann.
      The gastrointestinal tract is a multi-organ system crucial for efficient nutrient uptake and barrier immunity. Advances in genomics and a surge in gastrointestinal diseases1,2 has fuelled efforts to catalogue cells constituting gastrointestinal tissues in health and disease3. Here we present systematic integration of 25 single-cell RNA sequencing datasets spanning the entire healthy gastrointestinal tract in development and in adulthood. We uniformly processed 385 samples from 189 healthy controls using a newly developed automated quality control approach (scAutoQC), leading to a healthy reference atlas with approximately 1.1 million cells and 136 fine-grained cell states. We anchor 12 gastrointestinal disease datasets spanning gastrointestinal cancers, coeliac disease, ulcerative colitis and Crohn's disease to this reference. Utilizing this 1.6 million cell resource (gutcellatlas.org), we discover epithelial cell metaplasia originating from stem cells in intestinal inflammatory diseases with transcriptional similarity to cells found in pyloric and Brunner's glands. Although previously linked to mucosal healing4, we now implicate pyloric gland metaplastic cells in inflammation through recruitment of immune cells including T cells and neutrophils. Overall, we describe inflammation-induced changes in stem cells that alter mucosal tissue architecture and promote further inflammation, a concept applicable to other tissues and diseases.
    DOI:  https://doi.org/10.1038/s41586-024-07571-1
  32. Nat Aging. 2024 Nov 22.
    Molecular and genetic insights into human ovarian aging from single-nuclei multi-omics analyses.
    Chen Jin, Xizhe Wang, Jiping Yang, Seungsoo Kim, Adam D Hudgins, Amir Gamliel, Mingzhuo Pei, Daniela Contreras, Melody Devos, Qinghua Guo, Jan Vijg, Marco Conti, Jan Hoeijmakers, Judith Campisi, Rogerio Lobo, Zev Williams, Michael G Rosenfeld, Yousin Suh.
      The ovary is the first organ to age in the human body, affecting both fertility and overall health. However, the biological mechanisms underlying human ovarian aging remain poorly understood. Here we present a comprehensive single-nuclei multi-omics atlas of four young (ages 23-29 years) and four reproductively aged (ages 49-54 years) human ovaries. Our analyses reveal coordinated changes in transcriptomes and chromatin accessibilities across cell types in the ovary during aging, notably mTOR signaling being a prominent ovary-specific aging pathway. Cell-type-specific regulatory networks reveal enhanced activity of the transcription factor CEBPD across cell types in the aged ovary. Integration of our multi-omics data with genetic variants associated with age at natural menopause demonstrates a global impact of functional variants on gene regulatory networks across ovarian cell types. We nominate functional non-coding regulatory variants, their target genes and ovarian cell types and regulatory mechanisms. This atlas provides a valuable resource for understanding the cellular, molecular and genetic basis of human ovarian aging.
    DOI:  https://doi.org/10.1038/s43587-024-00762-5
  33. Nature. 2024 Nov 20.
    Social state alters vision using three circuit mechanisms in Drosophila.
    Catherine E Schretter, Tom Hindmarsh Sten, Nathan Klapoetke, Mei Shao, Aljoscha Nern, Marisa Dreher, Daniel Bushey, Alice A Robie, Adam L Taylor, Kristin Branson, Adriane Otopalik, Vanessa Ruta, Gerald M Rubin.
      Animals are often bombarded with visual information and must prioritize specific visual features based on their current needs. The neuronal circuits that detect and relay visual features have been well studied1-8. Much less is known about how an animal adjusts its visual attention as its goals or environmental conditions change. During social behaviours, flies need to focus on nearby flies9-11. Here we study how the flow of visual information is altered when female Drosophila enter an aggressive state. From the connectome, we identify three state-dependent circuit motifs poised to modify the response of an aggressive female to fly-sized visual objects: convergence of excitatory inputs from neurons conveying select visual features and internal state; dendritic disinhibition of select visual feature detectors; and a switch that toggles between two visual feature detectors. Using cell-type-specific genetic tools, together with behavioural and neurophysiological analyses, we show that each of these circuit motifs is used during female aggression. We reveal that features of this same switch operate in male Drosophila during courtship pursuit, suggesting that disparate social behaviours may share circuit mechanisms. Our study provides a compelling example of using the connectome to infer circuit mechanisms that underlie dynamic processing of sensory signals.
    DOI:  https://doi.org/10.1038/s41586-024-08255-6
  34. Nature. 2024 Nov 18.
    Adipose tissue retains an epigenetic memory of obesity after weight loss.
    Laura C Hinte, Daniel Castellano-Castillo, Adhideb Ghosh, Kate Melrose, Emanuel Gasser, Falko Noé, Lucas Massier, Hua Dong, Wenfei Sun, Anne Hoffmann, Christian Wolfrum, Mikael Rydén, Niklas Mejhert, Matthias Blüher, Ferdinand von Meyenn.
      Reducing body weight to improve metabolic health and related comorbidities is a primary goal in treating obesity1,2. However, maintaining weight loss is a considerable challenge, especially as the body seems to retain an obesogenic memory that defends against body weight changes3,4. Overcoming this barrier for long-term treatment success is difficult because the molecular mechanisms underpinning this phenomenon remain largely unknown. Here, by using single-nucleus RNA sequencing, we show that both human and mouse adipose tissues retain cellular transcriptional changes after appreciable weight loss. Furthermore, we find persistent obesity-induced alterations in the epigenome of mouse adipocytes that negatively affect their function and response to metabolic stimuli. Mice carrying this obesogenic memory show accelerated rebound weight gain, and the epigenetic memory can explain future transcriptional deregulation in adipocytes in response to further high-fat diet feeding. In summary, our findings indicate the existence of an obesogenic memory, largely on the basis of stable epigenetic changes, in mouse adipocytes and probably other cell types. These changes seem to prime cells for pathological responses in an obesogenic environment, contributing to the problematic 'yo-yo' effect often seen with dieting. Targeting these changes in the future could improve long-term weight management and health outcomes.
    DOI:  https://doi.org/10.1038/s41586-024-08165-7
  35. bioRxiv. 2024 Oct 28. pii: 2024.10.23.619897. [Epub ahead of print]
    Coordinated translational control of multiple immune checkpoints by the integrated stress response pathway in lung cancer.
    Shayna Thomas-Jardin, Shruthy Suresh, Ariana Arce, Nicole Novaresi, Emily Stein, Lisa Thomas, Cheryl Lewis, Chul Ahn, Bret M Evers, Maria E Salvatierra, Wei Lui, Khaja Khan, Luisa Maris Solis Soto, Ignacio Wistuba, John D Minna, Kathryn A O'Donnell.
      The integrated stress response (ISR) is an adaptive pathway hijacked by cancer cells to survive cellular stresses in the tumor microenvironment. ISR activation potently induces Programmed Death Ligand 1 (PD-L1), leading to suppression of anti-tumor immunity. Here we sought to uncover additional immune checkpoint proteins regulated by the ISR to elucidate mechanisms of tumor immune escape. We show that CD155 and PD-L1 are coordinately induced by the ISR, enhancing translation of both immune checkpoint proteins through bypass of inhibitory upstream open reading frames (uORFs) in their 5' UTRs. Analysis of primary human lung tumors identifies a significant correlation between PD-L1 and CD155 expression. ISR activation accelerates tumorigenesis and inhibits T cell function, effects that can be overcome by combining PD-1 blockade with the ISR inhibitor ISRIB. These studies uncover a novel mechanism by which two immune checkpoint proteins are coordinately regulated and suggest a new therapeutic strategy for lung cancer patients.
    Statement of Significance: This study uncovers a novel mechanism for the coordinated translational regulation of the PD-L1/PD1 and CD155/TIGIT immune checkpoint pathways and highlights the ISR as a therapeutic vulnerability for lung cancer. Inhibition of the ISR pathway bolsters PD-1 blockade, potentially unveiling a new therapeutic strategy for lung cancer patients.
    DOI:  https://doi.org/10.1101/2024.10.23.619897
  36. bioRxiv. 2024 Nov 03. pii: 2024.11.03.621721. [Epub ahead of print]
    Methylglyoxal is an antibacterial effector produced by macrophages during infection.
    Andrea Anaya-Sanchez, Samuel B Berry, Scott Espich, Alex Zilinskas, Phuong M Tran, Carolina Agudelo, Helia Samani, K Heran Darwin, Daniel A Portnoy, Sarah A Stanley.
      Infected macrophages transition into aerobic glycolysis, a metabolic program crucial for control of bacterial infection. However, antimicrobial mechanisms supported by aerobic glycolysis are unclear. Methylglyoxal is a highly toxic aldehyde that modifies proteins and DNA and is produced as a side-product of glycolysis. Here we show that despite the toxicity of this aldehyde, infected macrophages generate high levels of methylglyoxal during aerobic glycolysis while downregulating the detoxification system. We use targeted mutations in mice to modulate methylglyoxal generation and show that reducing methylglyoxal production by the host promotes survival of Listeria monocytogenes and Mycobacterium tuberculosis , whereas increasing methylglyoxal levels improves control of bacterial infection. Furthermore, we show that bacteria that are unable to detoxify methylglyoxal are avirulent and experience up to 1000-fold greater genomic mutation frequency during infection. Taken together, these results suggest that methylglyoxal is an antimicrobial innate immune effector that defends the host against bacterial pathogens.
    DOI:  https://doi.org/10.1101/2024.11.03.621721
  37. Science. 2024 Nov 22. 386(6724): 850-851
    Macrophage modulation of tumor immunity.
    Peter Savage.
      Macrophages deliver polarizing messages to promote immune suppression in tumors.
    DOI:  https://doi.org/10.1126/science.adt5661
  38. EMBO Mol Med. 2024 Nov 20.
    Pathogenic PDE12 variants impair mitochondrial RNA processing causing neonatal mitochondrial disease.
    Lindsey Van Haute, Petra Páleníková, Jia Xin Tang, Pavel A Nash, Mariella T Simon, Angela Pyle, Monika Oláhová, Christopher A Powell, Pedro Rebelo-Guiomar, Alexander Stover, Michael Champion, Charulata Deshpande, Emma L Baple, Karen L Stals, Sian Ellard, Olivia Anselem, Clémence Molac, Giulia Petrilli, Laurence Loeuillet, Sarah Grotto, Tania Attie-Bitach, Jose E Abdenur, Robert W Taylor, Michal Minczuk.
      Pathogenic variants in either the mitochondrial or nuclear genomes are associated with a diverse group of human disorders characterized by impaired mitochondrial function. Within this group, an increasing number of families have been identified, where Mendelian genetic disorders implicate defective mitochondrial RNA biology. The PDE12 gene encodes the poly(A)-specific exoribonuclease, involved in the quality control of mitochondrial non-coding RNAs. Here, we report that disease-causing PDE12 variants in three unrelated families are associated with mitochondrial respiratory chain deficiencies and wide-ranging clinical presentations in utero and within the neonatal period, with muscle and brain involvement leading to marked cytochrome c oxidase (COX) deficiency in muscle and severe lactic acidosis. Whole exome sequencing of affected probands revealed novel, segregating bi-allelic missense PDE12 variants affecting conserved residues. Patient-derived primary fibroblasts demonstrate diminished steady-state levels of PDE12 protein, whilst mitochondrial poly(A)-tail RNA sequencing (MPAT-Seq) revealed an accumulation of spuriously polyadenylated mitochondrial RNA, consistent with perturbed function of PDE12 protein. Our data suggest that PDE12 regulates mitochondrial RNA processing and its loss results in neurological and muscular phenotypes.
    Keywords:  Exome Sequencing; Lactic Acidosis; Mitochondrial Disease; RNA Processing; tRNA
    DOI:  https://doi.org/10.1038/s44321-024-00172-5
  39. Nat Immunol. 2024 Nov 18.
    Cutaneous T cell lymphoma atlas reveals malignant TH2 cells supported by a B cell-rich tumor microenvironment.
    Ruoyan Li, Johanna Strobl, Elizabeth F M Poyner, Aya Balbaa, Fereshteh Torabi, Pavel V Mazin, Nana-Jane Chipampe, Emily Stephenson, Ciro Ramírez-Suástegi, Vijaya Baskar Mahalingam Shanmugiah, Louis Gardner, Bayanne Olabi, Rowen Coulthard, Rachel A Botting, Nina Zila, Elena Prigmore, Nusayhah H Gopee, Marta A Chroscik, Efpraxia Kritikaki, Justin Engelbert, Issac Goh, Hon Man Chan, Harriet F Johnson, Jasmine Ellis, Victoria Rowe, Win Tun, Gary Reynolds, Dexin Yang, April Rose Foster, Laure Gambardella, Elena Winheim, Chloe Admane, Benjamin Rumney, Lloyd Steele, Laura Jardine, Julia Nenonen, Keir Pickard, Jennifer Lumley, Philip Hampton, Simeng Hu, Fengjie Liu, Xiangjun Liu, David Horsfall, Daniela Basurto-Lozada, Louise Grimble, Chris M Bacon, Sophie C Weatherhead, Hanna Brauner, Yang Wang, Fan Bai, Nick J Reynolds, Judith E Allen, Constanze Jonak, Patrick M Brunner, Sarah A Teichmann, Muzlifah Haniffa.
      Cutaneous T cell lymphoma (CTCL) is a potentially fatal clonal malignancy of T cells primarily affecting the skin. The most common form of CTCL, mycosis fungoides, can be difficult to diagnose, resulting in treatment delay. We performed single-cell and spatial transcriptomics analysis of skin from patients with mycosis fungoides-type CTCL and an integrated comparative analysis with human skin cell atlas datasets from healthy and inflamed skin. We revealed the co-optation of T helper 2 (TH2) cell-immune gene programs by malignant CTCL cells and modeling of the tumor microenvironment to support their survival. We identified MHC-II+ fibroblasts and dendritic cells that can maintain TH2 cell-like tumor cells. CTCL tumor cells are spatially associated with B cells, forming tertiary lymphoid structure-like aggregates. Finally, we validated the enrichment of B cells in CTCL and its association with disease progression across three independent patient cohorts. Our findings provide diagnostic aids, potential biomarkers for disease staging and therapeutic strategies for CTCL.
    DOI:  https://doi.org/10.1038/s41590-024-02018-1
  40. bioRxiv. 2024 Nov 08. pii: 2024.11.05.622105. [Epub ahead of print]
    Sticky enzymes: increased metabolic efficiency via substrate-dependent enzyme clustering.
    Alejandro Martínez-Calvo, Jello Zhou, Yaojun Zhang, Ned S Wingreen.
      Coclustering of subsequent enzymes in a pathway can accelerate the processing of metabolic intermediates, with benefits including increased pathway fluxes, reduced toxicity, and sensitive branch-point regulation. While the optimal organization of such clusters has been explored theoretically, little is known about how to achieve such organization inside cells. Here we propose that phase-separating enzymes can self-organize into nearly-optimally sized and spaced clusters, provided that their "stickiness" is regulated by local substrate availability. In a nutshell, enzyme clusters only form when and where they are needed to process substrate. We study a mathematical model that implements this scheme for simple metabolic pathways, including all thermodynamic constraints. We find that pathway fluxes can be increased by 50 to 1000-fold and toxic metabolites can be decreased by 10 to 100-fold, at realistic enzyme densities. Finally, we discuss how enzyme "stickiness" could be allosterically regulated. This study presents a self-organization strategy that goes beyond current paradigms for natural and engineered enzyme clusters, and thus represents a motivating challenge to the fields of synthetic biology and metabolic engineering.
    DOI:  https://doi.org/10.1101/2024.11.05.622105
  41. bioRxiv. 2024 Nov 01. pii: 2024.11.01.618293. [Epub ahead of print]
    Role of Arginine and its Metabolism in TGF-β-Induced Activation of Lung Fibroblasts.
    Robert B Hamanaka, Kun Woo D Shin, M Volkan Atalay, Rengul Cetin-Atalay, Hardik Shah, Jennifer C Houpy Szafran, Parker S Woods, Angelo Y Meliton, Obada R Shamaa, Yufeng Tian, Takugo Cho, Gökhan M Mutlu.
      Arginine is a conditionally essential amino acid with known roles in protein production, nitric oxide synthesis, biosynthesis of proline and polyamines, and regulation of intracellular signaling pathways. Arginine biosynthesis and catabolism have been linked to TGF-β-induced activation of fibroblasts in the context of pulmonary fibrosis; however, a thorough study on the metabolic and signaling roles of arginine in the process of fibroblast activation has not been conducted. Here, we used metabolic dropouts and labeling strategies to determine how activated fibroblasts utilize arginine. We found that arginine limitation leads to activation of GCN2 while inhibiting TGF-β-induced mTORC1 activation and collagen protein production. Extracellular citrulline could rescue the effect of arginine deprivation in an ASS1-dependent manner. Using metabolic tracers of arginine and its precursors, we found little evidence of arginine synthesis or catabolism in lung fibroblasts treated with TGF-β. Extracellular ornithine or glutamine were the primary sources of ornithine and polyamines, not arginine. Our findings suggest that the major role for arginine in lung fibroblasts is for charging of arginyl-tRNAs and for promotion of mTOR signaling.
    Keywords:  Arginine; Fibroblast; Metabolism; Pulmonary Fibrosis
    DOI:  https://doi.org/10.1101/2024.11.01.618293
  42. JCI Insight. 2024 Nov 22. pii: e184279. [Epub ahead of print]9(22):
    Human metabolic chambers reveal a coordinated metabolic-physiologic response to nutrition.
    Andrew S Perry, Paolo Piaggi, Shi Huang, Matthew Nayor, Jane Freedman, Kari E North, Jennifer E Below, Clary B Clish, Venkatesh L Murthy, Jonathan Krakoff, Ravi V Shah.
      Human studies linking metabolism with organism-wide physiologic function have been challenged by confounding, adherence, and precisionHere, we united physiologic and molecular phenotypes of metabolism during controlled dietary intervention to understand integrated metabolic-physiologic responses to nutrition. In an inpatient study of individuals who underwent serial 24-hour metabolic chamber experiments (indirect calorimetry) and metabolite profiling, we mapped a human metabolome onto substrate oxidation rates and energy expenditure across up to 7 dietary conditions (energy balance, fasting, multiple 200% caloric excess overfeeding of varying fat, protein, and carbohydrate composition). Diets exhibiting greater fat oxidation (e.g., fasting, high-fat) were associated with changes in metabolites within pathways of mitochondrial β-oxidation, ketogenesis, adipose tissue fatty acid liberation, and/or multiple anapleurotic substrates for tricarboxylic acid cycle flux, with inverse associations for diets with greater carbohydrate availability. Changes in each of these metabolite classes were strongly related to 24-hour respiratory quotient (RQ) and substrate oxidation rates (e.g., acylcarnitines related to lower 24-hour RQ and higher 24-hour lipid oxidation), underscoring links between substrate availability, physiology, and metabolism in humans. Physiologic responses to diet determined by gold-standard human metabolic chambers are strongly coordinated with biologically consistent, interconnected metabolic pathways encoded in the metabolome.
    Keywords:  Amino acid metabolism; Carbohydrate metabolism; Intermediary metabolism; Metabolism
    DOI:  https://doi.org/10.1172/jci.insight.184279
  43. Nat Commun. 2024 Nov 21. 15(1): 10107
    Acid-exposed and hypoxic cancer cells do not overlap but are interdependent for unsaturated fatty acid resources.
    Katarzyna Głowacka, Sébastien Ibanez, Ophélie Renoult, Perrine Vermonden, Maria Virginia Giolito, Kübra Özkan, Charline Degavre, Léo Aubert, Céline Guilbaud, Florine Laloux-Morris, Elena Richiardone, Jérôme Ambroise, Caroline Bouzin, Davide Brusa, Jonas Dehairs, Johan Swinnen, Cyril Corbet, Yvan Larondelle, Olivier Feron.
      Cancer cells in acidic tumor regions are aggressive and a key therapeutic target, but distinguishing between acid-exposed and hypoxic cells is challenging. Here, we use carbonic anhydrase 9 (CA9) antibodies to mark acidic areas in both hypoxic and respiring tumor areas, along with an HRE-GFP reporter for hypoxia, to isolate distinct cell populations from 3D tumor spheroids. Transcriptomic analysis of CA9-positive, hypoxia-negative cells highlights enriched fatty acid desaturase activity. Inhibiting or silencing stearoyl-CoA desaturase-1 (SCD1) induces ferroptosis in CA9-positive acidic cancer cells and delays mouse tumor growth, an effect enhanced by omega-3 fatty acid supplementation. Using acid-exposed cancer cells and patient-derived tumor organoids, we show that SCD1 inhibition increases acidic cancer cell reliance on external mono-unsaturated fatty acids, depriving hypoxic cells of essential resources. This bystander effect provides unbiased evidence for a lack of full overlap between hypoxic and acidic tumor compartments, highlighting a rationale for targeting desaturase activity in cancer.
    DOI:  https://doi.org/10.1038/s41467-024-54435-3
  44. Kidney Int. 2024 Nov 18. pii: S0085-2538(24)00788-9. [Epub ahead of print]
    The critical role of endoplasmic reticulum stress and the stimulator of interferon genes (STING) pathway in kidney fibrosis.
    Magaiver Andrade-Silva, Poonam Dhillon, Andrea Sanchez-Navarro, Dhanunjay Mukhi, Hailong Hu, Lakshmi P Kolligundla, Andrea Bergeson, Amin Abedini, Jonathan Levinsohn, Bernhard Dumoulin, Niels O S Câmara, Jonathan J Miner, Katalin Susztak.
      Endoplasmic Reticulum (ER) stress is a condition in which the ER is overwhelmed and unable to manage its protein load properly. The precise activation mechanisms and role of ER stress in kidney disease remain unclear. To study this, we performed unbiased transcriptomics analysis to demonstrate ER stress in kidneys of patients with chronic kidney disease and in mouse models of acute and chronic kidney injury (cisplatin and unilateral ureteral obstruction and reanalyzed previously published data on folic acid and mitochondrial transcription factor A(TFAM) knockout mice). Inhibiting the protein kinase RNA-like ER kinase (PERK) arm of ER stress but not activating transcription factor 6 or inositol-requiring enzyme 1, protected mice from kidney fibrosis. The stimulator of interferon genes (STING) was identified as an important upstream activator of ER stress in kidney tubule cells. STING and PERK were found to physically interact, and STING agonists induced PERK activation in kidney tubule cells. Mice with a STING activating mutation presented with ER stress and kidney fibroinflammation. We also generated mice with a tubule specific STING deletion that were resistant to ER stress and kidney fibrosis. Human kidney spatial transcriptomics highlighted a spatial correlation between STING, ER stress and fibrotic gene expression. Thus, our results indicate that STING is an important upstream regulator of PERK and ER stress in tubule cells during kidney fibrosis development.
    Keywords:  PERK; chronic kidney disease; kidney fibrosis; nucleotide sensors; unfolded protein response
    DOI:  https://doi.org/10.1016/j.kint.2024.10.021
  45. bioRxiv. 2024 Nov 03. pii: 2024.10.30.621162. [Epub ahead of print]
    H 2 S remodels mitochondrial ultrastructure and destabilizes respiratory supercomplexes.
    David A Hanna, Brandon Chen, Yatrik M Shah, Oleh Khalimonchuk, Brian Cunniff, Ruma Banerjee.
      Mitochondrial form and function are intimately interconnected, responding to cellular stresses and changes in energy demand. Hydrogen sulfide, a product of amino acid metabolism, has dual roles as an electron transport chain substrate and complex IV (CIV) inhibitor, leading to a reductive shift, which has pleiotropic metabolic consequences. Luminal sulfide concentration in colon is high due to microbial activity, and in this study, we demonstrate that chronic sulfide exposure of colonocyte-derived cells leads to lower Mic60 and Mic19 expression that is correlated with a profound loss of cristae and lower mitochondrial networking. Sulfide-induced depolarization of the inner mitochondrial membrane activates Oma1-dependent cleavage of Opa1 and is associated with a profound loss of CI and CIV activities associated with respirasomes. Our study reveals a potential role for sulfide as an endogenous modulator of mitochondrial dynamics and suggests that this regulation is corrupted in hereditary or acquired diseases associated with elevated sulfide.
    Significance Statement: Hydrogen sulfide is a product of host as well as gut microbial metabolism and has the dual capacity for activating respiration as a substrate, and inhibiting it at the level of complex IV. In this study, we report that chronic albeit low-level sulfide exposure elicits profound changes in mitochondrial architecture in cultured human cells. Disruption of mitochondrial networks is reversed upon removal of sulfide from the growth chamber atmosphere. Sulfide-dependent depolarization of the inner mitochondrial membrane is associated with loss of cristae and respiratory supercomplexes. Our study reveals the potential for sulfide to be an endogenous regulator of mitochondrial ultrastructure and function via modulation of electron flux and for this process to be corrupted in sulfide dysregulated diseases.
    DOI:  https://doi.org/10.1101/2024.10.30.621162
  46. EMBO Rep. 2024 Nov 22.
    The DNA demethylase TET1 modifies the impact of maternal folic acid status on embryonic brain development.
    Lehua Chen, Bernard K van der Veer, Qiuying Chen, Spyridon Champeris Tsaniras, Wannes Brangers, Harm H M Kwak, Rita Khoueiry, Yunping Lei, Robert Cabrera, Steven S Gross, Richard H Finnell, Kian Peng Koh.
      Folic acid (FA) is well known to prevent neural tube defects (NTDs), but we do not know why many human NTD cases still remain refractory to FA supplementation. Here, we investigate how the DNA demethylase TET1 interacts with maternal FA status to regulate mouse embryonic brain development. We determined that cranial NTDs display higher penetrance in non-inbred than in inbred Tet1-/- embryos and are resistant to FA supplementation across strains. Maternal diets that are either too rich or deficient in FA are linked to an increased incidence of cranial deformities in wild type and Tet1+/- offspring and to altered DNA hypermethylation in Tet1-/- embryos, primarily at neurodevelopmental loci. Excess FA in Tet1-/- embryos results in phospholipid metabolite loss and reduced expression of multiple membrane solute carriers, including a FA transporter gene that exhibits increased promoter DNA methylation and thereby mimics FA deficiency. Moreover, FA deficiency reveals that Tet1 haploinsufficiency can contribute to DNA hypermethylation and susceptibility to NTDs. Overall, our study suggests that epigenetic dysregulation may underlie NTD development despite FA supplementation.
    Keywords:  DNA Methylation; Embryonic Brain; Folic Acid; Gene-environment; Neural Tube Closure
    DOI:  https://doi.org/10.1038/s44319-024-00316-1
  47. Virchows Arch. 2024 Nov 20.
    Morphological diversity in SDH-deficient renal carcinomas: a three-case exploration of variant features and dedifferentiation.
    Fanni Sánta, Antranik Dabaghian, Boglárka Pósfai, Béla Vasas, László Kaizer, Alex Jenei, Bálint Scheich, Vanda Téglási, Zoltán Sápi, Krisztina Bíró, Anikó Maráz, Mavrogenis Stelios, Henriett Butz, Petr Martínek, Kristýna Pivovarčíková, Zsombor Melegh, Mahmut Akgul, Levente Kuthi.
      Succinate dehydrogenase (SDH)-deficient renal cell carcinoma (RCC) is a rare subtype of renal neoplasm predominantly affecting younger individuals. It is characterized by germline mutations in SDHx genes, particularly type B. Histologically, SDH-deficient RCC features eosinophilic cytoplasmic cells forming solid nests or microcysts, sometimes entrapping normal tubules. We present three SDH-deficient RCC cases with overlapping morphological features with fumarate hydratase-deficient RCC and TFEB-rearranged RCC, an appearance that has not been previously described. All tumors lacked SDHB expression and harbored pathogenic SDHB mutations, with the germline nature confirmed in two cases. Metastasis developed in two patients. Our case set highlights the diagnostic challenges of molecularly defined renal tumors and expands the morphological spectrum of SDH-deficient RCC with unusual histological features. Clinically, these tumors appear to be aggressive.
    Keywords:  RCC; Renal cell carcinoma; SDHB; Succinate dehydrogenase
    DOI:  https://doi.org/10.1007/s00428-024-03978-3
  48. Dev Cell. 2024 Nov 15. pii: S1534-5807(24)00637-3. [Epub ahead of print]
    Lysosomal catabolic activity promotes the exit of murine totipotent 2-cell state by silencing early-embryonic retrotransposons.
    Hao Wu, Lanrui Cao, Xinpeng Wen, Jiawei Fan, Yuan Wang, Heyong Hu, Shuyan Ji, Yinli Zhang, Cunqi Ye, Wei Xie, Jin Zhang, Haoxing Xu, Xudong Fu.
      During mouse preimplantation development, a subset of retrotransposons/genes are transiently expressed in the totipotent 2-cell (2C) embryos. These 2C transcripts rapidly shut down their expression beyond the 2C stage of embryos, promoting the embryo to exit from the 2C stage. However, the mechanisms regulating this shutdown remain unclear. Here, we identified that lysosomal catabolism played a role in the exit of the totipotent 2C state. Our results showed that the activation of embryonic lysosomal catabolism promoted the embryo to exit from the 2C stage and suppressed 2C transcript expression. Mechanistically, our results indicated that lysosomal catabolism suppressed 2C transcripts through replenishing cellular amino-acid levels, thereby inactivating transcriptional factors TFE3/TFEB and abolishing their transcriptional activation of 2C retrotransposons, MERVL (murine endogenous retrovirus-L)/MT2_Mm. Collectively, our study identified that lysosomal activity modulated the transcriptomic landscape and development in mouse embryos and identified an unanticipated layer of transcriptional control on early-embryonic retrotransposons from lysosomal signaling.
    Keywords:  2-cell-like cells; lysosomal signaling; retrotransposons; totipotency
    DOI:  https://doi.org/10.1016/j.devcel.2024.10.018
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