bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2024–03–03
57 papers selected by
Christian Frezza, Universität zu Köln
  1. PMF-seq: a highly scalable screening strategy for linking genetics to mitochondrial bioenergetics.
  2. PKM2 diverts glycolytic flux in dependence on mitochondrial one-carbon cycle.
  3. Accumulation of G3P and pEtN drives cellular senescence via altered lipid metabolism.
  4. Enhanced branched-chain amino acid metabolism improves age-related reproduction in C. elegans.
  5. Histone butyrylation in the mouse intestine is mediated by the microbiota and associated with regulation of gene expression.
  6. Histone butyrylation is a dietary link to epigenetics.
  7. Intratumoral TREX1 induction promotes immune evasion by limiting type I interferon.
  8. Triaging of α-helical proteins to the mitochondrial outer membrane by distinct chaperone machinery based on substrate topology.
  9. Targeting stromal metabolism in pancreatic ductal adenocarcinoma.
  10. Mitochondrial DNA competition: starving out the mutant genome.
  11. The weight-loss-independent benefits of fasting.
  12. Central Role for Glycolysis and Fatty Acids in LH-responsive Progesterone Synthesis.
  13. An iron rheostat controls hematopoietic stem cell fate.
  14. SOX17 enables immune evasion of early colorectal adenomas and cancers.
  15. Slowing reproductive ageing by preserving BCAT-1.
  16. A spatial map of hepatic mitochondria uncovers functional heterogeneity shaped by nutrient-sensing signaling.
  17. Adeno-to-squamous transition drives resistance to KRAS inhibition in LKB1 mutant lung cancer.
  18. Functional hypoxia reduces mitochondrial calcium uptake.
  19. Quiescence enables unrestricted cell fate in naive embryonic stem cells.
  20. The transcription factor ChREBP Orchestrates liver carcinogenesis by coordinating the PI3K/AKT signaling and cancer metabolism.
  21. Cellular reprogramming in vivo initiated by SOX4 pioneer factor activity.
  22. Cancer-associated fibroblast-derived acetate promotes pancreatic cancer development by altering polyamine metabolism via the ACSS2-SP1-SAT1 axis.
  23. Metabolic rewiring of macrophages by epidermal-derived lactate promotes sterile inflammation in the murine skin.
  24. Reorganization of mitochondria-organelle interactions during postnatal development in skeletal muscle.
  25. Aging STINGs: mitophagy at the crossroads of neuroinflammation.
  26. Identification of a leucine-mediated threshold effect governing macrophage mTOR signalling and cardiovascular risk.
  27. Sarcoma microenvironment cell states and ecosystems are associated with prognosis and predict response to immunotherapy.
  28. Tom20 gates PINK1 activity and mediates its tethering of the TOM and TIM23 translocases upon mitochondrial stress.
  29. Identifying potential dietary treatments for inherited metabolic disorders using Drosophila nutrigenomics.
  30. Ion and lipid orchestration of secondary active transport.
  31. Optic atrophy 1 mediates muscle differentiation by promoting a metabolic switch via the supercomplex assembly factor SCAF1.
  32. Translational response to mitochondrial stresses is orchestrated by tRNA modifications.
  33. A guideline on the molecular ecosystem regulating ferroptosis.
  34. Mitochondria in disease: changes in shapes and dynamics.
  35. A leucine-macrophage mTORC1 connection drives increased risk of atherosclerosis with high-protein diets.
  36. The emergence of circadian timekeeping in the intestine.
  37. Metabolic cell death in cancer: Ferroptosis, cuproptosis, disulfidptosis, and beyond.
  38. An Organism-Level Quantitative Flux Model of Mammalian Energy Metabolism.
  39. Targeting PHGDH reverses the immunosuppressive phenotype of tumor-associated macrophages through α-ketoglutarate and mTORC1 signaling.
  40. Nutrient scavenging-fueled growth in pancreatic cancer depends on caveolae-mediated endocytosis under nutrient-deprived conditions.
  41. Resisting weight gain with prebiotic fibre.
  42. How egg cells handle their cellular rubbish.
  43. Deficiency of factor-inhibiting HIF creates a tumor-promoting immune microenvironment.
  44. Epigenome and early selection determine the tumour-immune evolutionary trajectory of colorectal cancer.
  45. A homoeostatic switch causing glycerol-3-phosphate and phosphoethanolamine accumulation triggers senescence by rewiring lipid metabolism.
  46. An atlas of epithelial cell states and plasticity in lung adenocarcinoma.
  47. Nucleosides are overlooked fuels in central carbon metabolism.
  48. Epigenetic control of circadian clocks by environmental signals.
  49. Cancer neoepitopes viewed through negative selection and peripheral tolerance: a new path to cancer vaccines.
  50. The genomic and evolutionary landscapes of anaplastic thyroid carcinoma.
  51. A unified framework for evolutionary genetic and physiological theories of aging.
  52. The CRL5-SPSB3 ubiquitin ligase targets nuclear cGAS for degradation.
  53. Mitochondrial derived vesicles- Quo Vadis?
  54. Acetyl-CoA carboxylase 1 controls a lipid droplet-peroxisome axis and is a vulnerability of endocrine-resistant ER+ breast cancer.
  55. Metabolites that feed upper glycolytic branches support glucose independent human cytomegalovirus replication.
  56. Bile acid metabolism mediates cholesterol homeostasis and promotes tumorigenesis in clear cell renal cell carcinoma.
  57. Versatile roles of cysteine persulfides in tumor biology.
  1. Nat Metab. 2024 Feb 27.
    PMF-seq: a highly scalable screening strategy for linking genetics to mitochondrial bioenergetics.
    Tsz-Leung To, Jason G McCoy, Naomi K Ostriker, Lev S Sandler, Carmen A Mannella, Vamsi K Mootha.
      Our current understanding of mitochondrial organelle physiology has benefited from two broad approaches: classically, cuvette-based measurements with suspensions of isolated mitochondria, in which bioenergetic parameters are monitored acutely in response to respiratory chain substrates and inhibitors1-4, and more recently, highly scalable genetic screens for fitness phenotypes associated with coarse-grained properties of the mitochondrial state5-10. Here we introduce permeabilized-cell mitochondrial function sequencing (PMF-seq) to combine strengths of these two approaches to connect genes to detailed bioenergetic phenotypes. In PMF-seq, the plasma membranes within a pool of CRISPR mutagenized cells are gently permeabilized under conditions that preserve mitochondrial physiology, where detailed bioenergetics can be probed in the same way as with isolated organelles. Cells with desired bioenergetic parameters are selected optically using flow cytometry and subjected to next-generation sequencing. Using PMF-seq, we recover genes differentially required for mitochondrial respiratory chain branching and reversibility. We demonstrate that human D-lactate dehydrogenase specifically conveys electrons from D-lactate into cytochrome c to support mitochondrial membrane polarization. Finally, we screen for genetic modifiers of tBID, a pro-apoptotic protein that acts directly and acutely on mitochondria. We find the loss of the complex V assembly factor ATPAF2 acts as a genetic sensitizer of tBID's acute action. We anticipate that PMF-seq will be valuable for defining genes critical to the physiology of mitochondria and other organelles.
    DOI:  https://doi.org/10.1038/s42255-024-00994-0
  2. Cell Rep. 2024 Feb 28. pii: S2211-1247(24)00196-7. [Epub ahead of print]43(3): 113868
    PKM2 diverts glycolytic flux in dependence on mitochondrial one-carbon cycle.
    Mohaned Benzarti, Laura Neises, Anais Oudin, Christina Krötz, Elodie Viry, Ernesto Gargiulo, Coralie Pulido, Maryse Schmoetten, Vitaly Pozdeev, Nadia I Lorenz, Michael W Ronellenfitsch, David Sumpton, Marc Warmoes, Christian Jaeger, Antoine Lesur, Björn Becker, Etienne Moussay, Jerome Paggetti, Simone P Niclou, Elisabeth Letellier, Johannes Meiser.
      Modeling tumor metabolism in vitro remains challenging. Here, we used galactose as an in vitro tool compound to mimic glycolytic limitation. In contrast to the established idea that high glycolytic flux reduces pyruvate kinase isozyme M2 (PKM2) activity to support anabolic processes, we have discovered that glycolytic limitation also affects PKM2 activity. Surprisingly, despite limited carbon availability and energetic stress, cells induce a near-complete block of PKM2 to divert carbons toward serine metabolism. Simultaneously, TCA cycle flux is sustained, and oxygen consumption is increased, supported by glutamine. Glutamine not only supports TCA cycle flux but also serine synthesis via distinct mechanisms that are directed through PKM2 inhibition. Finally, deleting mitochondrial one-carbon (1C) cycle reversed the PKM2 block, suggesting a potential formate-dependent crosstalk that coordinates mitochondrial 1C flux and cytosolic glycolysis to support cell survival and proliferation during nutrient-scarce conditions.
    Keywords:  CP: Cancer; CP: Metabolism
    DOI:  https://doi.org/10.1016/j.celrep.2024.113868
  3. Nat Metab. 2024 Feb;6(2): 205-206
    Accumulation of G3P and pEtN drives cellular senescence via altered lipid metabolism.
      
    DOI:  https://doi.org/10.1038/s42255-024-00975-3
  4. Nat Metab. 2024 Feb 28.
    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 ageing is one of the earliest human ageing 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 Caenorhabditis 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. Notably, 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/10.1038/s42255-024-00996-y
  5. Nat Metab. 2024 Feb 27.
    Histone butyrylation in the mouse intestine is mediated by the microbiota and associated with regulation of gene expression.
    Leah A Gates, Bernardo Sgarbi Reis, Peder J Lund, Matthew R Paul, Marylene Leboeuf, Annaelle M Djomo, Zara Nadeem, Mariana Lopes, Francisca N Vitorino, Gokhan Unlu, Thomas S Carroll, Kivanç Birsoy, Benjamin A Garcia, Daniel Mucida, C David Allis.
      Post-translational modifications (PTMs) on histones are a key source of regulation on chromatin through impacting cellular processes, including gene expression1. These PTMs often arise from metabolites and are thus impacted by metabolism and environmental cues2-7. One class of metabolically regulated PTMs are histone acylations, which include histone acetylation, butyrylation, crotonylation and propionylation3,8. As these PTMs can be derived from short-chain fatty acids, which are generated by the commensal microbiota in the intestinal lumen9-11, we aimed to define how microbes impact the host intestinal chromatin landscape, mainly in female mice. Here we show that in addition to acetylation, intestinal epithelial cells from the caecum and distal mouse intestine also harbour high levels of butyrylation and propionylation on lysines 9 and 27 of histone H3. We demonstrate that these acylations are regulated by the microbiota and that histone butyrylation is additionally regulated by the metabolite tributyrin. Tributyrin-regulated gene programmes are correlated with histone butyrylation, which is associated with active gene-regulatory elements and levels of gene expression. Together, our study uncovers a regulatory layer of how the microbiota and metabolites influence the intestinal epithelium through chromatin, demonstrating a physiological setting in which histone acylations are dynamically regulated and associated with gene regulation.
    DOI:  https://doi.org/10.1038/s42255-024-00992-2
  6. Nat Metab. 2024 Feb 27.
    Histone butyrylation is a dietary link to epigenetics.
    Yudong Sun, Jason W Locasale.
      
    DOI:  https://doi.org/10.1038/s42255-024-01013-y
  7. Cancer Immunol Res. 2024 Feb 26.
    Intratumoral TREX1 induction promotes immune evasion by limiting type I interferon.
    Eléonore Toufektchan, Alexandra Dananberg, Josefine Striepen, James H Hickling, Abraham Shim, Yanyang Chen, Ashley Nichols, Mercedes A Duran Paez, Lisa Mohr, Samuel F Bakhoum, John Maciejowski.
      Chromosomal instability is a hallmark of human cancer that is associated with aggressive disease characteristics. Chromosome mis-segregations help fuel natural selection, but they risk provoking a cGAS-STING immune response through the accumulation of cytosolic DNA. The mechanisms of how tumors benefit from chromosomal instability while mitigating associated risks, such as enhanced immune surveillance, are poorly understood. Here, we identify cGAS-STING-dependent upregulation of the nuclease TREX1 as an adaptive, negative feedback mechanism that promotes immune evasion through digestion of cytosolic DNA. TREX1 loss diminishes tumor growth, prolongs survival of host animals, increases tumor immune infiltration, and potentiates response to immune checkpoint blockade selectively in tumors capable of mounting a type I interferon response downstream of STING. Together, these data demonstrate that TREX1 induction shields chromosomally unstable tumors from immune surveillance by dampening type I interferon production and suggest that TREX1 inhibitors might be used to selectively target tumors that have retained the inherent ability to mount an interferon response downstream of STING.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-23-1093
  8. Mol Cell. 2024 Feb 27. pii: S1097-2765(24)00095-9. [Epub ahead of print]
    Triaging of α-helical proteins to the mitochondrial outer membrane by distinct chaperone machinery based on substrate topology.
    Gayathri Muthukumar, Taylor A Stevens, Alison J Inglis, Theodore K Esantsi, Reuben A Saunders, Fabian Schulte, Rebecca M Voorhees, Alina Guna, Jonathan S Weissman.
      Mitochondrial outer membrane ⍺-helical proteins play critical roles in mitochondrial-cytoplasmic communication, but the rules governing the targeting and insertion of these biophysically diverse proteins remain unknown. Here, we first defined the complement of required mammalian biogenesis machinery through genome-wide CRISPRi screens using topologically distinct membrane proteins. Systematic analysis of nine identified factors across 21 diverse ⍺-helical substrates reveals that these components are organized into distinct targeting pathways that act on substrates based on their topology. NAC is required for the efficient targeting of polytopic proteins, whereas signal-anchored proteins require TTC1, a cytosolic chaperone that physically engages substrates. Biochemical and mutational studies reveal that TTC1 employs a conserved TPR domain and a hydrophobic groove in its C-terminal domain to support substrate solubilization and insertion into mitochondria. Thus, the targeting of diverse mitochondrial membrane proteins is achieved through topological triaging in the cytosol using principles with similarities to ER membrane protein biogenesis systems.
    Keywords:  CRISPR; NAC; TTC1; cell biology; cytosolic targeting; genetic screens; membrane protein insertion; mitochondrial outer membrane; topology
    DOI:  https://doi.org/10.1016/j.molcel.2024.01.028
  9. Nat Cell Biol. 2024 Mar 01.
    Targeting stromal metabolism in pancreatic ductal adenocarcinoma.
    Miao Yin, Qun-Ying Lei.
      
    DOI:  https://doi.org/10.1038/s41556-023-01330-6
  10. Trends Pharmacol Sci. 2024 Feb 23. pii: S0165-6147(24)00024-5. [Epub ahead of print]
    Mitochondrial DNA competition: starving out the mutant genome.
    Antonella Spinazzola, Diego Perez-Rodriguez, Jan Ježek, Ian J Holt.
      High levels of pathogenic mitochondrial DNA (mtDNA) variants lead to severe genetic diseases, and the accumulation of such mutants may also contribute to common disorders. Thus, selecting against these mutants is a major goal in mitochondrial medicine. Although mutant mtDNA can drift randomly, mounting evidence indicates that active forces play a role in the selection for and against mtDNA variants. The underlying mechanisms are beginning to be clarified, and recent studies suggest that metabolic cues, including fuel availability, contribute to shaping mtDNA heteroplasmy. In the context of pathological mtDNAs, remodeling of nutrient metabolism supports mitochondria with deleterious mtDNAs and enables them to outcompete functional variants owing to a replicative advantage. The elevated nutrient requirement represents a mutant Achilles' heel because small molecules that restrict nutrient consumption or interfere with nutrient sensing can purge cells of deleterious mtDNAs and restore mitochondrial respiration. These advances herald the dawn of a new era of small-molecule therapies to counteract pathological mtDNAs.
    Keywords:  2-Deoxy-d-glucose; epigenetic rewiring; heteroplasmy; mitochondrial DNA; nutrient metabolism; nutrient signaling
    DOI:  https://doi.org/10.1016/j.tips.2024.01.011
  11. Nat Metab. 2024 Mar 01.
    The weight-loss-independent benefits of fasting.
    Benjamin D Horne.
      
    DOI:  https://doi.org/10.1038/s42255-024-01012-z
  12. bioRxiv. 2024 Feb 14. pii: 2024.02.14.580329. [Epub ahead of print]
    Central Role for Glycolysis and Fatty Acids in LH-responsive Progesterone Synthesis.
    Emilia Przygrodzka, Fatema Binderwala, Robert Powers, Renee M McFee, Andrea S Cupp, Jennifer R Wood, John S Davis.
      Progesterone production by the corpus luteum is fundamental for establishing and maintaining pregnancy. The pituitary gonadotropin luteinizing hormone (LH) is recognized as the primary stimulus for luteal formation and progesterone synthesis, regardless of species. Previous studies demonstrated an elevation in abundance of genes related to glucose and lipid metabolism during the follicular to luteal transition. However, the metabolic phenotype of these highly steroidogenic cells has not been studied. Herein, we determined acute metabolic changes induced by LH in primary luteal cells and defined pathways required for progesterone synthesis. Untargeted metabolomics analysis revealed that LH induces rapid changes in vital metabolic pathways, including glycolysis, tricarboxylic acid (TCA) cycle, pentose phosphate pathway, de novo lipogenesis, and hydrolysis of phospholipids. LH stimulated glucose uptake, enhanced glycolysis, and flux of [U- 13 C 6 ]-labeled glucose-derived carbons into metabolic branches associated with adenosine 5'-triphosphate (ATP) and NADH/NADPH production, synthesis of nucleotides, proteins, and lipids, glycosylation of proteins or lipids, and redox homeostasis. Selective use of small molecule inhibitors targeting the most significantly changed pathways, such as glycolysis, TCA cycle, and lipogenesis, uncovered cellular metabolic routes required for LH-stimulated steroidogenesis. Furthermore, LH via the protein kinase A (PKA) pathway triggered post- translational modification of acetyl-CoA carboxylase alpha (ACACA) and ATP citrate lyase (ACLY), enzymes involved in de novo synthesis of fatty acids. Inhibition of ACLY and fatty acid transport into mitochondria reduced LH-stimulated ATP, cAMP production, PKA activation, and progesterone synthesis. Taken together, these findings reveal novel hormone-sensitive metabolic pathways essential for maintaining LHCGR/PKA signaling and steroidogenesis in ovarian luteal cells.
    Significance: The establishment and maintenance of pregnancy require a well-developed corpus luteum, an endocrine gland within the ovary that produces progesterone. Although there is increased awareness of intracellular signaling events initiating the massive production of progesterone during the reproductive cycle and pregnancy, there are critical gaps in our knowledge of the metabolic and lipidomic pathways required for initiating and maintaining luteal progesterone synthesis. Here, we describe rapid, hormonally triggered metabolic pathways, and define metabolic targets crucial for progesterone synthesis by ovarian steroidogenic cells. Understanding hormonal control of metabolic pathways may help elucidate approaches for improving ovarian function and successful reproduction or identifying metabolic targets for developing nonhormonal contraceptives.
    DOI:  https://doi.org/10.1101/2024.02.14.580329
  13. Cell Stem Cell. 2024 Feb 19. pii: S1934-5909(24)00041-9. [Epub ahead of print]
    An iron rheostat controls hematopoietic stem cell fate.
    Yun-Ruei Kao, Jiahao Chen, Rajni Kumari, Anita Ng, Aliona Zintiridou, Madhuri Tatiparthy, Yuhong Ma, Maria M Aivalioti, Deeposree Moulik, Sriram Sundaravel, Daqian Sun, Julie A Reisz, Juliane Grimm, Nuria Martinez-Lopez, Stephanie Stransky, Simone Sidoli, Ulrich Steidl, Rajat Singh, Angelo D'Alessandro, Britta Will.
      Mechanisms governing the maintenance of blood-producing hematopoietic stem and multipotent progenitor cells (HSPCs) are incompletely understood, particularly those regulating fate, ensuring long-term maintenance, and preventing aging-associated stem cell dysfunction. We uncovered a role for transitory free cytoplasmic iron as a rheostat for adult stem cell fate control. We found that HSPCs harbor comparatively small amounts of free iron and show the activation of a conserved molecular response to limited iron-particularly during mitosis. To study the functional and molecular consequences of iron restriction, we developed models allowing for transient iron bioavailability limitation and combined single-molecule RNA quantification, metabolomics, and single-cell transcriptomic analyses with functional studies. Our data reveal that the activation of the limited iron response triggers coordinated metabolic and epigenetic events, establishing stemness-conferring gene regulation. Notably, we find that aging-associated cytoplasmic iron loading reversibly attenuates iron-dependent cell fate control, explicating intervention strategies for dysfunctional aged stem cells.
    Keywords:  Tip60/KAT5; aging; gene regulation; hematopoiesis; iron; metabolism; stem cells
    DOI:  https://doi.org/10.1016/j.stem.2024.01.011
  14. Nature. 2024 Feb 28.
    SOX17 enables immune evasion of early colorectal adenomas and cancers.
    Norihiro Goto, Peter M K Westcott, Saori Goto, Shinya Imada, Martin S Taylor, George Eng, Jonathan Braverman, Vikram Deshpande, Tyler Jacks, Judith Agudo, Ömer H Yilmaz.
      A hallmark of cancer is the avoidance of immune destruction. This process has been primarily investigated in locally advanced or metastatic cancer1-3; however, much less is known about how pre-malignant or early invasive tumours evade immune detection. Here, to understand this process in early colorectal cancers (CRCs), we investigated how naive colon cancer organoids that were engineered in vitro to harbour Apc-null, KrasG12D and Trp53-null (AKP) mutations adapted to the in vivo native colonic environment. Comprehensive transcriptomic and chromatin analyses revealed that the endoderm-specifying transcription factor SOX17 became strongly upregulated in vivo. Notably, whereas SOX17 loss did not affect AKP organoid propagation in vitro, its loss markedly reduced the ability of AKP tumours to persist in vivo. The small fraction of SOX17-null tumours that grew displayed notable interferon-γ (IFNγ)-producing effector-like CD8+ T cell infiltrates in contrast to the immune-suppressive microenvironment in wild-type counterparts. Mechanistically, in both endogenous Apc-null pre-malignant adenomas and transplanted organoid-derived AKP CRCs, SOX17 suppresses the ability of tumour cells to sense and respond to IFNγ, preventing anti-tumour T cell responses. Finally, SOX17 engages a fetal intestinal programme that drives differentiation away from LGR5+ tumour cells to produce immune-evasive LGR5- tumour cells with lower expression of major histocompatibility complex class I (MHC-I). We propose that SOX17 is a transcription factor that is engaged during the early steps of colon cancer to orchestrate an immune-evasive programme that permits CRC initiation and progression.
    DOI:  https://doi.org/10.1038/s41586-024-07135-3
  15. Nat Metab. 2024 Feb 28.
    Slowing reproductive ageing by preserving BCAT-1.
    Leah E Jamerson, Patrick C Bradshaw.
      
    DOI:  https://doi.org/10.1038/s42255-024-01009-8
  16. Nat Commun. 2024 Feb 28. 15(1): 1799
    A spatial map of hepatic mitochondria uncovers functional heterogeneity shaped by nutrient-sensing signaling.
    Sun Woo Sophie Kang, Rory P Cunningham, Colin B Miller, Lauryn A Brown, Constance M Cultraro, Adam Harned, Kedar Narayan, Jonathan Hernandez, Lisa M Jenkins, Alexei Lobanov, Maggie Cam, Natalie Porat-Shliom.
      In the liver, mitochondria are exposed to different concentrations of nutrients due to their spatial positioning across the periportal and pericentral axis. How the mitochondria sense and integrate these signals to respond and maintain homeostasis is not known. Here, we combine intravital microscopy, spatial proteomics, and functional assessment to investigate mitochondrial heterogeneity in the context of liver zonation. We find that periportal and pericentral mitochondria are morphologically and functionally distinct; beta-oxidation is elevated in periportal regions, while lipid synthesis is predominant in the pericentral mitochondria. In addition, comparative phosphoproteomics reveals spatially distinct patterns of mitochondrial composition and potential regulation via phosphorylation. Acute pharmacological modulation of nutrient sensing through AMPK and mTOR shifts mitochondrial phenotypes in the periportal and pericentral regions, linking nutrient gradients across the lobule and mitochondrial heterogeneity. This study highlights the role of protein phosphorylation in mitochondrial structure, function, and overall homeostasis in hepatic metabolic zonation. These findings have important implications for liver physiology and disease.
    DOI:  https://doi.org/10.1038/s41467-024-45751-9
  17. Cancer Cell. 2024 Feb 20. pii: S1535-6108(24)00036-9. [Epub ahead of print]
    Adeno-to-squamous transition drives resistance to KRAS inhibition in LKB1 mutant lung cancer.
    Xinyuan Tong, Ayushi S Patel, Eejung Kim, Hongjun Li, Yueqing Chen, Shuai Li, Shengwu Liu, Julien Dilly, Kevin S Kapner, Ningxia Zhang, Yun Xue, Laura Hover, Suman Mukhopadhyay, Fiona Sherman, Khrystyna Myndzar, Priyanka Sahu, Yijun Gao, Fei Li, Fuming Li, Zhaoyuan Fang, Yujuan Jin, Juntao Gao, Minglei Shi, Satrajit Sinha, Luonan Chen, Yang Chen, Thian Kheoh, Wenjing Yang, Itai Yanai, Andre L Moreira, Vamsidhar Velcheti, Benjamin G Neel, Liang Hu, James G Christensen, Peter Olson, Dong Gao, Michael Q Zhang, Andrew J Aguirre, Kwok-Kin Wong, Hongbin Ji.
      KRASG12C inhibitors (adagrasib and sotorasib) have shown clinical promise in targeting KRASG12C-mutated lung cancers; however, most patients eventually develop resistance. In lung patients with adenocarcinoma with KRASG12C and STK11/LKB1 co-mutations, we find an enrichment of the squamous cell carcinoma gene signature in pre-treatment biopsies correlates with a poor response to adagrasib. Studies of Lkb1-deficient KRASG12C and KrasG12D lung cancer mouse models and organoids treated with KRAS inhibitors reveal tumors invoke a lineage plasticity program, adeno-to-squamous transition (AST), that enables resistance to KRAS inhibition. Transcriptomic and epigenomic analyses reveal ΔNp63 drives AST and modulates response to KRAS inhibition. We identify an intermediate high-plastic cell state marked by expression of an AST plasticity signature and Krt6a. Notably, expression of the AST plasticity signature and KRT6A at baseline correlates with poor adagrasib responses. These data indicate the role of AST in KRAS inhibitor resistance and provide predictive biomarkers for KRAS-targeted therapies in lung cancer.
    Keywords:  KRAS inhibitor; KRT6A; LKB1; adeno-to-squamous transition, AST; organoid
    DOI:  https://doi.org/10.1016/j.ccell.2024.01.012
  18. Redox Biol. 2024 Jan 17. pii: S2213-2317(24)00013-2. [Epub ahead of print]71 103037
    Functional hypoxia reduces mitochondrial calcium uptake.
    Chris Donnelly, Timea Komlódi, Cristiane Cecatto, Luiza H D Cardoso, Anne-Claire Compagnion, Alessandro Matera, Daniele Tavernari, Olivier Campiche, Rosa Chiara Paolicelli, Nadège Zanou, Bengt Kayser, Erich Gnaiger, Nicolas Place.
      Mitochondrial respiration extends beyond ATP generation, with the organelle participating in many cellular and physiological processes. Parallel changes in components of the mitochondrial electron transfer system with respiration render it an appropriate hub for coordinating cellular adaption to changes in oxygen levels. How changes in respiration under functional hypoxia (i.e., when intracellular O2 levels limit mitochondrial respiration) are relayed by the electron transfer system to impact mitochondrial adaption and remodeling after hypoxic exposure remains poorly defined. This is largely due to challenges integrating findings under controlled and defined O2 levels in studies connecting functions of isolated mitochondria to humans during physical exercise. Here we present experiments under conditions of hypoxia in isolated mitochondria, myotubes and exercising humans. Performing steady-state respirometry with isolated mitochondria we found that oxygen limitation of respiration reduced electron flow and oxidative phosphorylation, lowered the mitochondrial membrane potential difference, and decreased mitochondrial calcium influx. Similarly, in myotubes under functional hypoxia mitochondrial calcium uptake decreased in response to sarcoplasmic reticulum calcium release for contraction. In both myotubes and human skeletal muscle this blunted mitochondrial adaptive responses and remodeling upon contractions. Our results suggest that by regulating calcium uptake the mitochondrial electron transfer system is a hub for coordinating cellular adaption under functional hypoxia.
    Keywords:  Coenzyme Q; Exercise; Membrane potential; Respirometry; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.redox.2024.103037
  19. Nat Commun. 2024 Feb 26. 15(1): 1721
    Quiescence enables unrestricted cell fate in naive embryonic stem cells.
    Le Tran Phuc Khoa, Wentao Yang, Mengrou Shan, Li Zhang, Fengbiao Mao, Bo Zhou, Qiang Li, Rebecca Malcore, Clair Harris, Lili Zhao, Rajesh Rao, Shigeki Iwase, Sundeep Kalantry, Stephanie L Bielas, Costas A Lyssiotis, Yali Dou.
      Quiescence in stem cells is traditionally considered as a state of inactive dormancy or with poised potential. Naive mouse embryonic stem cells (ESCs) can enter quiescence spontaneously or upon inhibition of MYC or fatty acid oxidation, mimicking embryonic diapause in vivo. The molecular underpinning and developmental potential of quiescent ESCs (qESCs) are relatively unexplored. Here we show that qESCs possess an expanded or unrestricted cell fate, capable of generating both embryonic and extraembryonic cell types (e.g., trophoblast stem cells). These cells have a divergent metabolic landscape comparing to the cycling ESCs, with a notable decrease of the one-carbon metabolite S-adenosylmethionine. The metabolic changes are accompanied by a global reduction of H3K27me3, an increase of chromatin accessibility, as well as the de-repression of endogenous retrovirus MERVL and trophoblast master regulators. Depletion of methionine adenosyltransferase Mat2a or deletion of Eed in the polycomb repressive complex 2 results in removal of the developmental constraints towards the extraembryonic lineages. Our findings suggest that quiescent ESCs are not dormant but rather undergo an active transition towards an unrestricted cell fate.
    DOI:  https://doi.org/10.1038/s41467-024-46121-1
  20. Nat Commun. 2024 Feb 29. 15(1): 1879
    The transcription factor ChREBP Orchestrates liver carcinogenesis by coordinating the PI3K/AKT signaling and cancer metabolism.
    Emmanuel Benichou, Bolaji Seffou, Selin Topçu, Ophélie Renoult, Véronique Lenoir, Julien Planchais, Caroline Bonner, Catherine Postic, Carina Prip-Buus, Claire Pecqueur, Sandra Guilmeau, Marie-Clotilde Alves-Guerra, Renaud Dentin.
      Cancer cells integrate multiple biosynthetic demands to drive unrestricted proliferation. How these cellular processes crosstalk to fuel cancer cell growth is still not fully understood. Here, we uncover the mechanisms by which the transcription factor Carbohydrate responsive element binding protein (ChREBP) functions as an oncogene during hepatocellular carcinoma (HCC) development. Mechanistically, ChREBP triggers the expression of the PI3K regulatory subunit p85α, to sustain the activity of the pro-oncogenic PI3K/AKT signaling pathway in HCC. In parallel, increased ChREBP activity reroutes glucose and glutamine metabolic fluxes into fatty acid and nucleic acid synthesis to support PI3K/AKT-mediated HCC growth. Thus, HCC cells have a ChREBP-driven circuitry that ensures balanced coordination between PI3K/AKT signaling and appropriate cell anabolism to support HCC development. Finally, pharmacological inhibition of ChREBP by SBI-993 significantly suppresses in vivo HCC tumor growth. Overall, we show that targeting ChREBP with specific inhibitors provides an attractive therapeutic window for HCC treatment.
    DOI:  https://doi.org/10.1038/s41467-024-45548-w
  21. Nat Commun. 2024 Feb 26. 15(1): 1761
    Cellular reprogramming in vivo initiated by SOX4 pioneer factor activity.
    Takeshi Katsuda, Jonathan H Sussman, Kenji Ito, Andrew Katznelson, Salina Yuan, Naomi Takenaka, Jinyang Li, Allyson J Merrell, Hector Cure, Qinglan Li, Reyaz Ur Rasool, Irfan A Asangani, Kenneth S Zaret, Ben Z Stanger.
      Tissue damage elicits cell fate switching through a process called metaplasia, but how the starting cell fate is silenced and the new cell fate is activated has not been investigated in animals. In cell culture, pioneer transcription factors mediate "reprogramming" by opening new chromatin sites for expression that can attract transcription factors from the starting cell's enhancers. Here we report that SOX4 is sufficient to initiate hepatobiliary metaplasia in the adult mouse liver, closely mimicking metaplasia initiated by toxic damage to the liver. In lineage-traced cells, we assessed the timing of SOX4-mediated opening of enhancer chromatin versus enhancer decommissioning. Initially, SOX4 directly binds to and closes hepatocyte regulatory sequences via an overlapping motif with HNF4A, a hepatocyte master regulatory transcription factor. Subsequently, SOX4 exerts pioneer factor activity to open biliary regulatory sequences. The results delineate a hierarchy by which gene networks become reprogrammed under physiological conditions, providing deeper insight into the basis for cell fate transitions in animals.
    DOI:  https://doi.org/10.1038/s41467-024-45939-z
  22. Nat Cell Biol. 2024 Mar 01.
    Cancer-associated fibroblast-derived acetate promotes pancreatic cancer development by altering polyamine metabolism via the ACSS2-SP1-SAT1 axis.
    Divya Murthy, Kuldeep S Attri, Surendra K Shukla, Ravi Thakur, Nina V Chaika, Chunbo He, Dezhen Wang, Kanupriya Jha, Aneesha Dasgupta, Ryan J King, Scott E Mulder, Joshua Souchek, Teklab Gebregiworgis, Vikant Rai, Rohit Patel, Tuo Hu, Sandeep Rana, Sai Sundeep Kollala, Camila Pacheco, Paul M Grandgenett, Fang Yu, Vikas Kumar, Audrey J Lazenby, Adrian R Black, Susanna Ulhannan, Ajay Jain, Barish H Edil, David L Klinkebiel, Robert Powers, Amarnath Natarajan, Michael A Hollingsworth, Kamiya Mehla, Quan Ly, Sarika Chaudhary, Rosa F Hwang, Kathryn E Wellen, Pankaj K Singh.
      The ability of tumour cells to thrive in harsh microenvironments depends on the utilization of nutrients available in the milieu. Here we show that pancreatic cancer-associated fibroblasts (CAFs) regulate tumour cell metabolism through the secretion of acetate, which can be blocked by silencing ATP citrate lyase (ACLY) in CAFs. We further show that acetyl-CoA synthetase short-chain family member 2 (ACSS2) channels the exogenous acetate to regulate the dynamic cancer epigenome and transcriptome, thereby facilitating cancer cell survival in an acidic microenvironment. Comparative H3K27ac ChIP-seq and RNA-seq analyses revealed alterations in polyamine homeostasis through regulation of SAT1 gene expression and enrichment of the SP1-responsive signature. We identified acetate/ACSS2-mediated acetylation of SP1 at the lysine 19 residue that increased SP1 protein stability and transcriptional activity. Genetic or pharmacologic inhibition of the ACSS2-SP1-SAT1 axis diminished the tumour burden in mouse models. These results reveal that the metabolic flexibility imparted by the stroma-derived acetate enabled cancer cell survival under acidosis via the ACSS2-SP1-SAT1 axis.
    DOI:  https://doi.org/10.1038/s41556-024-01372-4
  23. EMBO J. 2024 Feb 28.
    Metabolic rewiring of macrophages by epidermal-derived lactate promotes sterile inflammation in the murine skin.
    Uttkarsh Ayyangar, Aneesh Karkhanis, Heather Tay, Aliya Farissa Binte Afandi, Oindrila Bhattacharjee, Lalitha Ks, Sze Han Lee, James Chan, Srikala Raghavan.
      Dysregulated macrophage responses and changes in tissue metabolism are hallmarks of chronic inflammation in the skin. However, the metabolic cues that direct and support macrophage functions in the skin are poorly understood. Here, we show that during sterile skin inflammation, the epidermis and macrophages uniquely depend on glycolysis and the TCA cycle, respectively. This compartmentalisation is initiated by ROS-induced HIF-1α stabilization leading to enhanced glycolysis in the epidermis. The end-product of glycolysis, lactate, is then exported by epithelial cells and utilized by the dermal macrophages to induce their M2-like fates through NF-κB pathway activation. In addition, we show that psoriatic skin disorder is also driven by such lactate metabolite-mediated crosstalk between the epidermis and macrophages. Notably, small-molecule inhibitors of lactate transport in this setting attenuate sterile inflammation and psoriasis disease burden, and suppress M2-like fate acquisition in dermal macrophages. Our study identifies an essential role for the metabolite lactate in regulating macrophage responses to inflammation, which may be effectively targeted to treat inflammatory skin disorders such as psoriasis.
    Keywords:  Epithelial-immune Crosstalk; Lactate Metabolism; Metabolic Compartmentation; Psoriasis; Sterile Inflammation
    DOI:  https://doi.org/10.1038/s44318-024-00039-y
  24. J Physiol. 2024 Mar 01.
    Reorganization of mitochondria-organelle interactions during postnatal development in skeletal muscle.
    Yuho Kim, Hailey A Parry, T Bradley Willingham, Greg Alspaugh, Eric Lindberg, Christian A Combs, Jay R Knutson, Christopher K E Bleck, Brian Glancy.
      Skeletal muscle cellular development requires the integrated assembly of mitochondria and other organelles adjacent to the sarcomere in support of muscle contractile performance. However, it remains unclear how interactions among organelles and with the sarcomere relates to the development of muscle cell function. Here, we combine 3D volume electron microscopy, proteomic analyses, and live cell functional imaging to investigate the postnatal reorganization of mitochondria-organelle interactions in skeletal muscle. We show that while mitochondrial networks are disorganized and loosely associated with the contractile apparatus at birth, contact sites among mitochondria, lipid droplets and the sarcoplasmic reticulum are highly abundant in neonatal muscles. The maturation process is characterized by a transition to highly organized mitochondrial networks wrapped tightly around the muscle sarcomere but also to less frequent interactions with both lipid droplets and the sarcoplasmic reticulum. Concomitantly, expression of proteins involved in mitochondria-organelle membrane contact sites decreases during postnatal development in tandem with a decrease in abundance of proteins associated with sarcomere assembly despite an overall increase in contractile protein abundance. Functionally, parallel measures of mitochondrial membrane potential, NADH redox status, and NADH flux within intact cells revealed that mitochondria in adult skeletal muscle fibres maintain a more activated electron transport chain compared with neonatal muscle mitochondria. These data demonstrate a developmental redesign reflecting a shift from muscle cell assembly and frequent inter-organelle communication toward a muscle fibre with mitochondrial structure, interactions, composition and function specialized to support contractile function. KEY POINTS: Mitochondrial network organization is remodelled during skeletal muscle postnatal development. The mitochondrial outer membrane is in frequent contact with other organelles at birth and transitions to more close associations with the contractile apparatus in mature muscles. Mitochondrial energy metabolism becomes more activated during postnatal development. Understanding the developmental redesign process within skeletal muscle cells may help pinpoint specific areas of deficit in muscles with developmental disorders.
    Keywords:  3D mitochondrial structure; functional cellular imaging; organelle interactions; postnatal muscle development; volume electron microscopy
    DOI:  https://doi.org/10.1113/JP285014
  25. Autophagy. 2024 Feb 27.
    Aging STINGs: mitophagy at the crossroads of neuroinflammation.
    Juan Ignacio Jiménez-Loygorri, Patricia Boya.
      Loss of proteostasis and dysregulated mitochondrial function are part of the traditional hallmarks of aging, and in their last revision impaired macroautophagy and chronic inflammation are also included. Mitophagy is at the intersection of all these processes but whether it undergoes age-associated perturbations was not known. In our recent work, we performed a systematic and systemic analysis of mitolysosome levels in mice and found that, despite the already-known decrease in non-selective macroautophagy, mitophagy remains stable or increases upon aging in all tissues analyzed and is mediated by the PINK1-PRKN-dependent pathway. Further analyses revealed a concomitant increase in mtDNA leakage into the cytosol and activation of the CGAS-STING1 inflammation axis. Notably, both phenomena are also observed in primary fibroblasts from aged human donors. We hypothesized that mitophagy might be selectively upregulated during aging to improve mitochondrial fitness and reduce mtDNA-induced inflammation. Treatment with the mitophagy inducer urolithin A alleviates age-associated neurological decline, including improved synaptic connectivity, cognitive memory and visual function. Supporting our initial hypothesis, urolithin A reduces the levels of cytosolic mtDNA, CGAS-STING1 activation and neuroinflammation. Finally, using an in vitro model of mitochondrial membrane permeabilization we validated that PINK1-PRKN-mediated mitophagy is essential to resolve cytosolic mtDNA-triggered inflammation. These findings open up an integrative approach to tackle aging and increase healthspan via mitophagy induction.
    Keywords:  Inflammation; PINK1; Parkin; mitochondria; mtDNA; retina
    DOI:  https://doi.org/10.1080/15548627.2024.2322421
  26. Nat Metab. 2024 Feb;6(2): 359-377
    Identification of a leucine-mediated threshold effect governing macrophage mTOR signalling and cardiovascular risk.
    Xiangyu Zhang, Divya Kapoor, Se-Jin Jeong, Alan Fappi, Jeremiah Stitham, Vasavi Shabrish, Ismail Sergin, Eman Yousif, Astrid Rodriguez-Velez, Yu-Sheng Yeh, Arick Park, Arif Yurdagul, Oren Rom, Slava Epelman, Joel D Schilling, Marco Sardiello, Abhinav Diwan, Jaehyung Cho, Nathan O Stitziel, Ali Javaheri, Irfan J Lodhi, Bettina Mittendorfer, Babak Razani.
      High protein intake is common in western societies and is often promoted as part of a healthy lifestyle; however, amino-acid-mediated mammalian target of rapamycin (mTOR) signalling in macrophages has been implicated in the pathogenesis of ischaemic cardiovascular disease. In a series of clinical studies on male and female participants ( NCT03946774 and NCT03994367 ) that involved graded amounts of protein ingestion together with detailed plasma amino acid analysis and human monocyte/macrophage experiments, we identify leucine as the key activator of mTOR signalling in macrophages. We describe a threshold effect of high protein intake and circulating leucine on monocytes/macrophages wherein only protein in excess of ∼25 g per meal induces mTOR activation and functional effects. By designing specific diets modified in protein and leucine content representative of the intake in the general population, we confirm this threshold effect in mouse models and find ingestion of protein in excess of ∼22% of dietary energy requirements drives atherosclerosis in male mice. These data demonstrate a mechanistic basis for the adverse impact of excessive dietary protein on cardiovascular risk.
    DOI:  https://doi.org/10.1038/s42255-024-00984-2
  27. Nat Cancer. 2024 Mar 01.
    Sarcoma microenvironment cell states and ecosystems are associated with prognosis and predict response to immunotherapy.
    Ajay Subramanian, Neda Nemat-Gorgani, Timothy J Ellis-Caleo, David G P van IJzendoorn, Timothy J Sears, Anish Somani, Bogdan A Luca, Maggie Y Zhou, Martina Bradic, Ileana A Torres, Eniola Oladipo, Christin New, Deborah E Kenney, Raffi S Avedian, Robert J Steffner, Michael S Binkley, David G Mohler, William D Tap, Sandra P D'Angelo, Matt van de Rijn, Kristen N Ganjoo, Nam Q Bui, Gregory W Charville, Aaron M Newman, Everett J Moding.
      Characterization of the diverse malignant and stromal cell states that make up soft tissue sarcomas and their correlation with patient outcomes has proven difficult using fixed clinical specimens. Here, we employed EcoTyper, a machine-learning framework, to identify the fundamental cell states and cellular ecosystems that make up sarcomas on a large scale using bulk transcriptomes with clinical annotations. We identified and validated 23 sarcoma-specific, transcriptionally defined cell states, many of which were highly prognostic of patient outcomes across independent datasets. We discovered three conserved cellular communities or ecotypes associated with underlying genomic alterations and distinct clinical outcomes. We show that one ecotype defined by tumor-associated macrophages and epithelial-like malignant cells predicts response to immune-checkpoint inhibition but not chemotherapy and validate our findings in an independent cohort. Our results may enable identification of patients with soft tissue sarcomas who could benefit from immunotherapy and help develop new therapeutic strategies.
    DOI:  https://doi.org/10.1038/s43018-024-00743-y
  28. Proc Natl Acad Sci U S A. 2024 Mar 05. 121(10): e2313540121
    Tom20 gates PINK1 activity and mediates its tethering of the TOM and TIM23 translocases upon mitochondrial stress.
    Mohamed A Eldeeb, Andrew N Bayne, Armaan Fallahi, Thomas Goiran, Emma J MacDougall, Andrea Soumbasis, Cornelia E Zorca, Jace-Jones Tabah, Rhalena A Thomas, Nathan Karpilovsky, Meghna Mathur, Thomas M Durcan, Jean-François Trempe, Edward A Fon.
      Mutations in PTEN-induced putative kinase 1 (PINK1) cause autosomal recessive early-onset Parkinson's disease (PD). PINK1 is a Ser/Thr kinase that regulates mitochondrial quality control by triggering mitophagy mediated by the ubiquitin (Ub) ligase Parkin. Upon mitochondrial damage, PINK1 accumulates on the outer mitochondrial membrane forming a high-molecular-weight complex with the translocase of the outer membrane (TOM). PINK1 then phosphorylates Ub, which enables recruitment and activation of Parkin followed by autophagic clearance of the damaged mitochondrion. Thus, Parkin-dependent mitophagy hinges on the stable accumulation of PINK1 on the TOM complex. Yet, the mechanism linking mitochondrial stressors to PINK1 accumulation and whether the translocases of the inner membrane (TIMs) are also involved remain unclear. Herein, we demonstrate that mitochondrial stress induces the formation of a PINK1-TOM-TIM23 supercomplex in human cultured cell lines, dopamine neurons, and midbrain organoids. Moreover, we show that PINK1 is required to stably tether the TOM to TIM23 complexes in response to stress such that the supercomplex fails to accumulate in cells lacking PINK1. This tethering is dependent on an interaction between the PINK1 N-terminal-C-terminal extension module and the cytosolic domain of the Tom20 subunit of the TOM complex, the disruption of which, by either designer or PD-associated PINK1 mutations, inhibits downstream mitophagy. Together, the findings provide key insight into how PINK1 interfaces with the mitochondrial import machinery, with important implications for the mechanisms of mitochondrial quality control and PD pathogenesis.
    Keywords:  PINK1; mitochondrial import; mitochondrial quality control; mitophagy; proteolysis
    DOI:  https://doi.org/10.1073/pnas.2313540121
  29. Cell Rep. 2024 Feb 27. pii: S2211-1247(24)00189-X. [Epub ahead of print]43(3): 113861
    Identifying potential dietary treatments for inherited metabolic disorders using Drosophila nutrigenomics.
    Felipe Martelli, Jiayi Lin, Sarah Mele, Wendy Imlach, Oguz Kanca, Christopher K Barlow, Jefferson Paril, Ralf B Schittenhelm, John Christodoulou, Hugo J Bellen, Matthew D W Piper, Travis K Johnson.
      Inherited metabolic disorders are a group of genetic conditions that can cause severe neurological impairment and child mortality. Uniquely, these disorders respond to dietary treatment; however, this option remains largely unexplored because of low disorder prevalence and the lack of a suitable paradigm for testing diets. Here, we screened 35 Drosophila amino acid disorder models for disease-diet interactions and found 26 with diet-altered development and/or survival. Using a targeted multi-nutrient array, we examine the interaction in a model of isolated sulfite oxidase deficiency, an infant-lethal disorder. We show that dietary cysteine depletion normalizes their metabolic profile and rescues development, neurophysiology, behavior, and lifelong fly survival, thus providing a basis for further study into the pathogenic mechanisms involved in this disorder. Our work highlights the diet-sensitive nature of metabolic disorders and establishes Drosophila as a valuable tool for nutrigenomic studies for informing potential dietary therapies.
    Keywords:  CP: Developmental biology; CP: Metabolism; amino acid metabolism; diet; fruit fly; inherited metabolic disease; isolated sulfite oxidase deficiency; nutrition
    DOI:  https://doi.org/10.1016/j.celrep.2024.113861
  30. Nature. 2024 Feb;626(8001): 963-974
    Ion and lipid orchestration of secondary active transport.
    David Drew, Olga Boudker.
      Transporting small molecules across cell membranes is an essential process in cell physiology. Many structurally diverse, secondary active transporters harness transmembrane electrochemical gradients of ions to power the uptake or efflux of nutrients, signalling molecules, drugs and other ions across cell membranes. Transporters reside in lipid bilayers on the interface between two aqueous compartments, where they are energized and regulated by symported, antiported and allosteric ions on both sides of the membrane and the membrane bilayer itself. Here we outline the mechanisms by which transporters couple ion and solute fluxes and discuss how structural and mechanistic variations enable them to meet specific physiological needs and adapt to environmental conditions. We then consider how general bilayer properties and specific lipid binding modulate transporter activity. Together, ion gradients and lipid properties ensure the effective transport, regulation and distribution of small molecules across cell membranes.
    DOI:  https://doi.org/10.1038/s41586-024-07062-3
  31. iScience. 2024 Mar 15. 27(3): 109164
    Optic atrophy 1 mediates muscle differentiation by promoting a metabolic switch via the supercomplex assembly factor SCAF1.
    Matthew Triolo, Nicole Baker, Soniya Agarwal, Nikita Larionov, Tina Podinić, Mireille Khacho.
      Myogenic differentiation is integral for the regeneration of skeletal muscle following tissue damage. Though high-energy post-mitotic muscle relies predominantly on mitochondrial respiration, the importance of mitochondrial remodeling in enabling muscle differentiation and the players involved are not fully known. Here we show that the mitochondrial fusion protein OPA1 is essential for muscle differentiation. Our study demonstrates that OPA1 loss or inhibition, through genetic and pharmacological means, abolishes in vivo muscle regeneration and in vitro myotube formation. We show that both the inhibition and genetic deletion of OPA1 prevent the early onset metabolic switch required to drive myoblast differentiation. In addition, we observe an OPA1-dependent upregulation of the supercomplex assembly factor, SCAF1, at the onset of differentiation. Importantly, preventing the upregulation of SCAF1, through OPA1 loss or siRNA-mediated SCAF1 knockdown, impairs metabolic reprogramming and muscle differentiation. These findings reveal the integral role of OPA1 and mitochondrial reprogramming at the onset of myogenic differentiation.
    Keywords:  Molecular biology; Physiology
    DOI:  https://doi.org/10.1016/j.isci.2024.109164
  32. bioRxiv. 2024 Feb 14. pii: 2024.02.14.580389. [Epub ahead of print]
    Translational response to mitochondrial stresses is orchestrated by tRNA modifications.
    Sherif Rashad, Shadi Al-Mesitef, Abdulrahman Mousa, Yuan Zhou, Daisuke Ando, Guangxin Sun, Tomoko Fukuuchi, Yuko Iwasaki, Jingdong Xiang, Shane R Byrne, Jingjing Sun, Masamitsu Maekawa, Daisuke Saigusa, Thomas J Begley, Peter C Dedon, Kuniyasu Niizuma.
      Mitochondrial stress and dysfunction play important roles in many pathologies. However, how cells respond to mitochondrial stress is not fully understood. Here, we examined the translational response to electron transport chain (ETC) inhibition and arsenite induced mitochondrial stresses. Our analysis revealed that during mitochondrial stress, tRNA modifications (namely f5C, hm5C, queuosine and its derivatives, and mcm5U) dynamically change to fine tune codon decoding, usage, and optimality. These changes in codon optimality drive the translation of many pathways and gene sets, such as the ATF4 pathway and selenoproteins, involved in the cellular response to mitochondrial stress. We further examined several of these modifications using targeted approaches. ALKBH1 knockout (KO) abrogated f5C and hm5C levels and led to mitochondrial dysfunction, reduced proliferation, and impacted mRNA translation rates. Our analysis revealed that tRNA queuosine (tRNA-Q) is a master regulator of the mitochondrial stress response. KO of QTRT1 or QTRT2, the enzymes responsible for tRNA-Q synthesis, led to mitochondrial dysfunction, translational dysregulation, and metabolic alterations in mitochondria-related pathways, without altering cellular proliferation. In addition, our analysis revealed that tRNA-Q loss led to a domino effect on various tRNA modifications. Some of these changes could be explained by metabolic profiling. Our analysis also revealed that utilizing serum deprivation or alteration with Queuine supplementation to study tRNA-Q or stress response can introduce various confounding factors by altering many other tRNA modifications. In summary, our data show that tRNA modifications are master regulators of the mitochondrial stress response by driving changes in codon decoding.
    Keywords:  Codon usage; Mitochondrial stress; Oxidative stress; Queuine; Queuosine; RNA modifications; mRNA translation; tRNA; tRNA modifications
    DOI:  https://doi.org/10.1101/2024.02.14.580389
  33. Nat Cell Biol. 2024 Feb 29.
    A guideline on the molecular ecosystem regulating ferroptosis.
    Enyong Dai, Xin Chen, Andreas Linkermann, Xuejun Jiang, Rui Kang, Valerian E Kagan, Hülya Bayir, Wan Seok Yang, Ana J Garcia-Saez, Maria S Ioannou, Tobias Janowitz, Qitao Ran, Wei Gu, Boyi Gan, Dmitri V Krysko, Xiaofeng Zhu, Jiayi Wang, Stefan Krautwald, Shinya Toyokuni, Yangchun Xie, Florian R Greten, Qing Yi, Joel Schick, Jiao Liu, Dmitry I Gabrilovich, Jinbao Liu, Herbert J Zeh, Donna D Zhang, Minghua Yang, Juan Iovanna, Manfred Kopf, Timon E Adolph, Jen-Tsan Chi, Changfeng Li, Hidenori Ichijo, Michael Karin, Vijay G Sankaran, Weiping Zou, Lorenzo Galluzzi, Ashley I Bush, Binghui Li, Gerry Melino, Eric H Baehrecke, Michael T Lotze, Daniel J Klionsky, Brent R Stockwell, Guido Kroemer, Daolin Tang.
      Ferroptosis, an intricately regulated form of cell death characterized by uncontrolled lipid peroxidation, has garnered substantial interest since this term was first coined in 2012. Recent years have witnessed remarkable progress in elucidating the detailed molecular mechanisms that govern ferroptosis induction and defence, with particular emphasis on the roles of heterogeneity and plasticity. In this Review, we discuss the molecular ecosystem of ferroptosis, with implications that may inform and enable safe and effective therapeutic strategies across a broad spectrum of diseases.
    DOI:  https://doi.org/10.1038/s41556-024-01360-8
  34. Trends Biochem Sci. 2024 Feb 23. pii: S0968-0004(24)00031-8. [Epub ahead of print]
    Mitochondria in disease: changes in shapes and dynamics.
    Brenita C Jenkins, Kit Neikirk, Prasanna Katti, Steven M Claypool, Annet Kirabo, Melanie R McReynolds, Antentor Hinton.
      Mitochondrial structure often determines the function of these highly dynamic, multifunctional, eukaryotic organelles, which are essential for maintaining cellular health. The dynamic nature of mitochondria is apparent in descriptions of different mitochondrial shapes [e.g., donuts, megamitochondria (MGs), and nanotunnels] and crista dynamics. This review explores the significance of dynamic alterations in mitochondrial morphology and regulators of mitochondrial and cristae shape. We focus on studies across tissue types and also describe new microscopy techniques for detecting mitochondrial morphologies both in vivo and in vitro that can improve understanding of mitochondrial structure. We highlight the potential therapeutic benefits of regulating mitochondrial morphology and discuss prospective avenues to restore mitochondrial bioenergetics to manage diseases related to mitochondrial dysfunction.
    Keywords:  clinical diagnostics; contact sites; cristae dynamics; microscopy; mitochondrial morphology; mitochondrial shapes
    DOI:  https://doi.org/10.1016/j.tibs.2024.01.011
  35. Nat Metab. 2024 Feb;6(2): 203-204
    A leucine-macrophage mTORC1 connection drives increased risk of atherosclerosis with high-protein diets.
    Adam J Rose, Patricia M Rusu.
      
    DOI:  https://doi.org/10.1038/s42255-023-00952-2
  36. Nat Commun. 2024 Feb 27. 15(1): 1788
    The emergence of circadian timekeeping in the intestine.
    Kathyani Parasram, Amy Zuccato, Minjeong Shin, Reegan Willms, Brian DeVeale, Edan Foley, Phillip Karpowicz.
      The circadian clock is a molecular timekeeper, present from cyanobacteria to mammals, that coordinates internal physiology with the external environment. The clock has a 24-h period however development proceeds with its own timing, raising the question of how these interact. Using the intestine of Drosophila melanogaster as a model for organ development, we track how and when the circadian clock emerges in specific cell types. We find that the circadian clock begins abruptly in the adult intestine and gradually synchronizes to the environment after intestinal development is complete. This delayed start occurs because individual cells at earlier stages lack the complete circadian clock gene network. As the intestine develops, the circadian clock is first consolidated in intestinal stem cells with changes in Ecdysone and Hnf4 signalling influencing the transcriptional activity of Clk/cyc to drive the expression of tim, Pdp1, and vri. In the mature intestine, stem cell lineage commitment transiently disrupts clock activity in differentiating progeny, mirroring early developmental clock-less transitions. Our data show that clock function and differentiation are incompatible and provide a paradigm for studying circadian clocks in development and stem cell lineages.
    DOI:  https://doi.org/10.1038/s41467-024-45942-4
  37. Protein Cell. 2024 Mar 01. pii: pwae003. [Epub ahead of print]
    Metabolic cell death in cancer: Ferroptosis, cuproptosis, disulfidptosis, and beyond.
    Chao Mao, Min Wang, Li Zhuang, Boyi Gan.
      Cell death resistance represents a hallmark of cancer. Recent studies have identified metabolic cell death as unique forms of regulated cell death resulting from an imbalance in the cellular metabolism. This review discusses the mechanisms of metabolic cell death-ferroptosis, cuproptosis, disulfidptosis, lysozincrosis, and alkaliptosis-and explores their potential in cancer therapy. Our review underscores the complexity of the metabolic cell death pathways and offers insights into innovative therapeutic avenues for cancer treatment.
    Keywords:  cancer treatment; cell death; cuproptosis; disulfidptosis; ferroptosis
    DOI:  https://doi.org/10.1093/procel/pwae003
  38. bioRxiv. 2024 Feb 12. pii: 2024.02.11.579776. [Epub ahead of print]
    An Organism-Level Quantitative Flux Model of Mammalian Energy Metabolism.
    Bo Yuan, Karen E Inouye, Gökhan S Hotamışlıgil, Sheng Hui.
      Mammalian tissues feed on nutrients in the blood circulation. At the organism-level, mammalian energy metabolism comprises of oxidation, interconverting, storing and releasing of circulating nutrients. Though much is known about the individual processes and nutrients, a holistic and quantitative model describing these processes for all major circulating nutrients is lacking. Here, by integrating isotope tracer infusion, mass spectrometry, and isotope gas analyzer measurement, we developed a framework to systematically quantify fluxes through these processes for 10 major circulating energy nutrients in mice, resulting in an organism-level quantitative flux model of energy metabolism. This model revealed in wildtype mice that circulating nutrients' metabolic cycling fluxes are more dominant than their oxidation fluxes, with distinct partition between cycling and oxidation flux for individual circulating nutrients. Applications of this framework in obese mouse models showed on a per animal basis extensive elevation of metabolic cycling fluxes in ob/ob mice, but not in diet-induced obese mice. Thus, our framework describes quantitatively the functioning of energy metabolism at the organism-level, valuable for revealing new features of energy metabolism in physiological and disease conditions.
    Keywords:  circulating nutrients; energy metabolism; in vivo flux quantification; isotope tracing; obesity
    DOI:  https://doi.org/10.1101/2024.02.11.579776
  39. Cell Mol Immunol. 2024 Feb 27.
    Targeting PHGDH reverses the immunosuppressive phenotype of tumor-associated macrophages through α-ketoglutarate and mTORC1 signaling.
    Zhengnan Cai, Wan Li, Sonja Hager, Jayne Louise Wilson, Leila Afjehi-Sadat, Elke H Heiss, Thomas Weichhart, Petra Heffeter, Wolfram Weckwerth.
      Phosphoglycerate dehydrogenase (PHGDH) has emerged as a crucial factor in macromolecule synthesis, neutralizing oxidative stress, and regulating methylation reactions in cancer cells, lymphocytes, and endothelial cells. However, the role of PHGDH in tumor-associated macrophages (TAMs) is poorly understood. Here, we found that the T helper 2 (Th2) cytokine interleukin-4 and tumor-conditioned media upregulate the expression of PHGDH in macrophages and promote immunosuppressive M2 macrophage activation and proliferation. Loss of PHGDH disrupts cellular metabolism and mitochondrial respiration, which are essential for immunosuppressive macrophages. Mechanistically, PHGDH-mediated serine biosynthesis promotes α-ketoglutarate production, which activates mTORC1 signaling and contributes to the maintenance of an M2-like macrophage phenotype in the tumor microenvironment. Genetic ablation of PHGDH in macrophages from tumor-bearing mice results in attenuated tumor growth, reduced TAM infiltration, a phenotypic shift of M2-like TAMs toward an M1-like phenotype, downregulated PD-L1 expression and enhanced antitumor T-cell immunity. Our study provides a strong basis for further exploration of PHGDH as a potential target to counteract TAM-mediated immunosuppression and hinder tumor progression.
    Keywords:  PHGDH; de novo serine synthesis; mTORC1; protumorigenic; tumor-associated macrophages, metabolomics; α-ketoglutarate
    DOI:  https://doi.org/10.1038/s41423-024-01134-0
  40. Sci Adv. 2024 Mar;10(9): eadj3551
    Nutrient scavenging-fueled growth in pancreatic cancer depends on caveolae-mediated endocytosis under nutrient-deprived conditions.
    Adam R Wolfe, Tiantian Cui, Sooin Baie, Sergio Corrales-Guerrero, Amy Webb, Veronica Castro-Aceituno, Duan-Liang Shyu, Joanna M Karasinska, James T Topham, Daniel J Renouf, David F Schaeffer, Megan Halloran, Rebecca Packard, Ryan Robb, Wei Chen, Nicholas Denko, Michael Lisanti, Timothy C Thompson, Philippe Frank, Terence M Williams.
      Pancreatic ductal adenocarcinoma (PDAC) is characterized by its nutrient-scavenging ability, crucial for tumor progression. Here, we investigated the roles of caveolae-mediated endocytosis (CME) in PDAC progression. Analysis of patient data across diverse datasets revealed a strong association of high caveolin-1 (Cav-1) expression with higher histologic grade, the most aggressive PDAC molecular subtypes, and worse clinical outcomes. Cav-1 loss markedly promoted longer overall and tumor-free survival in a genetically engineered mouse model. Cav-1-deficient tumor cell lines exhibited significantly reduced proliferation, particularly under low nutrient conditions. Supplementing cells with albumin rescued the growth of Cav-1-proficient PDAC cells, but not in Cav-1-deficient PDAC cells under low glutamine conditions. In addition, Cav-1 depletion led to significant metabolic defects, including decreased glycolytic and mitochondrial metabolism, and downstream protein translation signaling pathways. These findings highlight the crucial role of Cav-1 and CME in fueling pancreatic tumorigenesis, sustaining tumor growth, and promoting survival through nutrient scavenging.
    DOI:  https://doi.org/10.1126/sciadv.adj3551
  41. Nat Metab. 2024 Feb 26.
    Resisting weight gain with prebiotic fibre.
    Matthew M Carter, Sean P Spencer.
      
    DOI:  https://doi.org/10.1038/s42255-024-00998-w
  42. Nature. 2024 Feb;626(8001): 931
    How egg cells handle their cellular rubbish.
      
    Keywords:  Developmental biology
    DOI:  https://doi.org/10.1038/d41586-024-00498-7
  43. Proc Natl Acad Sci U S A. 2024 Mar 05. 121(10): e2309957121
    Deficiency of factor-inhibiting HIF creates a tumor-promoting immune microenvironment.
    Jingyi Ma, Khatoun Al Moussawi, Hantao Lou, Hok Fung Chan, Yihua Wang, Joseph Chadwick, Chansavath Phetsouphanh, Elizabeth A Slee, Shan Zhong, Thomas M Leissing, Andrew Roth, Xiao Qin, Shuo Chen, Jie Yin, Indrika Ratnayaka, Yang Hu, Pakavarin Louphrasitthiphol, Lewis Taylor, Paulo J G Bettencourt, Mary Muers, David R Greaves, Helen McShane, Robert Goldin, Elizabeth J Soilleux, Mathew L Coleman, Peter J Ratcliffe, Xin Lu.
      Hypoxia signaling influences tumor development through both cell-intrinsic and -extrinsic pathways. Inhibiting hypoxia-inducible factor (HIF) function has recently been approved as a cancer treatment strategy. Hence, it is important to understand how regulators of HIF may affect tumor growth under physiological conditions. Here we report that in aging mice factor-inhibiting HIF (FIH), one of the most studied negative regulators of HIF, is a haploinsufficient suppressor of spontaneous B cell lymphomas, particular pulmonary B cell lymphomas. FIH deficiency alters immune composition in aged mice and creates a tumor-supportive immune environment demonstrated in syngeneic mouse tumor models. Mechanistically, FIH-defective myeloid cells acquire tumor-supportive properties in response to signals secreted by cancer cells or produced in the tumor microenvironment with enhanced arginase expression and cytokine-directed migration. Together, these data demonstrate that under physiological conditions, FIH plays a key role in maintaining immune homeostasis and can suppress tumorigenesis through a cell-extrinsic pathway.
    Keywords:  B cell lymphoma; factor-inhibiting HIF; hypoxia-inducible factor; tumor microenvironment; tumor suppression
    DOI:  https://doi.org/10.1073/pnas.2309957121
  44. bioRxiv. 2024 Feb 14. pii: 2024.02.12.579956. [Epub ahead of print]
    Epigenome and early selection determine the tumour-immune evolutionary trajectory of colorectal cancer.
    Eszter Lakatos, Vinaya Gunasri, Luis Zapata, Jacob Househam, Timon Heide, Nicholas Trahearn, Ottilie Swinyard, Luis Cisneros, Claire Lynn, Maximilian Mossner, Chris Kimberley, Inmaculada Spiteri, George D Cresswell, Gerard Llibre-Palomar, Miriam Mitchison, Carlo C Maley, Marnix Jansen, Manuel Rodriguez-Justo, John Bridgewater, Ann-Marie Baker, Andrea Sottoriva, Trevor A Graham.
      Immune system control is a major hurdle that cancer evolution must circumvent. The relative timing and evolutionary dynamics of subclones that have escaped immune control remain incompletely characterized, and how immune-mediated selection shapes the epigenome has received little attention. Here, we infer the genome- and epigenome-driven evolutionary dynamics of tumour-immune coevolution within primary colorectal cancers (CRCs). We utilise our existing CRC multi-region multi-omic dataset that we supplement with high-resolution spatially-resolved neoantigen sequencing data and highly multiplexed imaging of the tumour microenvironment (TME). Analysis of somatic chromatin accessibility alterations (SCAAs) reveals frequent somatic loss of accessibility at antigen presenting genes, and that SCAAs contribute to silencing of neoantigens. We observe that strong immune escape and exclusion occur at the outset of CRC formation, and that within tumours, including at the microscopic level of individual tumour glands, additional immune escape alterations have negligible consequences for the immunophenotype of cancer cells. Further minor immuno-editing occurs during local invasion and is associated with TME reorganisation, but that evolutionary bottleneck is relatively weak. Collectively, we show that immune evasion in CRC follows a "Big Bang" evolutionary pattern, whereby genetic, epigenetic and TME-driven immune evasion acquired by the time of transformation defines subsequent cancer-immune evolution.
    DOI:  https://doi.org/10.1101/2024.02.12.579956
  45. Nat Metab. 2024 Feb;6(2): 323-342
    A homoeostatic switch causing glycerol-3-phosphate and phosphoethanolamine accumulation triggers senescence by rewiring lipid metabolism.
    Khaled Tighanimine, José Américo Nabuco Leva Ferreira Freitas, Ivan Nemazanyy, Alexia Bankolé, Delphine Benarroch-Popivker, Susanne Brodesser, Gregory Doré, Lucas Robinson, Paule Benit, Sophia Ladraa, Yara Bou Saada, Bertrand Friguet, Philippe Bertolino, David Bernard, Guillaume Canaud, Pierre Rustin, Eric Gilson, Oliver Bischof, Stefano Fumagalli, Mario Pende.
      Cellular senescence affects many physiological and pathological processes and is characterized by durable cell cycle arrest, an inflammatory secretory phenotype and metabolic reprogramming. Here, by using dynamic transcriptome and metabolome profiling in human fibroblasts with different subtypes of senescence, we show that a homoeostatic switch that results in glycerol-3-phosphate (G3P) and phosphoethanolamine (pEtN) accumulation links lipid metabolism to the senescence gene expression programme. Mechanistically, p53-dependent glycerol kinase activation and post-translational inactivation of phosphate cytidylyltransferase 2, ethanolamine regulate this metabolic switch, which promotes triglyceride accumulation in lipid droplets and induces the senescence gene expression programme. Conversely, G3P phosphatase and ethanolamine-phosphate phospho-lyase-based scavenging of G3P and pEtN acts in a senomorphic way by reducing G3P and pEtN accumulation. Collectively, our study ties G3P and pEtN accumulation to controlling lipid droplet biogenesis and phospholipid flux in senescent cells, providing a potential therapeutic avenue for targeting senescence and related pathophysiology.
    DOI:  https://doi.org/10.1038/s42255-023-00972-y
  46. Nature. 2024 Feb 28.
    An atlas of epithelial cell states and plasticity in lung adenocarcinoma.
    Guangchun Han, Ansam Sinjab, Zahraa Rahal, Anne M Lynch, Warapen Treekitkarnmongkol, Yuejiang Liu, Alejandra G Serrano, Jiping Feng, Ke Liang, Khaja Khan, Wei Lu, Sharia D Hernandez, Yunhe Liu, Xuanye Cao, Enyu Dai, Guangsheng Pei, Jian Hu, Camille Abaya, Lorena I Gomez-Bolanos, Fuduan Peng, Minyue Chen, Edwin R Parra, Tina Cascone, Boris Sepesi, Seyed Javad Moghaddam, Paul Scheet, Marcelo V Negrao, John V Heymach, Mingyao Li, Steven M Dubinett, Christopher S Stevenson, Avrum E Spira, Junya Fujimoto, Luisa M Solis, Ignacio I Wistuba, Jichao Chen, Linghua Wang, Humam Kadara.
      Understanding the cellular processes that underlie early lung adenocarcinoma (LUAD) development is needed to devise intervention strategies1. Here we studied 246,102 single epithelial cells from 16 early-stage LUADs and 47 matched normal lung samples. Epithelial cells comprised diverse normal and cancer cell states, and diversity among cancer cells was strongly linked to LUAD-specific oncogenic drivers. KRAS mutant cancer cells showed distinct transcriptional features, reduced differentiation and low levels of aneuploidy. Non-malignant areas surrounding human LUAD samples were enriched with alveolar intermediate cells that displayed elevated KRT8 expression (termed KRT8+ alveolar intermediate cells (KACs) here), reduced differentiation, increased plasticity and driver KRAS mutations. Expression profiles of KACs were enriched in lung precancer cells and in LUAD cells and signified poor survival. In mice exposed to tobacco carcinogen, KACs emerged before lung tumours and persisted for months after cessation of carcinogen exposure. Moreover, they acquired Kras mutations and conveyed sensitivity to targeted KRAS inhibition in KAC-enriched organoids derived from alveolar type 2 (AT2) cells. Last, lineage-labelling of AT2 cells or KRT8+ cells following carcinogen exposure showed that KACs are possible intermediates in AT2-to-tumour cell transformation. This study provides new insights into epithelial cell states at the root of LUAD development, and such states could harbour potential targets for prevention or intervention.
    DOI:  https://doi.org/10.1038/s41586-024-07113-9
  47. Trends Endocrinol Metab. 2024 Feb 29. pii: S1043-2760(24)00027-4. [Epub ahead of print]
    Nucleosides are overlooked fuels in central carbon metabolism.
    Abigail Strefeler, Joan Blanco-Fernandez, Alexis A Jourdain.
      From our daily nutrition and synthesis within cells, nucleosides enter the bloodstream and circulate throughout the body and tissues. Nucleosides and nucleotides are classically viewed as precursors of nucleic acids, but recently they have emerged as a novel energy source for central carbon metabolism. Through catabolism by nucleoside phosphorylases, the ribose sugar group is released and can provide substrates for lower steps in glycolysis. In environments with limited glucose, such as at sites of infection or in the tumor microenvironment (TME), cells can use, and may even require, this alternative energy source. Here, we discuss the implications of these new findings in health and disease and speculate on the potential new roles of nucleosides and nucleic acids in energy metabolism.
    Keywords:  Metabolism; UPP1; cancer; immunity; uridine; uridinolysis
    DOI:  https://doi.org/10.1016/j.tem.2024.01.013
  48. Trends Cell Biol. 2024 Feb 28. pii: S0962-8924(24)00028-X. [Epub ahead of print]
    Epigenetic control of circadian clocks by environmental signals.
    Xiao-Lan Liu, Zeyu Duan, Muqun Yu, Xiao Liu.
      Circadian clocks have evolved to enable organisms to respond to daily environmental changes. Maintaining a robust circadian rhythm under various perturbations and stresses is essential for the fitness of an organism. In the core circadian oscillator conserved in eukaryotes (from fungi to mammals), a negative feedback loop based on both transcription and translation drives circadian rhythms. The expression of circadian clock genes depends both on the binding of transcription activators at the promoter and on the chromatin state of the clock genes, and epigenetic modifications of chromatin are crucial for transcriptional regulation of circadian clock genes. Herein we review current knowledge of epigenetic regulation of circadian clock mechanisms and discuss how environmental cues can control clock gene expression by affecting chromatin states.
    Keywords:  chromatin dynamics; circadian rhythm; clock genes; epigenetic regulation; stress response
    DOI:  https://doi.org/10.1016/j.tcb.2024.02.005
  49. J Clin Invest. 2024 Mar 01. pii: e176740. [Epub ahead of print]134(5):
    Cancer neoepitopes viewed through negative selection and peripheral tolerance: a new path to cancer vaccines.
    Pramod K Srivastava.
      A proportion of somatic mutations in tumors create neoepitopes that can prime T cell responses that target the MHC I-neoepitope complexes on tumor cells, mediating tumor control or rejection. Despite the compelling centrality of neoepitopes to cancer immunity, we know remarkably little about what constitutes a neoepitope that can mediate tumor control in vivo and what distinguishes such a neoepitope from the vast majority of similar candidate neoepitopes that are inefficacious in vivo. Studies in mice as well as clinical trials have begun to reveal the unexpected paradoxes in this area. Because cancer neoepitopes straddle that ambiguous ground between self and non-self, some rules that are fundamental to immunology of frankly non-self antigens, such as viral or model antigens, do not appear to apply to neoepitopes. Because neoepitopes are so similar to self-epitopes, with only small changes that render them non-self, immune response to them is regulated at least partially the way immune response to self is regulated. Therefore, neoepitopes are viewed and understood here through the clarifying lens of negative thymic selection. Here, the emergent questions in the biology and clinical applications of neoepitopes are discussed critically and a mechanistic and testable framework that explains the complexity and translational potential of these wonderful antigens is proposed.
    DOI:  https://doi.org/10.1172/JCI176740
  50. Cell Rep. 2024 Feb 26. pii: S2211-1247(24)00154-2. [Epub ahead of print]43(3): 113826
    The genomic and evolutionary landscapes of anaplastic thyroid carcinoma.
    Peter Y F Zeng, Stephenie D Prokopec, Stephen Y Lai, Nicole Pinto, Michelle A Chan-Seng-Yue, Roderick Clifton-Bligh, Michelle D Williams, Christopher J Howlett, Paul Plantinga, Matthew J Cecchini, Alfred K Lam, Iram Siddiqui, Jianxin Wang, Ren X Sun, John D Watson, Reju Korah, Tobias Carling, Nishant Agrawal, Nicole Cipriani, Douglas Ball, Barry Nelkin, Lisa M Rooper, Justin A Bishop, Cathie Garnis, Ken Berean, Norman G Nicolson, Paul Weinberger, Ying C Henderson, Christopher M Lalansingh, Mao Tian, Takafumi N Yamaguchi, Julie Livingstone, Adriana Salcedo, Krupal Patel, Frederick Vizeacoumar, Alessandro Datti, Liu Xi, Yuri E Nikiforov, Robert Smallridge, John A Copland, Laura A Marlow, Martin D Hyrcza, Leigh Delbridge, Stan Sidhu, Mark Sywak, Bruce Robinson, Kevin Fung, Farhad Ghasemi, Keith Kwan, S Danielle MacNeil, Adrian Mendez, David A Palma, Mohammed I Khan, Mushfiq Shaikh, Kara M Ruicci, Bret Wehrli, Eric Winquist, John Yoo, Joe S Mymryk, James W Rocco, David Wheeler, Steve Scherer, Thomas J Giordano, John W Barrett, William C Faquin, Anthony J Gill, Gary Clayman, Paul C Boutros, Anthony C Nichols.
      Anaplastic thyroid carcinoma is arguably the most lethal human malignancy. It often co-occurs with differentiated thyroid cancers, yet the molecular origins of its aggressivity are unknown. We sequenced tumor DNA from 329 regions of thyroid cancer, including 213 from patients with primary anaplastic thyroid carcinomas. We also whole genome sequenced 9 patients using multi-region sequencing of both differentiated and anaplastic thyroid cancer components. Using these data, we demonstrate thatanaplastic thyroid carcinomas have a higher burden of mutations than other thyroid cancers, with distinct mutational signatures and molecular subtypes. Further, different cancer driver genes are mutated in anaplastic and differentiated thyroid carcinomas, even those arising in a single patient. Finally, we unambiguously demonstrate that anaplastic thyroid carcinomas share a genomic origin with co-occurring differentiated carcinomas and emerge from a common malignant field through acquisition of characteristic clonal driver mutations.
    Keywords:  CP: Cancer; CP: Genomics; anaplastic thyroid cancer; cancer progression; genomics; tumour evolution; tumour heterogeneity
    DOI:  https://doi.org/10.1016/j.celrep.2024.113826
  51. PLoS Biol. 2024 Feb;22(2): e3002513
    A unified framework for evolutionary genetic and physiological theories of aging.
    Jean-François Lemaître, Jacob Moorad, Jean-Michel Gaillard, Alexei A Maklakov, Daniel H Nussey.
      Why and how we age are 2 intertwined questions that have fascinated scientists for many decades. However, attempts to answer these questions remain compartmentalized, preventing a comprehensive understanding of the aging process. We argue that the current lack of knowledge about the evolution of aging mechanisms is due to a lack of clarity regarding evolutionary theories of aging that explicitly involve physiological processes: the disposable soma theory (DST) and the developmental theory of aging (DTA). In this Essay, we propose a new hierarchical model linking genes to vital rates, enabling us to critically reevaluate the DST and DTA in terms of their relationship to evolutionary genetic theories of aging (mutation accumulation (MA) and antagonistic pleiotropy (AP)). We also demonstrate how these 2 theories can be incorporated in a unified hierarchical framework. The new framework will help to generate testable hypotheses of how the hallmarks of aging are shaped by natural selection.
    DOI:  https://doi.org/10.1371/journal.pbio.3002513
  52. Nature. 2024 Feb 28.
    The CRL5-SPSB3 ubiquitin ligase targets nuclear cGAS for degradation.
    Pengbiao Xu, Ying Liu, Chong Liu, Baptiste Guey, Lingyun Li, Pauline Melenec, Jonathan Ricci, Andrea Ablasser.
      Cyclic GMP-AMP synthase (cGAS) senses aberrant DNA during infection, cancer and inflammatory disease, and initiates potent innate immune responses through the synthesis of 2'3'-cyclic GMP-AMP (cGAMP)1-7. The indiscriminate activity of cGAS towards DNA demands tight regulatory mechanisms that are necessary to maintain cell and tissue homeostasis under normal conditions. Inside the cell nucleus, anchoring to nucleosomes and competition with chromatin architectural proteins jointly prohibit cGAS activation by genomic DNA8-15. However, the fate of nuclear cGAS and its role in cell physiology remains unclear. Here we show that the ubiquitin proteasomal system (UPS) degrades nuclear cGAS in cycling cells. We identify SPSB3 as the cGAS-targeting substrate receptor that associates with the cullin-RING ubiquitin ligase 5 (CRL5) complex to ligate ubiquitin onto nuclear cGAS. A cryo-electron microscopy structure of nucleosome-bound cGAS in a complex with SPSB3 reveals a highly conserved Asn-Asn (NN) minimal degron motif at the C terminus of cGAS that directs SPSB3 recruitment, ubiquitylation and cGAS protein stability. Interference with SPSB3-regulated nuclear cGAS degradation primes cells for type I interferon signalling, conferring heightened protection against infection by DNA viruses. Our research defines protein degradation as a determinant of cGAS regulation in the nucleus and provides structural insights into an element of cGAS that is amenable to therapeutic exploitation.
    DOI:  https://doi.org/10.1038/s41586-024-07112-w
  53. FEBS J. 2024 Feb 27.
    Mitochondrial derived vesicles- Quo Vadis?
    Reut Hazan Ben-Menachem, Ophry Pines, Ann Saada.
      Mitochondria are dynamic, intracellular organelles with a separate genome originating from prokaryotes. They perform numerous functions essential for cellular metabolism and energy production. Mitochondrial-derived vesicles (MDVs) are single or double membrane-enclosed vesicles, formed and released from the mitochondrial sub-compartments into the cytosol, in response to various triggers. MDVs interact with other organelles such as lysosomes and peroxisomes or may be incorporated and excreted via extracellular vesicles (EVs). MDVs selectively incorporate diverse protein and lipid cargoes and are involved in various functions such as mitochondrial quality control, immunomodulation, energy complementation, and compartmentalization and transport. This review aims to provide a summary of the current knowledge of MDVs biogenesis, release, cargoes, and roles.
    Keywords:  membrane; mitochondria; mitochondrial-derived vesicles
    DOI:  https://doi.org/10.1111/febs.17103
  54. Sci Transl Med. 2024 Feb 28. 16(736): eadf9874
    Acetyl-CoA carboxylase 1 controls a lipid droplet-peroxisome axis and is a vulnerability of endocrine-resistant ER+ breast cancer.
    Marina Bacci, Nicla Lorito, Alfredo Smiriglia, Angela Subbiani, Francesca Bonechi, Giuseppina Comito, Ludivine Morriset, Rania El Botty, Matteo Benelli, Joanna I López-Velazco, Maria M Caffarel, Ander Urruticoechea, George Sflomos, Luca Malorni, Michela Corsini, Luigi Ippolito, Elisa Giannoni, Icro Meattini, Vittoria Matafora, Kristina Havas, Angela Bachi, Paola Chiarugi, Elisabetta Marangoni, Andrea Morandi.
      Targeting aromatase deprives ER+ breast cancers of estrogens and is an effective therapeutic approach for these tumors. However, drug resistance is an unmet clinical need. Lipidomic analysis of long-term estrogen-deprived (LTED) ER+ breast cancer cells, a model of aromatase inhibitor resistance, revealed enhanced intracellular lipid storage. Functional metabolic analysis showed that lipid droplets together with peroxisomes, which we showed to be enriched and active in the LTED cells, controlled redox homeostasis and conferred metabolic adaptability to the resistant tumors. This reprogramming was controlled by acetyl-CoA-carboxylase-1 (ACC1), whose targeting selectively impaired LTED survival. However, the addition of branched- and very long-chain fatty acids reverted ACC1 inhibition, a process that was mediated by peroxisome function and redox homeostasis. The therapeutic relevance of these findings was validated in aromatase inhibitor-treated patient-derived samples. Last, targeting ACC1 reduced tumor growth of resistant patient-derived xenografts, thus identifying a targetable hub to combat the acquisition of estrogen independence in ER+ breast cancers.
    DOI:  https://doi.org/10.1126/scitranslmed.adf9874
  55. bioRxiv. 2024 Feb 12. pii: 2024.02.12.579992. [Epub ahead of print]
    Metabolites that feed upper glycolytic branches support glucose independent human cytomegalovirus replication.
    Rebekah L Mokry, John G Purdy.
      The broad tissue distribution and cell tropism of human cytomegalovirus indicates that the virus successfully replicates in tissues with various nutrient environments. HCMV requires and reprograms central carbon metabolism for viral replication. However, many studies focus on reprogramming of metabolism in high nutrient conditions that do not recapitulate physiological nutrient environments in the body. In this study, we investigate how HCMV successfully replicates when nutrients are suboptimal. We limited glucose following HCMV infection to determine how glucose supports virus replication and how nutrients potentially present in the physiological environment contribute to successful glucose independent HCMV replication. Glucose is required for HCMV viral genome synthesis, viral protein production and glycosylation, and virus production. However, supplement of glucose-free cultures with uridine, ribose, or UDP-GlcNAc-metabolites that support upper glycolytic branches-resulted in partially restored viral genome synthesis and subsequent partial restoration of viral protein levels. Low levels of virus production were also restored. Supplementing lower glycolysis in glucose-free cultures using pyruvate had no effect on virus replication. These results indicate nutrients that support upper glycolytic branches like the pentose phosphate pathway and hexosamine pathway can compensate for glucose during HCMV replication to support low levels of virus production. More broadly, our findings suggest that HCMV could successfully replicate in diverse metabolic niches, including those in the body with low levels of glucose, through alternative nutrient usage.
    IMPORTANCE: The metabolic environment is a determinant in the ability of a virus to successfully replicate. HCMV has broad cell tropism and replicates in various tissues that have diverse and/or limiting metabolic environments. We know that HCMV reprograms host central carbon metabolism to support viral replication, but we have little understanding of HCMV replication in diverse metabolic niches as most studies use high nutrient culture media. Here, we show that glucose limitation suppresses virus production through loss of viral genome synthesis and viral protein glycosylation. However, nutrient compensation by uridine, ribose, and UDP-GlcNAc, metabolites that fuel upper glycolytic branches such as the non-oxidative pentose phosphate pathway support low levels of glucose-independent virus production. Our work indicates that metabolite compensation may facilitate HCMV replication in nutrient limited niches in the body.
    DOI:  https://doi.org/10.1101/2024.02.12.579992
  56. Cancer Res. 2024 Feb 28.
    Bile acid metabolism mediates cholesterol homeostasis and promotes tumorigenesis in clear cell renal cell carcinoma.
    Romain Riscal, Sarah M Gardner, Nathan J Coffey, Madeleine Carens, Clementina Mesaros, Jimmy P Xu, Yizheng Xue, Leah Davis, Sara Demczyszyn, Austin Vogt, Adam Olia, Jennifer M Finan, Jason Godfrey, David C Schultz, Ian A Blair, Brian Keith, Ronen Marmorstein, Nicolas Skuli, M Celeste Simon.
      Clear cell renal cell carcinoma (ccRCC) incidence has risen steadily over the last decade. Elevated lipid uptake and storage is required for ccRCC cell viability. As stored cholesterol is the most abundant component in ccRCC intracellular lipid droplets, it may also play an important role in ccRCC cellular homeostasis. In support of this hypothesis, ccRCC cells acquire exogenous cholesterol through the HDL receptor SCARB1, inhibition or suppression of which induces apoptosis. Here, we showed that elevated expression of 3 beta-hydroxy steroid dehydrogenase type 7 (HSD3B7), which metabolizes cholesterol-derived oxysterols in the bile acid biosynthetic pathway, is also essential for ccRCC cell survival. Development of an HSD3B7 enzymatic assay and screening for small molecule inhibitors uncovered the compound celastrol as a potent HSD3B7 inhibitor with low micromolar activity. Repressing HSD3B7 expression genetically or treating ccRCC cells with celastrol resulted in toxic oxysterol accumulation, impaired proliferation, and increased apoptosis in vitro and in vivo. These data demonstrate that bile acid synthesis regulates cholesterol homeostasis in ccRCC and identifies HSD3B7 as a plausible therapeutic target.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-23-0821
  57. Curr Opin Chem Biol. 2024 Feb 28. pii: S1367-5931(24)00016-4. [Epub ahead of print]79 102440
    Versatile roles of cysteine persulfides in tumor biology.
    Klaudia Borbényi-Galambos, Ágnes Czikora, Katalin Erdélyi, Péter Nagy.
      Rewiring the transsulfuration pathway is recognized as a rapid adaptive metabolic response to environmental conditions in cancer cells to support their increased cysteine demand and to produce Reactive Sulfur Species (RSS) including hydrogen sulfide (H2S) and cysteine persulfide. This can directly (via RSS) or indirectly (by supplying Cys) trigger chemical or enzyme catalyzed persulfidation on critical protein cysteine residues to protect them from oxidative damage and to orchestrate protein functions, and thereby contribute to cancer cell plasticity. In this review key aspects of persulfide-mediated biological processes are highlighted and critically discussed in relation to cancer cell survival, bioenergetics, proliferation as well as in tumor angiogenesis, adaptation to hypoxia and oxidative stress, and regulation of epithelial to mesenchymal transition.
    Keywords:  Cancer; Cysteine; Persulfidation; Persulfide; Transsulfuration
    DOI:  https://doi.org/10.1016/j.cbpa.2024.102440
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