bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2024–07–21
fifty papers selected by
Christian Frezza, Universität zu Köln
  1. Regulation of and challenges in targeting NAD+ metabolism.
  2. Hypermetabolic state is associated with circadian rhythm disruption in mouse and human cancer cells.
  3. Amino acids trigger MDC-dependent mitochondrial remodeling by altering mitochondrial function.
  4. Mice live longer when inflammation-boosting protein is blocked.
  5. Replication timing alterations are associated with mutation acquisition during breast and lung cancer evolution.
  6. Fatty acid synthesis promotes inflammasome activation through NLRP3 palmitoylation.
  7. Metal Uptake by Mitochondrial Carrier Family Proteins Using Lactococcus lactis.
  8. Machine learning of cellular metabolic rewiring.
  9. Adipose glutaminolysis resurfaces in metabolic disease.
  10. Robustness of mitochondrial biogenesis and respiration explain aerobic glycolysis.
  11. Hydrogen sulfide produced by the gut microbiota impairs host metabolism via reducing GLP-1 levels in male mice.
  12. Metabolic Reprogramming Is an Initial Step in Pancreatic Carcinogenesis That Can Be Targeted to Inhibit Acinar-to-Ductal Metaplasia.
  13. Single-cell multiomics reveals ENL mutation perturbs kidney developmental trajectory by rewiring gene regulatory landscape.
  14. ATAD1 prevents clogging of TOM and damage caused by un-imported mitochondrial proteins.
  15. Co-expression in tissue-specific gene networks links genes in cancer-susceptibility loci to known somatic driver genes.
  16. Polyamines regulate cell fate by altering the activity of histone-modifying enzymes.
  17. Clonal inactivation of TERT impairs stem cell competition.
  18. Spatial transcriptomics reveals influence of microenvironment on intrinsic fates in melanoma therapy resistance.
  19. Metabolic imaging across scales reveals distinct prostate cancer phenotypes.
  20. In vivo single-cell CRISPR uncovers distinct TNF programmes in tumour evolution.
  21. PRC2-AgeIndex as a universal biomarker of aging and rejuvenation.
  22. Cross-talk between ILC2 and Gata3high Tregs locally constrains adaptive type 2 immunity.
  23. Whole genome sequencing refines stratification and therapy of patients with clear cell renal cell carcinoma.
  24. Quantification of circadian rhythms in mammalian lung tissue snapshot data.
  25. Acetyl-CoA synthetase activity is enzymatically regulated by lysine acetylation using acetyl-CoA or acetyl-phosphate as donor molecule.
  26. The Spectrum of "TFEopathies" - Flipping the mTOR Switch in Renal Tumorigenesis.
  27. Reduced adipocyte glutaminase activity promotes energy expenditure and metabolic health.
  28. INF2-mediated actin polymerization at ER-organelle contacts regulates organelle size and movement.
  29. Developmental disruption of the mitochondrial fission gene drp-1 extends the longevity of daf-2 insulin/IGF-1 receptor mutant.
  30. Ketogenesis supports hepatic polyunsaturated fatty acid homeostasis via fatty acid elongation.
  31. Sphinganine recruits TLR4 adaptors in macrophages and promotes inflammation in murine models of sepsis and melanoma.
  32. Adaptation to photoperiod via dynamic neurotransmitter segregation.
  33. H2S as a metabolic saboteur.
  34. Crosstalk between Circadian Rhythm Dysregulation and Tumorigenesis, Tumor Metabolism and Tumor Immune Response.
  35. Competition between two HUSH complexes orchestrates the immune response to retroelement invasion.
  36. The Human Engine: Studies of metabolism reveal surprising insights into how we burn calories-and how cooperative food production helped Homo sapiens flourish.
  37. Phosphorylation of GCN2 by mTOR confers adaptation to conditions of hyper-mTOR activation under stress.
  38. T cell dysfunction and therapeutic intervention in cancer.
  39. Ferroptosis regulation by Cap'n'collar family transcription factors.
  40. Tubulin code eraser CCP5 binds branch glutamates by substrate deformation.
  41. Transcriptional landscape of a hypoxia response identifies cell-specific pathways for adaptation.
  42. Inhibition of IL-11 signalling extends mammalian healthspan and lifespan.
  43. Acetate drives ovarian cancer quiescence via ACSS2-mediated acetyl-CoA production.
  44. Frequent transitions in self-assembly across the evolution of a central metabolic enzyme.
  45. Molecular analysis of primary and metastatic sites in patients with renal cell carcinoma.
  46. Analysis and Quantification of the Mitochondrial-ER Lipidome.
  47. Imaging Tumor Metabolism.
  48. Sulfur Amino Acid Restriction Enhances Exercise Capacity in Mice by Boosting Fat Oxidation in Muscle.
  49. The human mitochondrial mRNA structurome reveals mechanisms of gene expression.
  50. Zeb1 mediates EMT/plasticity-associated ferroptosis sensitivity in cancer cells by regulating lipogenic enzyme expression and phospholipid composition.
  1. Nat Rev Mol Cell Biol. 2024 Jul 18.
    Regulation of and challenges in targeting NAD+ metabolism.
    Marie E Migaud, Mathias Ziegler, Joseph A Baur.
      Nicotinamide adenine dinucleotide, in its oxidized (NAD+) and reduced (NADH) forms, is a reduction-oxidation (redox) co-factor and substrate for signalling enzymes that have essential roles in metabolism. The recognition that NAD+ levels fall in response to stress and can be readily replenished through supplementation has fostered great interest in the potential benefits of increasing or restoring NAD+ levels in humans to prevent or delay diseases and degenerative processes. However, much about the biology of NAD+ and related molecules remains poorly understood. In this Review, we discuss the current knowledge of NAD+ metabolism, including limitations of, assumptions about and unappreciated factors that might influence the success or contribute to risks of NAD+ supplementation. We highlight several ongoing controversies in the field, and discuss the role of the microbiome in modulating the availability of NAD+ precursors such as nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), the presence of multiple cellular compartments that have distinct pools of NAD+ and NADH, and non-canonical NAD+ and NADH degradation pathways. We conclude that a substantial investment in understanding the fundamental biology of NAD+, its detection and its metabolites in specific cells and cellular compartments is needed to support current translational efforts to safely boost NAD+ levels in humans.
    DOI:  https://doi.org/10.1038/s41580-024-00752-w
  2. Proc Natl Acad Sci U S A. 2024 Jul 23. 121(30): e2319782121
    Hypermetabolic state is associated with circadian rhythm disruption in mouse and human cancer cells.
    Daniel Maxim Iascone, Xue Zhang, Patricia Brafford, Clementina Mesaros, Yogev Sela, Samuel Hofbauer, Shirley L Zhang, Sukanya Madhwal, Kieona Cook, Pavel Pivarshev, Ben Z Stanger, Stewart Anderson, Chi V Dang, Amita Sehgal.
      Crosstalk between metabolism and circadian rhythms is a fundamental building block of multicellular life, and disruption of this reciprocal communication could be relevant to disease. Here, we investigated whether maintenance of circadian rhythms depends on specific metabolic pathways, particularly in the context of cancer. We found that in adult mouse fibroblasts, ATP levels were a major contributor to signal from a clock gene luciferase reporter, although not necessarily to the strength of circadian cycling. In contrast, we identified significant metabolic control of circadian function across a series of pancreatic adenocarcinoma cell lines. Metabolic profiling of congenic tumor cell clones revealed substantial diversity among these lines that we used to identify clones to generate circadian reporter lines. We observed diverse circadian profiles among these lines that varied with their metabolic phenotype: The most hypometabolic line [exhibiting low levels of oxidative phosphorylation (OxPhos) and glycolysis] had the strongest rhythms, while the most hypermetabolic line had the weakest rhythms. Pharmacological enhancement of OxPhos decreased the amplitude of circadian oscillation in a subset of tumor cell lines. Strikingly, inhibition of OxPhos enhanced circadian rhythms only in the tumor cell line in which glycolysis was also low, thereby establishing a hypometabolic state. We further analyzed metabolic and circadian phenotypes across a panel of human patient-derived melanoma cell lines and observed a significant negative association between metabolic activity and circadian cycling strength. Together, these findings suggest that metabolic heterogeneity in cancer directly contributes to circadian function and that high levels of glycolysis or OxPhos independently disrupt circadian rhythms in these cells.
    Keywords:  adenocarcinoma; cancer; circadian rhythms; luciferase; metabolism
    DOI:  https://doi.org/10.1073/pnas.2319782121
  3. bioRxiv. 2024 Jul 12. pii: 2024.07.09.602707. [Epub ahead of print]
    Amino acids trigger MDC-dependent mitochondrial remodeling by altering mitochondrial function.
    Nidhi Raghuram, Adam Hughes.
      Cells utilize numerous pathways to maintain mitochondrial homeostasis, including a recently identified mechanism that adjusts the content of the outer mitochondrial membrane (OMM) through formation of OMM-derived multilamellar domains called mitochondrial-derived compartments, or MDCs. MDCs are triggered by perturbations in mitochondrial lipid and protein content, as well as increases in intracellular amino acids. Here, we sought to understand how amino acids trigger MDCs. We show that amino acid-activation of MDCs is dependent on the functional state of mitochondria. While amino acid excess triggers MDC formation when cells are grown on fermentable carbon sources, stimulating mitochondrial biogenesis blocks MDC formation. Moreover, amino acid elevation depletes TCA cycle metabolites in yeast, and preventing consumption of TCA cycle intermediates for amino acid catabolism suppresses MDC formation. Finally, we show that directly impairing the TCA cycle is sufficient to trigger MDC formation in the absence of amino acid stress. These results demonstrate that amino acids stimulate MDC formation by perturbing mitochondrial metabolism.
    DOI:  https://doi.org/10.1101/2024.07.09.602707
  4. Nature. 2024 Jul 17.
    Mice live longer when inflammation-boosting protein is blocked.
    Heidi Ledford.
      
    Keywords:  Ageing; Immunology; Metabolism
    DOI:  https://doi.org/10.1038/d41586-024-02298-5
  5. Nat Commun. 2024 Jul 18. 15(1): 6039
    Replication timing alterations are associated with mutation acquisition during breast and lung cancer evolution.
    Michelle Dietzen, Haoran Zhai, Olivia Lucas, Oriol Pich, Christopher Barrington, Wei-Ting Lu, Sophia Ward, Yanping Guo, Robert E Hynds, Simone Zaccaria, Charles Swanton, Nicholas McGranahan, Nnennaya Kanu.
      During each cell cycle, the process of DNA replication timing is tightly regulated to ensure the accurate duplication of the genome. The extent and significance of alterations in this process during malignant transformation have not been extensively explored. Here, we assess the impact of altered replication timing (ART) on cancer evolution by analysing replication-timing sequencing of cancer and normal cell lines and 952 whole-genome sequenced lung and breast tumours. We find that 6%-18% of the cancer genome exhibits ART, with regions with a change from early to late replication displaying an increased mutation rate and distinct mutational signatures. Whereas regions changing from late to early replication contain genes with increased expression and present a preponderance of APOBEC3-mediated mutation clusters and associated driver mutations. We demonstrate that ART occurs relatively early during cancer evolution and that ART may have a stronger correlation with mutation acquisition than alterations in chromatin structure.
    DOI:  https://doi.org/10.1038/s41467-024-50107-4
  6. Cell Rep. 2024 Jul 17. pii: S2211-1247(24)00845-3. [Epub ahead of print]43(8): 114516
    Fatty acid synthesis promotes inflammasome activation through NLRP3 palmitoylation.
    Stuart Leishman, Najd M Aljadeed, Liyunhe Qian, Shamshad Cockcroft, Jacques Behmoaras, Paras K Anand.
      Despite its significance, the role of lipid metabolism in NLRP3 inflammasome remains elusive. Here, we reveal a critical role for fatty acid synthase (FASN) in NLRP3 inflammasome activation. We demonstrate that pharmacological or genetic depletion of FASN dampens NLRP3 activation in primary mouse and human macrophages and in mice. This disruption in NLRP3 activation is contingent upon FASN activity. Accordingly, abolishing cellular palmitoylation, a post-translational modification in which the FASN product palmitate is reversibly conjugated to cysteine residues of target proteins, blunts inflammasome signaling. Correspondingly, an acyl-biotin exchange assay corroborated NLRP3 palmitoylation. Mechanistically, Toll-like receptor (TLR) ligation introduces palmitoylation at NLRP3 Cys898, permitting NLRP3 translocation to dispersed trans-Golgi network (dTGN) vesicles, the site of inflammasome assembly, upon NLRP3 activation. Accordingly, the NLRP3 Cys898 mutant exhibits reduced palmitoylation, limited translocation to the dTGN compartment, and diminished inflammasome activation. These results underscore mechanistic insights through which lipid metabolism licenses NLRP3 inflammasome assembly and activation.
    Keywords:  CP: Immunology; CP: Metabolism; FASN; NLRP3; SREBP1; immunometabolism; inflammasome; lipid biosynthesis; lipid metabolism; palmitoylation; pyroptosis; trans Golgi network
    DOI:  https://doi.org/10.1016/j.celrep.2024.114516
  7. Methods Mol Biol. 2024 ;2839 99-110
    Metal Uptake by Mitochondrial Carrier Family Proteins Using Lactococcus lactis.
    Xinyu Zhu, Laura E Oldfather, Paul A Cobine.
      Metal ion homeostasis in mitochondria is essential to maintaining proper cellular physiology. However, the ability of metals to bind off target or form complexes with multiple metabolites presents major challenges to understanding the mechanisms that govern this homeostasis. Adding further to the complexity, some of the major mitochondrial transporters have shown substrate promiscuity. In many cases, mitochondrial metals are found in the matrix compartment that is surrounded by the impermeable inner membrane. Four major classes of transporters facilitate the movement of solute across the inner membrane. These are mitochondrial carrier family, ATP-binding cassette transporters, mitochondrial pyruvate carriers, and sideroflexins. For iron, the matrix is the site of iron-sulfur clusters and heme synthesis and therefore transport must occur in a coordinated fashion with the cellular needs for these critical cofactors. Iron could be transported in numerous forms as it has been shown to form complexes with abundant metabolites such as citrate, nucleotides, or glutathione. Here, we describe assays to study iron (or any metal) transport by mitochondrial carrier family proteins expressed in Lactococcus lactis using a nisin-controlled expression system.
    Keywords:  Iron; Mitochondria; Mitochondrial carrier family; Mitochondrial inner membrane; Transport
    DOI:  https://doi.org/10.1007/978-1-0716-4043-2_6
  8. Biol Methods Protoc. 2024 ;9(1): bpae048
    Machine learning of cellular metabolic rewiring.
    Joao B Xavier.
      Metabolic rewiring allows cells to adapt their metabolism in response to evolving environmental conditions. Traditional metabolomics techniques, whether targeted or untargeted, often struggle to interpret these adaptive shifts. Here, we introduce MetaboLiteLearner, a lightweight machine learning framework that harnesses the detailed fragmentation patterns from electron ionization (EI) collected in scan mode during gas chromatography/mass spectrometry to predict changes in the metabolite composition of metabolically adapted cells. When tested on breast cancer cells with different preferences to metastasize to specific organs, MetaboLiteLearner predicted the impact of metabolic rewiring on metabolites withheld from the training dataset using only the EI spectra, without metabolite identification or pre-existing knowledge of metabolic networks. Despite its simplicity, the model learned captured shared and unique metabolomic shifts between brain- and lung-homing metastatic lineages, suggesting cellular adaptations associated with metastasis to specific organs. Integrating machine learning and metabolomics paves the way for new insights into complex cellular adaptations.
    DOI:  https://doi.org/10.1093/biomethods/bpae048
  9. Nat Metab. 2024 Jul 15.
    Adipose glutaminolysis resurfaces in metabolic disease.
    John A Haley, David A Guertin.
      
    DOI:  https://doi.org/10.1038/s42255-024-01084-x
  10. bioRxiv. 2024 Jul 05. pii: 2024.07.04.601975. [Epub ahead of print]
    Robustness of mitochondrial biogenesis and respiration explain aerobic glycolysis.
    Easun Arunachalam, Felix C Keber, Richard C Law, Chirag K Kumar, Yihui Shen, Junyoung O Park, Martin Wühr, Daniel J Needleman.
      A long-standing observation is that in fast-growing cells, respiration rate declines with increasing growth rate and is compensated by an increase in fermentation, despite respiration being more efficient than fermentation. This apparent preference for fermentation even in the presence of oxygen is known as aerobic glycolysis, and occurs in bacteria, yeast, and cancer cells. Considerable work has focused on understanding the potential benefits that might justify this seemingly wasteful metabolic strategy, but its mechanistic basis remains unclear. Here we show that aerobic glycolysis results from the saturation of mitochondrial respiration and the decoupling of mitochondrial biogenesis from the production of other cellular components. Respiration rate is insensitive to acute perturbations of cellular energetic demands or nutrient supplies, and is explained simply by the amount of mitochondria per cell. Mitochondria accumulate at a nearly constant rate across different growth conditions, resulting in mitochondrial amount being largely determined by cell division time. In contrast, glucose uptake rate is not saturated, and is accurately predicted by the abundances and affinities of glucose transporters. Combining these models of glucose uptake and respiration provides a quantitative, mechanistic explanation for aerobic glycolysis. The robustness of specific respiration rate and mitochondrial biogenesis, paired with the flexibility of other bioenergetic and biosynthetic fluxes, may play a broad role in shaping eukaryotic cell metabolism.
    DOI:  https://doi.org/10.1101/2024.07.04.601975
  11. Nat Metab. 2024 Jul 19.
    Hydrogen sulfide produced by the gut microbiota impairs host metabolism via reducing GLP-1 levels in male mice.
    Qingqing Qi, Huijie Zhang, Zheyu Jin, Changchun Wang, Mengyu Xia, Bandy Chen, Bomin Lv, Ludmila Peres Diaz, Xue Li, Ru Feng, Mengdi Qiu, Yang Li, David Meseguer, Xiaojiao Zheng, Wei Wang, Wei Song, He Huang, Hao Wu, Lei Chen, Marc Schneeberger, Xiaofei Yu.
      Dysbiosis of the gut microbiota has been implicated in the pathogenesis of metabolic syndrome (MetS) and may impair host metabolism through harmful metabolites. Here, we show that Desulfovibrio, an intestinal symbiont enriched in patients with MetS, suppresses the production of the gut hormone glucagon-like peptide 1 (GLP-1) through the production of hydrogen sulfide (H2S) in male mice. Desulfovibrio-derived H2S is found to inhibit mitochondrial respiration and induce the unfolded protein response in intestinal L cells, thereby hindering GLP-1 secretion and gene expression. Remarkably, blocking Desulfovibrio and H2S with an over-the-counter drug, bismuth subsalicylate, improves GLP-1 production and ameliorates diet-induced metabolic disorder in male mice. Together, our study uncovers that Desulfovibrio-derived H2S compromises GLP-1 production, shedding light on the gut-relayed mechanisms by which harmful microbiota-derived metabolites impair host metabolism in MetS and suggesting new possibilities for treating MetS.
    DOI:  https://doi.org/10.1038/s42255-024-01068-x
  12. Cancer Res. 2024 Jul 15. 84(14): 2297-2312
    Metabolic Reprogramming Is an Initial Step in Pancreatic Carcinogenesis That Can Be Targeted to Inhibit Acinar-to-Ductal Metaplasia.
    Thorsten Neuß, Min-Chun Chen, Nils Wirges, Sinem Usluer, Rupert Oellinger, Svenja Lier, Michael Dudek, Tobias Madl, Martin Jastroch, Katja Steiger, Werner Schmitz, Henrik Einwächter, Roland M Schmid.
      Metabolic reprogramming is a hallmark of cancer and is crucial for cancer progression, making it an attractive therapeutic target. Understanding the role of metabolic reprogramming in cancer initiation could help identify prevention strategies. To address this, we investigated metabolism during acinar-to-ductal metaplasia (ADM), the first step of pancreatic carcinogenesis. Glycolytic markers were elevated in ADM lesions compared with normal tissue from human samples. Comprehensive metabolic assessment in three mouse models with pancreas-specific activation of KRAS, PI3K, or MEK1 using Seahorse measurements, nuclear magnetic resonance metabolome analysis, mass spectrometry, isotope tracing, and RNA sequencing analysis revealed a switch from oxidative phosphorylation to glycolysis in ADM. Blocking the metabolic switch attenuated ADM formation. Furthermore, mitochondrial metabolism was required for de novo synthesis of serine and glutathione (GSH) but not for ATP production. MYC mediated the increase in GSH intermediates in ADM, and inhibition of GSH synthesis suppressed ADM development. This study thus identifies metabolic changes and vulnerabilities in the early stages of pancreatic carcinogenesis. Significance: Metabolic reprogramming from oxidative phosphorylation to glycolysis mediated by MYC plays a crucial role in the development of pancreatic cancer, revealing a mechanism driving tumorigenesis and potential therapeutic targets. See related commentary by Storz, p. 2225.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-23-2213
  13. Nat Commun. 2024 Jul 15. 15(1): 5937
    Single-cell multiomics reveals ENL mutation perturbs kidney developmental trajectory by rewiring gene regulatory landscape.
    Lele Song, Qinglan Li, Lingbo Xia, Arushi Eesha Sahay, Qi Qiu, Yuanyuan Li, Haitao Li, Kotaro Sasaki, Katalin Susztak, Hao Wu, Liling Wan.
      How disruptions to normal cell differentiation link to tumorigenesis remains incompletely understood. Wilms tumor, an embryonal tumor associated with disrupted organogenesis, often harbors mutations in epigenetic regulators, but their role in kidney development remains unexplored. Here, we show at single-cell resolution that a Wilms tumor-associated mutation in the histone acetylation reader ENL disrupts kidney differentiation in mice by rewiring the gene regulatory landscape. Mutant ENL promotes nephron progenitor commitment while restricting their differentiation by dysregulating transcription factors such as Hox clusters. It also induces abnormal progenitors that lose kidney-associated chromatin identity. Furthermore, mutant ENL alters the transcriptome and chromatin accessibility of stromal progenitors, resulting in hyperactivation of Wnt signaling. The impacts of mutant ENL on both nephron and stroma lineages lead to profound kidney developmental defects and postnatal mortality in mice. Notably, a small molecule inhibiting mutant ENL's histone acetylation binding activity largely reverses these defects. This study provides insights into how mutations in epigenetic regulators disrupt kidney development and suggests a potential therapeutic approach.
    DOI:  https://doi.org/10.1038/s41467-024-50171-w
  14. Cell Rep. 2024 Jul 17. pii: S2211-1247(24)00802-7. [Epub ahead of print]43(8): 114473
    ATAD1 prevents clogging of TOM and damage caused by un-imported mitochondrial proteins.
    John Kim, Madeleine Goldstein, Lauren Zecchel, Ryan Ghorayeb, Christopher A Maxwell, Hilla Weidberg.
      Mitochondria require the constant import of nuclear-encoded proteins for proper functioning. Impaired protein import not only depletes mitochondria of essential factors but also leads to toxic accumulation of un-imported proteins outside the organelle. Here, we investigate the consequences of impaired mitochondrial protein import in human cells. We demonstrate that un-imported proteins can clog the mitochondrial translocase of the outer membrane (TOM). ATAD1, a mitochondrial ATPase, removes clogged proteins from TOM to clear the entry gate into the mitochondria. ATAD1 interacts with both TOM and stalled proteins, and its knockout results in extensive accumulation of mitochondrial precursors as well as decreased protein import. Increased ATAD1 expression contributes to improved fitness of cells with inefficient mitochondrial protein import. Overall, we demonstrate the importance of the ATAD1 quality control pathway in surveilling protein import and its contribution to cellular health.
    Keywords:  AAA ATPase; ATAD1; CP: Cell biology; CP: Metabolism; TOM clogging; mitochondrial protein import; mitochondrial stress; protein quality control; proteotoxicity
    DOI:  https://doi.org/10.1016/j.celrep.2024.114473
  15. BMC Med Genomics. 2024 Jul 15. 17(1): 186
    Co-expression in tissue-specific gene networks links genes in cancer-susceptibility loci to known somatic driver genes.
    Carlos G Urzúa-Traslaviña, Tijs van Lieshout, Floranne Boulogne, Kevin Domanegg, Mahmoud Zidan, Olivier B Bakker, Annique Claringbould, Jeroen de Ridder, Wilbert Zwart, Harm-Jan Westra, Patrick Deelen, Lude Franke.
       BACKGROUND: The genetic background of cancer remains complex and challenging to integrate. Many somatic mutations within genes are known to cause and drive cancer, while genome-wide association studies (GWAS) of cancer have revealed many germline risk factors associated with cancer. However, the overlap between known somatic driver genes and positional candidate genes from GWAS loci is surprisingly small. We hypothesised that genes from multiple independent cancer GWAS loci should show tissue-specific co-regulation patterns that converge on cancer-specific driver genes.
    RESULTS: We studied recent well-powered GWAS of breast, prostate, colorectal and skin cancer by estimating co-expression between genes and subsequently prioritising genes that show significant co-expression with genes mapping within susceptibility loci from cancer GWAS. We observed that the prioritised genes were strongly enriched for cancer drivers defined by COSMIC, IntOGen and Dietlein et al. The enrichment of known cancer driver genes was most significant when using co-expression networks derived from non-cancer samples of the relevant tissue of origin.
    CONCLUSION: We show how genes within risk loci identified by cancer GWAS can be linked to known cancer driver genes through tissue-specific co-expression networks. This provides an important explanation for why seemingly unrelated sets of genes that harbour either germline risk factors or somatic mutations can eventually cause the same type of disease.
    Keywords:  Breast cancer; Cancer drivers; Cancer susceptibility genes; Colon cancer; GWAS; Gene networks; Omnigenic; Prostate cancer; Tissue-specific; recount3
    DOI:  https://doi.org/10.1186/s12920-024-01941-4
  16. bioRxiv. 2024 Jul 02. pii: 2024.07.02.600738. [Epub ahead of print]
    Polyamines regulate cell fate by altering the activity of histone-modifying enzymes.
    Maya Emmons-Bell, Grace Forsyth, Abby Sundquist, Sylvie Oldeman, Angeliki Gardikioti, Roshni de Souza, Jonathan Coene, Maryam H Kamel, Shine Ayyapan, Harrison A Fuchs, Steven Verhelst, Joanna Smeeton, Catherine A Musselman, Juan-Manuel Schvartzman.
      Polyamines are polycationic alkyl-amines abundant in proliferating stem and cancer cells. How these metabolites influence numerous cellular functions remains unclear. Here we show that polyamine levels decrease during differentiation and that inhibiting polyamine synthesis leads to a differentiated-like cell state. Polyamines concentrate in the nucleus and are further enriched in the nucleoli of cells in culture and in vivo . Loss of polyamines drives changes in chromatin accessibility that correlate with altered histone post-translational modifications. Polyamines interact electrostatically with DNA on the nucleosome core, stabilizing histone tails in conformations accessible to modifying enzymes. These data reveal a mechanism by which an abundant metabolite influences chromatin structure and function in a non-sequence specific manner, facilitating chromatin remodeling during reprogramming and limiting it during fate commitment.
    DOI:  https://doi.org/10.1101/2024.07.02.600738
  17. Nature. 2024 Jul 17.
    Clonal inactivation of TERT impairs stem cell competition.
    Kazuteru Hasegawa, Yang Zhao, Alina Garbuzov, M Ryan Corces, Patrick Neuhöfer, Victoria M Gillespie, Peggie Cheung, Julia A Belk, Yung-Hsin Huang, Yuning Wei, Lu Chen, Howard Y Chang, Steven E Artandi.
      Telomerase is intimately associated with stem cells and cancer, because it catalytically elongates telomeres-nucleoprotein caps that protect chromosome ends1. Overexpression of telomerase reverse transcriptase (TERT) enhances the proliferation of cells in a telomere-independent manner2-8, but so far, loss-of-function studies have provided no evidence that TERT has a direct role in stem cell function. In many tissues, homeostasis is shaped by stem cell competition, a process in which stem cells compete on the basis of inherent fitness. Here we show that conditional deletion of Tert in the spermatogonial stem cell (SSC)-containing population in mice markedly impairs competitive clone formation. Using lineage tracing from the Tert locus, we find that TERT-expressing SSCs yield long-lived clones, but that clonal inactivation of TERT promotes stem cell differentiation and a genome-wide reduction in open chromatin. This role for TERT in competitive clone formation occurs independently of both its reverse transcriptase activity and the canonical telomerase complex. Inactivation of TERT causes reduced activity of the MYC oncogene, and transgenic expression of MYC in the TERT-deleted pool of SSCs efficiently rescues clone formation. Together, these data reveal a catalytic-activity-independent requirement for TERT in enhancing stem cell competition, uncover a genetic connection between TERT and MYC and suggest that a selective advantage for stem cells with high levels of TERT contributes to telomere elongation in the male germline during homeostasis and ageing.
    DOI:  https://doi.org/10.1038/s41586-024-07700-w
  18. bioRxiv. 2024 Jul 02. pii: 2024.06.30.601416. [Epub ahead of print]
    Spatial transcriptomics reveals influence of microenvironment on intrinsic fates in melanoma therapy resistance.
    Ryan H Boe, Catherine G Triandafillou, Rossana Lazcano, Jennifer A Wargo, Arjun Raj.
      Resistance to cancer therapy is driven by both cell-intrinsic and microenvironmental factors. Previous work has revealed that multiple resistant cell fates emerge in melanoma following treatment with targeted therapy and that, in vitro, these resistant fates are determined by the transcriptional state of individual cells prior to exposure to treatment. What remains unclear is whether these resistant fates are shared across different genetic backgrounds and how, if at all, these resistant fates interact with the tumor microenvironment. Through spatial transcriptomics and single-cell RNA sequencing, we uncovered distinct resistance programs in melanoma cells shaped by both intrinsic cellular states and the tumor microenvironment. Consensus non-negative matrix factorization revealed shared intrinsic resistance programs across different cell lines, highlighting the presence of universal and unique resistance pathways. In patient samples, we demonstrated that these resistance programs coexist within individual tumors and associate with diverse immune signatures, suggesting that the tumor microenvironment and distribution of resistant fates are closely connected. Single-cell resolution spatial transcriptomics in xenograft models revealed both intrinsically determined and extrinsically influenced resistant fates. Overall, this work demonstrates that each therapy resistant fate coexists with a distinct immune microenvironment in tumors and that, in vivo, tissue features, such as regions of necrosis, can influence which resistant fate is adopted.
    DOI:  https://doi.org/10.1101/2024.06.30.601416
  19. Nat Commun. 2024 Jul 16. 15(1): 5980
    Metabolic imaging across scales reveals distinct prostate cancer phenotypes.
    Nikita Sushentsev, Gregory Hamm, Lucy Flint, Daniel Birtles, Aleksandr Zakirov, Jack Richings, Stephanie Ling, Jennifer Y Tan, Mary A McLean, Vinay Ayyappan, Ines Horvat Menih, Cara Brodie, Jodi L Miller, Ian G Mills, Vincent J Gnanapragasam, Anne Y Warren, Simon T Barry, Richard J A Goodwin, Tristan Barrett, Ferdia A Gallagher.
      Hyperpolarised magnetic resonance imaging (HP-13C-MRI) has shown promise as a clinical tool for detecting and characterising prostate cancer. Here we use a range of spatially resolved histological techniques to identify the biological mechanisms underpinning differential [1-13C]lactate labelling between benign and malignant prostate, as well as in tumours containing cribriform and non-cribriform Gleason pattern 4 disease. Here we show that elevated hyperpolarised [1-13C]lactate signal in prostate cancer compared to the benign prostate is primarily driven by increased tumour epithelial cell density and vascularity, rather than differences in epithelial lactate concentration between tumour and normal. We also demonstrate that some tumours of the cribriform subtype may lack [1-13C]lactate labelling, which is explained by lower epithelial lactate dehydrogenase expression, higher mitochondrial pyruvate carrier density, and increased lipid abundance compared to lactate-rich non-cribriform lesions. These findings highlight the potential of combining spatial metabolic imaging tools across scales to identify clinically significant metabolic phenotypes in prostate cancer.
    DOI:  https://doi.org/10.1038/s41467-024-50362-5
  20. Nature. 2024 Jul 17.
    In vivo single-cell CRISPR uncovers distinct TNF programmes in tumour evolution.
    Peter F Renz, Umesh Ghoshdastider, Simona Baghai Sain, Fabiola Valdivia-Francia, Ameya Khandekar, Mark Ormiston, Martino Bernasconi, Clara Duré, Jonas A Kretz, Minkyoung Lee, Katie Hyams, Merima Forny, Marcel Pohly, Xenia Ficht, Stephanie J Ellis, Andreas E Moor, Ataman Sendoel.
      The tumour evolution model posits that malignant transformation is preceded by randomly distributed driver mutations in cancer genes, which cause clonal expansions in phenotypically normal tissues. Although clonal expansions can remodel entire tissues1-3, the mechanisms that result in only a small number of clones transforming into malignant tumours remain unknown. Here we develop an in vivo single-cell CRISPR strategy to systematically investigate tissue-wide clonal dynamics of the 150 most frequently mutated squamous cell carcinoma genes. We couple ultrasound-guided in utero lentiviral microinjections, single-cell RNA sequencing and guide capture to longitudinally monitor clonal expansions and document their underlying gene programmes at single-cell transcriptomic resolution. We uncover a tumour necrosis factor (TNF) signalling module, which is dependent on TNF receptor 1 and involving macrophages, that acts as a generalizable driver of clonal expansions in epithelial tissues. Conversely, during tumorigenesis, the TNF signalling module is downregulated. Instead, we identify a subpopulation of invasive cancer cells that switch to an autocrine TNF gene programme associated with epithelial-mesenchymal transition. Finally, we provide in vivo evidence that the autocrine TNF gene programme is sufficient to mediate invasive properties and show that the TNF signature correlates with shorter overall survival of patients with squamous cell carcinoma. Collectively, our study demonstrates the power of applying in vivo single-cell CRISPR screening to mammalian tissues, unveils distinct TNF programmes in tumour evolution and highlights the importance of understanding the relationship between clonal expansions in epithelia and tumorigenesis.
    DOI:  https://doi.org/10.1038/s41586-024-07663-y
  21. Nat Commun. 2024 Jul 16. 15(1): 5956
    PRC2-AgeIndex as a universal biomarker of aging and rejuvenation.
    Mahdi Moqri, Andrea Cipriano, Daniel J Simpson, Sajede Rasouli, Tara Murty, Tineke Anna de Jong, Daniel Nachun, Guilherme de Sena Brandine, Kejun Ying, Andrei Tarkhov, Karolina A Aberg, Edwin van den Oord, Wanding Zhou, Andrew Smith, Crystal Mackall, Vadim N Gladyshev, Steve Horvath, Michael P Snyder, Vittorio Sebastiano.
      DNA methylation (DNAm) is one of the most reliable biomarkers of aging across mammalian tissues. While the age-dependent global loss of DNAm has been well characterized, DNAm gain is less characterized. Studies have demonstrated that CpGs which gain methylation with age are enriched in Polycomb Repressive Complex 2 (PRC2) targets. However, whole-genome examination of all PRC2 targets as well as determination of the pan-tissue or tissue-specific nature of these associations is lacking. Here, we show that low-methylated regions (LMRs) which are highly bound by PRC2 in embryonic stem cells (PRC2 LMRs) gain methylation with age in all examined somatic mitotic cells. We estimated that this epigenetic change represents around 90% of the age-dependent DNAm gain genome-wide. Therefore, we propose the "PRC2-AgeIndex," defined as the average DNAm in PRC2 LMRs, as a universal biomarker of cellular aging in somatic cells which can distinguish the effect of different anti-aging interventions.
    DOI:  https://doi.org/10.1038/s41467-024-50098-2
  22. Sci Immunol. 2024 Jul 19. 9(97): eadl1903
    Cross-talk between ILC2 and Gata3high Tregs locally constrains adaptive type 2 immunity.
    Julie Stockis, Thomas Yip, Julia Moreno-Vicente, Oliver Burton, Youhani Samarakoon, Martijn J Schuijs, Shwetha Raghunathan, Celine Garcia, Weike Luo, Sarah K Whiteside, Shaun Png, Charlotte Simpson, Stela Monk, Ashley Sawle, Kelvin Yin, Johanna Barbieri, Panagiotis Papadopoulos, Hannah Wong, Hans-Reimer Rodewald, Timothy Vyse, Andrew N J McKenzie, Mark S Cragg, Matthew Hoare, David R Withers, Hans Jörg Fehling, Rahul Roychoudhuri, Adrian Liston, Timotheus Y F Halim.
      Regulatory T cells (Tregs) control adaptive immunity and restrain type 2 inflammation in allergic disease. Interleukin-33 promotes the expansion of tissue-resident Tregs and group 2 innate lymphoid cells (ILC2s); however, how Tregs locally coordinate their function within the inflammatory niche is not understood. Here, we show that ILC2s are critical orchestrators of Treg function. Using spatial, cellular, and molecular profiling of the type 2 inflamed niche, we found that ILC2s and Tregs engage in a direct (OX40L-OX40) and chemotaxis-dependent (CCL1-CCR8) cellular dialogue that enforces the local accumulation of Gata3high Tregs, which are transcriptionally and functionally adapted to the type 2 environment. Genetic interruption of ILC2-Treg communication resulted in uncontrolled type 2 lung inflammation after allergen exposure. Mechanistically, we found that Gata3high Tregs can modulate the local bioavailability of the costimulatory molecule OX40L, which subsequently controlled effector memory T helper 2 cell numbers. Hence, ILC2-Treg interactions represent a critical feedback mechanism to control adaptive type 2 immunity.
    DOI:  https://doi.org/10.1126/sciimmunol.adl1903
  23. Nat Commun. 2024 Jul 15. 15(1): 5935
    Whole genome sequencing refines stratification and therapy of patients with clear cell renal cell carcinoma.
    Renal Cancer Genomics England Consortium
      Clear cell renal cell carcinoma (ccRCC) is the most common form of kidney cancer, but a comprehensive description of its genomic landscape is lacking. We report the whole genome sequencing of 778 ccRCC patients enrolled in the 100,000 Genomes Project, providing for a detailed description of the somatic mutational landscape of ccRCC. We identify candidate driver genes, which as well as emphasising the major role of epigenetic regulation in ccRCC highlight additional biological pathways extending opportunities for therapeutic interventions. Genomic characterisation identified patients with divergent clinical outcome; higher number of structural copy number alterations associated with poorer prognosis, whereas VHL mutations were independently associated with a better prognosis. The observations that higher T-cell infiltration is associated with better overall survival and that genetically predicted immune evasion is not common supports the rationale for immunotherapy. These findings should inform personalised surveillance and treatment strategies for ccRCC patients.
    DOI:  https://doi.org/10.1038/s41467-024-49692-1
  24. Sci Rep. 2024 Jul 14. 14(1): 16238
    Quantification of circadian rhythms in mammalian lung tissue snapshot data.
    Saskia Grabe, Bharath Ananthasubramaniam, Hanspeter Herzel.
      Healthy mammalian cells have a circadian clock, a gene regulatory network that allows them to schedule their physiological processes to optimal times of the day. When healthy cells turn into cancer cells, the circadian clock often becomes cancer specifically disturbed, so there is an interest in the extraction of circadian features from gene expression data of cancer. This is challenging, as clinical gene expression samples of cancer are snapshot-like and the circadian clock is best examined using gene expression time series. In this study, we obtained lists of intersecting circadian genes in public gene expression time series data of lung tissue of mouse and baboon. We base our circadian gene lists on correlations of gene expression levels of circadian genes, which are closely associated to the phase differences between them. Combining circadian gene expression patterns of diurnal and nocturnal species of different ages provides circadian genes that are also important in healthy and cancerous human lung tissue. We tested the quality of the representation of the circadian clock in our gene lists by PCA-based reconstructions of the circadian times of the mouse and baboon samples. Then we assigned potential circadian times to the human lung tissue samples and find an intact circadian clock in the healthy human lung tissue, but an altered, weak clock in the adjacent cancerous lung tissue.
    DOI:  https://doi.org/10.1038/s41598-024-66694-7
  25. Nat Commun. 2024 Jul 17. 15(1): 6002
    Acetyl-CoA synthetase activity is enzymatically regulated by lysine acetylation using acetyl-CoA or acetyl-phosphate as donor molecule.
    Chuan Qin, Leonie G Graf, Kilian Striska, Markus Janetzky, Norman Geist, Robin Specht, Sabrina Schulze, Gottfried J Palm, Britta Girbardt, Babett Dörre, Leona Berndt, Stefan Kemnitz, Mark Doerr, Uwe T Bornscheuer, Mihaela Delcea, Michael Lammers.
      The AMP-forming acetyl-CoA synthetase is regulated by lysine acetylation both in bacteria and eukaryotes. However, the underlying mechanism is poorly understood. The Bacillus subtilis acetyltransferase AcuA and the AMP-forming acetyl-CoA synthetase AcsA form an AcuA•AcsA complex, dissociating upon lysine acetylation of AcsA by AcuA. Crystal structures of AcsA from Chloroflexota bacterium in the apo form and in complex with acetyl-adenosine-5'-monophosphate (acetyl-AMP) support the flexible C-terminal domain adopting different conformations. AlphaFold2 predictions suggest binding of AcuA stabilizes AcsA in an undescribed conformation. We show the AcuA•AcsA complex dissociates upon acetyl-coenzyme A (acetyl-CoA) dependent acetylation of AcsA by AcuA. We discover an intrinsic phosphotransacetylase activity enabling AcuA•AcsA generating acetyl-CoA from acetyl-phosphate (AcP) and coenzyme A (CoA) used by AcuA to acetylate and inactivate AcsA. Here, we provide mechanistic insights into the regulation of AMP-forming acetyl-CoA synthetases by lysine acetylation and discover an intrinsic phosphotransacetylase allowing modulation of its activity based on AcP and CoA levels.
    DOI:  https://doi.org/10.1038/s41467-024-49952-0
  26. Physiology (Bethesda). 2024 Jul 16.
    The Spectrum of "TFEopathies" - Flipping the mTOR Switch in Renal Tumorigenesis.
    Nicola Alesi, Kaushal Asrani, Tamara L Lotan, Elizabeth P Henske.
      The Mammalian Target of Rapamycin Complex 1 (mTORC1) is a serine threonine kinase that couples nutrient and growth factor signaling to the cellular control of metabolism and plays a fundamental role in aberrant proliferation in cancer. mTORC1 has previously been considered an "on/off" switch, capable of phosphorylating the entire pool of its substrates when activated. However recent studies have indicated that mTORC1 may be active towards its canonical substrates, 4EBP1 and S6K, involved in mRNA translation and protein synthesis, and inactive towards TFEB and TFE3, transcription factors involved in the regulation of lysosome biogenesis, in several pathological contexts. Among these conditions are Birt Hogg Dube (BHD) and recently, Tuberous Sclerosis Complex (TSC). Furthermore, TFEB and TFE3 hyperactivation in these syndromes, and in translocation Renal Cell Carcinomas (tRCC), drives mTORC1 activity towards the canonical substrates, through the transcriptional activation of the Rag GTPases, thereby positioning TFEB and TFE3 upstream of mTORC1 activity towards 4EBP1 and S6K. The expanding importance of TFEB and TFE3 in the pathogenesis of these renal diseases warrants a novel clinical grouping that we term "TFEopathies". Currently, there no therapeutic options directly targeting TFEB and TFE3, which represents a challenging and critically required avenue for cancer research.
    Keywords:  Kidney TFEopathies; TFE3; TFEB; TSC; mTORC1
    DOI:  https://doi.org/10.1152/physiol.00026.2024
  27. Nat Metab. 2024 Jul 15.
    Reduced adipocyte glutaminase activity promotes energy expenditure and metabolic health.
    Simon Lecoutre, Salwan Maqdasy, David Rizo-Roca, Gianluca Renzi, Ivan Vlassakev, Lynn M Alaeddine, Romane Higos, Jutta Jalkanen, Jiawei Zhong, Danae S Zareifi, Scott Frendo-Cumbo, Lucas Massier, Ondrej Hodek, Marta Juvany, Thomas Moritz, Thais de Castro Barbosa, Muhmmad Omar-Hmeadi, Marta López-Yus, Fatiha Merabtene, Jimon Boniface Abatan, Geneviève Marcelin, Elie-Julien El Hachem, Christine Rouault, Martin O Bergo, Paul Petrus, Juleen R Zierath, Karine Clément, Anna Krook, Niklas Mejhert, Mikael Rydén.
      Glutamine and glutamate are interconverted by several enzymes and alterations in this metabolic cycle are linked to cardiometabolic traits. Herein, we show that obesity-associated insulin resistance is characterized by decreased plasma and white adipose tissue glutamine-to-glutamate ratios. We couple these stoichiometric changes to perturbed fat cell glutaminase and glutamine synthase messenger RNA and protein abundance, which together promote glutaminolysis. In human white adipocytes, reductions in glutaminase activity promote aerobic glycolysis and mitochondrial oxidative capacity via increases in hypoxia-inducible factor 1α abundance, lactate levels and p38 mitogen-activated protein kinase signalling. Systemic glutaminase inhibition in male and female mice, or genetically in adipocytes of male mice, triggers the activation of thermogenic gene programs in inguinal adipocytes. Consequently, the knockout mice display higher energy expenditure and improved glucose tolerance compared to control littermates, even under high-fat diet conditions. Altogether, our findings highlight white adipocyte glutamine turnover as an important determinant of energy expenditure and metabolic health.
    DOI:  https://doi.org/10.1038/s42255-024-01083-y
  28. bioRxiv. 2024 Jul 07. pii: 2024.07.06.602365. [Epub ahead of print]
    INF2-mediated actin polymerization at ER-organelle contacts regulates organelle size and movement.
    Cara R Schiavon, Yuning Wang, Jasmine W Feng, Stephanie Garrett, Tsung-Chang Sung, Yelena Dayn, Chunxin Wang, Richard J Youle, Omar A Quintero-Carmona, Gerald S Shadel, Uri Manor.
      Proper regulation of organelle dynamics and inter-organelle contacts is critical for cellular health and function. Both the endoplasmic reticulum (ER) and actin cytoskeleton are known to regulate organelle dynamics, but how, when, and where these two subcellular components are coordinated to control organelle dynamics remains unclear. Here, we show that ER-associated actin consistently marks mitochondrial, endosomal, and lysosomal fission sites. We also show that actin polymerization by the ER-anchored isoform of the formin protein INF2 is a key regulator of the morphology and mobility of these organelles. Together, our findings establish a mechanism by which INF2-mediated polymerization of ER-associated actin at ER-organelle contacts regulates organelle dynamics.
    DOI:  https://doi.org/10.1101/2024.07.06.602365
  29. Geroscience. 2024 Jul 19.
    Developmental disruption of the mitochondrial fission gene drp-1 extends the longevity of daf-2 insulin/IGF-1 receptor mutant.
    Annika Traa, Aura A Tamez González, Jeremy M Van Raamsdonk.
      The dynamic nature of the mitochondrial network is regulated by mitochondrial fission and fusion, allowing for re-organization of mitochondria to adapt to the cell's ever-changing needs. As organisms age, mitochondrial fission and fusion become dysregulated and mitochondrial networks become increasingly fragmented. Modulation of mitochondrial dynamics has been shown to affect longevity in fungi, yeast, Drosophila and C. elegans. Disruption of the mitochondrial fission gene drp-1 drastically increases the already long lifespan of daf-2 insulin/IGF-1 signaling (IIS) mutants. In this work, we determined the conditions required for drp-1 disruption to extend daf-2 longevity and explored the molecular mechanisms involved. We found that knockdown of drp-1 during development is sufficient to extend daf-2 lifespan, while tissue-specific knockdown of drp-1 in neurons, intestine or muscle failed to increase daf-2 longevity. Disruption of other genes involved in mitochondrial fission also increased daf-2 lifespan as did treatment with RNA interference clones that decrease mitochondrial fragmentation. In exploring potential mechanisms involved, we found that deletion of drp-1 increases resistance to chronic stresses. In addition, we found that disruption of drp-1 increased mitochondrial and peroxisomal connectedness in daf-2 worms, increased oxidative phosphorylation and ATP levels, and increased mitophagy in daf-2 worms, but did not affect their ROS levels, food consumption or mitochondrial membrane potential. Disruption of mitophagy through RNA interference targeting pink-1 decreased the lifespan of daf-2;drp-1 worms suggesting that increased mitophagy contributes to their extended lifespan. Overall, this work defined the conditions under which drp-1 disruption increases daf-2 lifespan and has identified multiple changes in daf-2;drp-1 mutants that may contribute to their lifespan extension.
    Keywords:   C. elegans ; Aging; Biological resilience; DRP1; Insulin/IGF-1 signaling; Mitochondrial fission
    DOI:  https://doi.org/10.1007/s11357-024-01276-z
  30. bioRxiv. 2024 Jul 11. pii: 2024.07.09.602593. [Epub ahead of print]
    Ketogenesis supports hepatic polyunsaturated fatty acid homeostasis via fatty acid elongation.
    Eric D Queathem, Zahra Moazzami, David B Stagg, Alisa B Nelson, Kyle Fulghum, Abdirahman Hayir, Alisha Seay, Jacob R Gillingham, D Andre d'Avignon, Xianlin Han, Hai-Bin Ruan, Peter A Crawford, Patrycja Puchalska.
      Therapeutic interventions targeting hepatic lipid metabolism in metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis (MASH) remain elusive. Using mass spectrometry-based stable isotope tracing and shotgun lipidomics, we established a novel link between ketogenesis and MASLD pathophysiology. Our findings show that mouse liver and primary hepatocytes consume ketone bodies to support fatty acid (FA) biosynthesis via both de novo lipogenesis (DNL) and FA elongation. Analysis of 13 C-labeled FAs in hepatocytes lacking mitochondrial D-β-hydroxybutyrate dehydrogenase (BDH1) revealed a partial reliance on mitochondrial conversion of D-βOHB to acetoacetate (AcAc) for cytoplasmic DNL contribution, whereas FA elongation from ketone bodies was fully dependent on cytosolic acetoacetyl-CoA synthetase (AACS). Ketone bodies were essential for polyunsaturated FA (PUFA) homeostasis in hepatocytes, as loss of AACS diminished both free and esterified PUFAs. Ketogenic insufficiency depleted liver PUFAs and increased triacylglycerols, mimicking human MASLD, suggesting that ketogenesis supports PUFA homeostasis, and may mitigate MASLD-MASH progression in humans.
    DOI:  https://doi.org/10.1101/2024.07.09.602593
  31. Nat Commun. 2024 Jul 18. 15(1): 6067
    Sphinganine recruits TLR4 adaptors in macrophages and promotes inflammation in murine models of sepsis and melanoma.
    Marvin Hering, Alaa Madi, Roger Sandhoff, Sicong Ma, Jingxia Wu, Alessa Mieg, Karsten Richter, Kerstin Mohr, Nora Knabe, Diana Stichling, Gernot Poschet, Felix Bestvater, Larissa Frank, Jochen Utikal, Viktor Umansky, Guoliang Cui.
      After recognizing its ligand lipopolysaccharide, Toll-like receptor 4 (TLR4) recruits adaptor proteins to the cell membrane, thereby initiating downstream signaling and triggering inflammation. Whether this recruitment of adaptor proteins is dependent solely on protein-protein interactions is unknown. Here, we report that the sphingolipid sphinganine physically interacts with the adaptor proteins MyD88 and TIRAP and promotes MyD88 recruitment in macrophages. Myeloid cell-specific deficiency in serine palmitoyltransferase long chain base subunit 2, which encodes the key enzyme catalyzing sphingolipid biosynthesis, decreases the membrane recruitment of MyD88 and inhibits inflammatory responses in in vitro bone marrow-derived macrophage and in vivo sepsis models. In a melanoma mouse model, serine palmitoyltransferase long chain base subunit 2 deficiency decreases anti-tumor myeloid cell responses and increases tumor growth. Therefore, sphinganine biosynthesis is required for the initiation of TLR4 signal transduction and serves as a checkpoint for macrophage pattern recognition in sepsis and melanoma mouse models.
    DOI:  https://doi.org/10.1038/s41467-024-50341-w
  32. Nature. 2024 Jul 17.
    Adaptation to photoperiod via dynamic neurotransmitter segregation.
    G Maddaloni, Y J Chang, R A Senft, S M Dymecki.
      Changes in the amount of daylight (photoperiod) alter physiology and behaviour1,2. Adaptive responses to seasonal photoperiods are vital to all organisms-dysregulation associates with disease, including affective disorders3 and metabolic syndromes4. The circadian rhythm circuitry is implicated in such responses5,6, yet little is known about the precise cellular substrates that underlie phase synchronization to photoperiod change. Here we identify a brain circuit and system of axon branch-specific and reversible neurotransmitter deployment that are critical for behavioural and sleep adaptation to photoperiod. A type of neuron called mrEn1-Pet17 in the mouse brainstem median raphe nucleus segregates serotonin from VGLUT3 (also known as SLC17A8, a proxy for glutamate) to different axonal branches that innervate specific brain regions involved in circadian rhythm and sleep-wake timing8,9. This branch-specific neurotransmitter deployment did not distinguish between daylight and dark phase; however, it reorganized with change in photoperiod. Axonal boutons, but not cell soma, changed neurochemical phenotype upon a shift away from equinox light/dark conditions, and these changes were reversed upon return to equinox conditions. When we genetically disabled Vglut3 in mrEn1-Pet1 neurons, sleep-wake periods, voluntary activity and clock gene expression did not synchronize to the new photoperiod or were delayed. Combining intersectional rabies virus tracing and projection-specific neuronal silencing, we delineated a preoptic area-to-mrEn1Pet1 connection that was responsible for decoding the photoperiodic inputs, driving the neurotransmitter reorganization and promoting behavioural synchronization. Our results reveal a brain circuit and periodic, branch-specific neurotransmitter deployment that regulates organismal adaptation to photoperiod change.
    DOI:  https://doi.org/10.1038/s41586-024-07692-7
  33. Nat Metab. 2024 Jul 19.
    H2S as a metabolic saboteur.
    Naisi Zhao, Guojun Wu, Liping Zhao.
      
    DOI:  https://doi.org/10.1038/s42255-024-01086-9
  34. Aging Dis. 2024 Jul 02.
    Crosstalk between Circadian Rhythm Dysregulation and Tumorigenesis, Tumor Metabolism and Tumor Immune Response.
    Yifei Zhu, Yao Zheng, Rongyu Dai, Xuyu Gu.
      Circadian rhythm is a self-regulating 24-hour system that synchronizes with the day and night cycle in organisms. The regulation of this system is controlled by clock genes, which function to harmoniously express molecular levels that facilitate the orderly coordination of various cellular processes, such as sleep, metabolism, endocrine function, cell proliferation and immunity. The root cause of tumorigenesis is that the body loses its normal regulation of cell growth at the genetic level. Long-term disruptions in circadian rhythms caused by factors such as shift work, jet lag, and unstable sleep patterns can impact cellular health, leading to various health problems, including cancer. Circadian rhythm controls most cellular functions related to cancer progression, which has a significant impact on the ability of immune cells to detect cancer cells and promote their clearance and has crucial implication for future tumor immunotherapy. This article aims to review the crosstalk between dysregulation of circadian rhythm and tumorigenesis, tumor metabolism, and immune response. Additionally, we discuss the role of circadian rhythm disruption in tumor therapy, highlighting its potential to optimize treatment timing and improve therapeutic outcomes.
    DOI:  https://doi.org/10.14336/AD.2024.0533
  35. Mol Cell. 2024 Jul 06. pii: S1097-2765(24)00527-6. [Epub ahead of print]
    Competition between two HUSH complexes orchestrates the immune response to retroelement invasion.
    Joshua Miguel C Danac, Rachael E Matthews, Akhila Gungi, Chuyan Qin, Harriet Parsons, Robin Antrobus, Richard T Timms, Iva A Tchasovnikarova.
      The human silencing hub (HUSH) preserves genome integrity through the epigenetic repression of invasive genetic elements. However, despite our understanding of HUSH as an obligate complex of three subunits, only loss of MPP8 or Periphilin, but not TASOR, triggers interferon signaling following derepression of endogenous retroelements. Here, we resolve this paradox by characterizing a second HUSH complex that shares MPP8 and Periphilin but assembles around TASOR2, an uncharacterized paralog of TASOR. Whereas HUSH represses LINE-1 retroelements marked by the repressive histone modification H3K9me3, HUSH2 is recruited by the transcription factor IRF2 to repress interferon-stimulated genes. Mechanistically, HUSH-mediated retroelement silencing sequesters the limited pool of the shared subunits MPP8 and Periphilin, preventing TASOR2 from forming HUSH2 complexes and hence relieving the HUSH2-mediated repression of interferon-stimulated genes. Thus, competition between two HUSH complexes intertwines retroelement silencing with the induction of an immune response, coupling epigenetic and immune aspects of genome defense.
    Keywords:  HUSH; HUSH2; IRF2; LINE-1; chromatin; epigenetics; immune response; interferon; retroelement; transposable elements
    DOI:  https://doi.org/10.1016/j.molcel.2024.06.020
  36. Sci Am. 2023 Jan 01. 328(1): 24
    The Human Engine: Studies of metabolism reveal surprising insights into how we burn calories-and how cooperative food production helped Homo sapiens flourish.
    Herman Pontzer.
      
    DOI:  https://doi.org/10.1038/scientificamerican0123-24
  37. J Biol Chem. 2024 Jul 14. pii: S0021-9258(24)02076-3. [Epub ahead of print] 107575
    Phosphorylation of GCN2 by mTOR confers adaptation to conditions of hyper-mTOR activation under stress.
    Odai Darawshi, Olaya Yassin, Miri Shmuel, Ronald C Wek, S Jalil Mahdizadeh, Leif A Eriksson, Maria Hatzoglou, Boaz Tirosh.
      Adaptation to shortage in free amino acids (AA) is mediated by two pathways, the integrated stress response (ISR) and the mechanistic target of rapamycin (mTOR). In response to reduced levels, primarily of leucine or arginine, mTOR in its complex 1 configuration (mTORC1) is suppressed leading to a decrease in translation initiation and elongation. The eIF2α kinase general control nonderepressible 2 (GCN2) is activated by uncharged tRNAs, leading to induction of the ISR in response to a broader range of AA shortage. ISR confers a reduced translation initiation, while promoting the selective synthesis of stress proteins, such as ATF4. To efficiently adapt to AA starvation, the two pathways are cross-regulated at multiple levels. Here we identified a new mechanism of ISR/mTORC1 crosstalk that optimizes survival under AA starvation, when mTORC1 is forced to remain active. mTORC1 activation during acute AA shortage, augmented ATF4 expression in a GCN2-dependent manner. Under these conditions, enhanced GCN2 activity was not dependent on tRNA sensing, inferring a different activation mechanism. We identified a labile physical interaction between GCN2 and mTOR that results in a phosphorylation of GCN2 on serine 230 by mTOR, which promotes GCN2 activity. When examined under prolonged AA starvation, GCN2 phosphorylation by mTOR promoted survival. Our data unveils an adaptive mechanism to AA starvation, when mTORC1 evades inhibition.
    DOI:  https://doi.org/10.1016/j.jbc.2024.107575
  38. Nat Immunol. 2024 Jul 18.
    T cell dysfunction and therapeutic intervention in cancer.
    Caitlin C Zebley, Dietmar Zehn, Stephen Gottshalk, Hongbo Chi.
      Recent advances in immunotherapy have affirmed the curative potential of T cell-based approaches for treating relapsed and refractory cancers. However, the therapeutic efficacy is limited in part owing to the ability of cancers to evade immunosurveillance and adapt to immunological pressure. In this Review, we provide a brief overview of cancer-mediated immunosuppressive mechanisms with a specific focus on the repression of the surveillance and effector function of T cells. We discuss CD8+ T cell exhaustion and functional heterogeneity and describe strategies for targeting the molecular checkpoints that restrict T cell differentiation and effector function to bolster immunotherapeutic effects. We also delineate the emerging contributions of the tumor microenvironment to T cell metabolism and conclude by highlighting discovery-based approaches for developing future cellular therapies. Continued exploration of T cell biology and engineering hold great promise for advancing therapeutic interventions for cancer.
    DOI:  https://doi.org/10.1038/s41590-024-01896-9
  39. J Biol Chem. 2024 Jul 16. pii: S0021-9258(24)02084-2. [Epub ahead of print] 107583
    Ferroptosis regulation by Cap'n'collar family transcription factors.
    Magdalena B Murray, Scott J Dixon.
      Ferroptosis is an iron-dependent cell death mechanism that may be important to prevent tumor formation and useful as a target for new cancer therapies. Transcriptional networks play a crucial role in shaping ferroptosis sensitivity by regulating the expression of transporters, metabolic enzymes, and other proteins. The Cap'n'collar (CNC) protein nuclear factor erythroid 2 like 2 (NFE2L2, also known as NRF2) is a key regulator of ferroptosis in many cells and contexts. Emerging evidence indicates that the related CNC family members BTB and CNC homology 1 (BACH1) and nuclear factor erythroid 2 like 1 (NFE2L1) also have non-redundant roles in ferroptosis regulation. Here, we comprehensively review the role of CNC transcription factors in governing cellular sensitivity to ferroptosis. We describe how CNC family members regulate ferroptosis sensitivity through modulation of iron, lipid, and redox metabolism. We also use examples of ferroptosis regulation by CNC proteins to illustrate the flexible and highly context-dependent nature of the ferroptosis mechanism between cells and conditions.
    Keywords:  BACH1; NFE2L1; NRF2; Nuclear factor 2 (erythroid‐derived 2‐like factor) (NFE2L2); Oxidative stress; glycosylation; iron metabolism; lipid peroxidation
    DOI:  https://doi.org/10.1016/j.jbc.2024.107583
  40. Nature. 2024 Jul 17.
    Tubulin code eraser CCP5 binds branch glutamates by substrate deformation.
    Jiayi Chen, Elena A Zehr, James M Gruschus, Agnieszka Szyk, Yanjie Liu, Martin E Tanner, Nico Tjandra, Antonina Roll-Mecak.
      Microtubule function is modulated by the tubulin code, diverse posttranslational modifications that are altered dynamically by writer and eraser enzymes1. Glutamylation-the addition of branched (isopeptide-linked) glutamate chains-is the most evolutionarily widespread tubulin modification2. It is introduced by tubulin tyrosine ligase-like enzymes and erased by carboxypeptidases of the cytosolic carboxypeptidase (CCP) family1. Glutamylation homeostasis, achieved through the balance of writers and erasers, is critical for normal cell function3-9, and mutations in CCPs lead to human disease10-13. Here we report cryo-electron microscopy structures of the glutamylation eraser CCP5 in complex with the microtubule, and X-ray structures in complex with transition-state analogues. Combined with NMR analysis, these analyses show that CCP5 deforms the tubulin main chain into a unique turn that enables lock-and-key recognition of the branch glutamate in a cationic pocket that is unique to CCP family proteins. CCP5 binding of the sequences flanking the branch point primarily through peptide backbone atoms enables processing of diverse tubulin isotypes and non-tubulin substrates. Unexpectedly, CCP5 exhibits inefficient processing of an abundant β-tubulin isotype in the brain. This work provides an atomistic view into glutamate branch recognition and resolution, and sheds light on homeostasis of the tubulin glutamylation syntax.
    DOI:  https://doi.org/10.1038/s41586-024-07699-0
  41. bioRxiv. 2024 Jul 04. pii: 2024.07.02.601765. [Epub ahead of print]
    Transcriptional landscape of a hypoxia response identifies cell-specific pathways for adaptation.
    Ji Na Kong, D Dipon Ghosh, Achilleus Savvidis, Steve R Sando, Rita Droste, H Robert Horvitz.
      How the HIF-1 (Hypoxia-Inducible) transcription factor drives and coordinates distinct responses to low oxygen across diverse cell types is poorly understood. We present a multi-tissue single-cell gene-expression atlas of the hypoxia response of the nematode Caenorhabditis elegans . This atlas highlights how cell-type-specific HIF-1 responses overlap and diverge among and within neuronal, intestinal, and muscle tissues. Using the atlas to guide functional analyses of candidate muscle-specific HIF-1 effectors, we discovered that HIF-1 activation drives downregulation of the tspo-1 ( TSPO, Translocator Protein) gene in vulval muscle cells to modulate a hypoxia-driven change in locomotion caused by contraction of body-wall muscle cells. We further showed that in human cardiomyocytes HIF-1 activation decreases levels of TSPO and thereby alters intracellular cholesterol transport and the mitochondrial network. We suggest that TSPO-1 is an evolutionarily conserved mediator of HIF-1-dependent modulation of muscle and conclude that our gene-expression atlas can help reveal how HIF-1 drives cell-specific adaptations to hypoxia.
    DOI:  https://doi.org/10.1101/2024.07.02.601765
  42. Nature. 2024 Jul 17.
    Inhibition of IL-11 signalling extends mammalian healthspan and lifespan.
    Anissa A Widjaja, Wei-Wen Lim, Sivakumar Viswanathan, Sonia Chothani, Ben Corden, Cibi Mary Dasan, Joyce Wei Ting Goh, Radiance Lim, Brijesh K Singh, Jessie Tan, Chee Jian Pua, Sze Yun Lim, Eleonora Adami, Sebastian Schafer, Benjamin L George, Mark Sweeney, Chen Xie, Madhulika Tripathi, Natalie A Sims, Norbert Hübner, Enrico Petretto, Dominic J Withers, Lena Ho, Jesus Gil, David Carling, Stuart A Cook.
      For healthspan and lifespan, ERK, AMPK and mTORC1 represent critical pathways and inflammation is a centrally important hallmark1-7. Here we examined whether IL-11, a pro-inflammatory cytokine of the IL-6 family, has a negative effect on age-associated disease and lifespan. As mice age, IL-11 is upregulated across cell types and tissues to regulate an ERK-AMPK-mTORC1 axis to modulate cellular, tissue- and organismal-level ageing pathologies. Deletion of Il11 or Il11ra1 protects against metabolic decline, multi-morbidity and frailty in old age. Administration of anti-IL-11 to 75-week-old mice for 25 weeks improves metabolism and muscle function, and reduces ageing biomarkers and frailty across sexes. In lifespan studies, genetic deletion of Il11 extended the lives of mice of both sexes, by 24.9% on average. Treatment with anti-IL-11 from 75 weeks of age until death extends the median lifespan of male mice by 22.5% and of female mice by 25%. Together, these results demonstrate a role for the pro-inflammatory factor IL-11 in mammalian healthspan and lifespan. We suggest that anti-IL-11 therapy, which is currently in early-stage clinical trials for fibrotic lung disease, may provide a translational opportunity to determine the effects of IL-11 inhibition on ageing pathologies in older people.
    DOI:  https://doi.org/10.1038/s41586-024-07701-9
  43. bioRxiv. 2024 Jul 14. pii: 2024.07.12.603313. [Epub ahead of print]
    Acetate drives ovarian cancer quiescence via ACSS2-mediated acetyl-CoA production.
    Allison C Sharrow, Emily Megill, Amanda J Chen, Afifa Farooqi, Stacy McGonigal, Nadine Hempel, Nathaniel W Snyder, Ronald J Buckanovich, Katherine M Aird.
      Quiescence is a reversible cell cycle exit traditionally thought to be associated with a metabolically inactive state. Recent work in muscle cells indicates that metabolic reprogramming is associated with quiescence. Whether metabolic changes occur in cancer to drive quiescence is unclear. Using a multi-omics approach, we found that the metabolic enzyme ACSS2, which converts acetate into acetyl-CoA, is both highly upregulated in quiescent ovarian cancer cells and required for their survival. Indeed, quiescent ovarian cancer cells have increased levels of acetate-derived acetyl-CoA, confirming increased ACSS2 activity in these cells. Furthermore, either inducing ACSS2 expression or supplementing cells with acetate was sufficient to induce a reversible quiescent cell cycle exit. RNA-Seq of acetate treated cells confirmed negative enrichment in multiple cell cycle pathways as well as enrichment of genes in a published G0 gene signature. Finally, analysis of patient data showed that ACSS2 expression is upregulated in tumor cells from ascites, which are thought to be more quiescent, compared to matched primary tumors. Additionally, high ACSS2 expression is associated with platinum resistance and worse outcomes. Together, this study points to a previously unrecognized ACSS2-mediated metabolic reprogramming that drives quiescence in ovarian cancer. As chemotherapies to treat ovarian cancer, such as platinum, have increased efficacy in highly proliferative cells, our data give rise to the intriguing question that metabolically-driven quiescence may affect therapeutic response.
    DOI:  https://doi.org/10.1101/2024.07.12.603313
  44. bioRxiv. 2024 Jul 07. pii: 2024.07.05.602260. [Epub ahead of print]
    Frequent transitions in self-assembly across the evolution of a central metabolic enzyme.
    Franziska L Sendker, Tabea Schlotthauer, Christopher-Nils Mais, Yat Kei Lo, Mathias Girbig, Stefan Bohn, Thomas Heimerl, Daniel Schindler, Arielle Weinstein, Brain P Metzger, Joseph W Thornton, Arvind Pillai, Gert Bange, Jan M Schuller, Georg K A Hochberg.
      Many enzymes assemble into homomeric protein complexes comprising multiple copies of one protein. Because structural form is usually assumed to follow function in biochemistry, these assemblies are thought to evolve because they provide some functional advantage. In many cases, however, no specific advantage is known and, in some cases, quaternary structure varies among orthologs. This has led to the proposition that self-assembly may instead vary neutrally within protein families. The extent of such variation has been difficult to ascertain because quaternary structure has until recently been difficult to measure on large scales. Here, we employ mass photometry, phylogenetics, and structural biology to interrogate the evolution of homo-oligomeric assembly across the entire phylogeny of prokaryotic citrate synthases - an enzyme with a highly conserved function. We discover a menagerie of different assembly types that come and go over the course of evolution, including cases of parallel evolution and reversions from complex to simple assemblies. Functional experiments in vitro and in vivo indicate that evolutionary transitions between different assemblies do not strongly influence enzyme catalysis. Our work suggests that enzymes can wander relatively freely through a large space of possible assemblies and demonstrates the power of characterizing structure-function relationships across entire phylogenies.
    DOI:  https://doi.org/10.1101/2024.07.05.602260
  45. J Clin Invest. 2024 May 30. pii: e176230. [Epub ahead of print]134(14):
    Molecular analysis of primary and metastatic sites in patients with renal cell carcinoma.
    Shuchi Gulati, Pedro C Barata, Andrew Elliott, Mehmet Asim Bilen, Earle F Burgess, Toni K Choueiri, Sourat Darabi, Nancy Ann Dawson, Benjamin Adam Gartrell, Hans J Hammers, Elisabeth I Heath, Daniel Magee, Arpit Rao, Charles J Ryan, Przemyslaw Twardowski, Shuanzeng Wei, James Brugarolas, Tian Zhang, Matthew R Zibelman, Chadi Nabhan, Rana R McKay.
      BACKGROUNDMetastases are the hallmark of lethal cancer, though underlying mechanisms that drive metastatic spread to specific organs remain poorly understood. Renal cell carcinoma (RCC) is known to have distinct sites of metastases, with lung, bone, liver, and lymph nodes being more common than brain, gastrointestinal tract, and endocrine glands. Previous studies have shown varying clinical behavior and prognosis associated with the site of metastatic spread; however, little is known about the molecular underpinnings that contribute to the differential outcomes observed by the site of metastasis.METHODSWe analyzed primary renal tumors and tumors derived from metastatic sites to comprehensively characterize genomic and transcriptomic features of tumor cells as well as to evaluate the tumor microenvironment at both sites.RESULTSWe included a total of 657 tumor samples (340 from the primary site [kidney] and 317 from various sites of metastasis). We show distinct genomic alterations, transcriptomic signatures, and immune and stromal tumor microenvironments across metastatic sites in a large cohort of patients with RCC.CONCLUSIONWe demonstrate significant heterogeneity among primary tumors and metastatic sites and elucidate the complex interplay between tumor cells and the extrinsic tumor microenvironment that is vital for developing effective anticancer therapies.
    Keywords:  Cancer; Oncology
    DOI:  https://doi.org/10.1172/JCI176230
  46. Bio Protoc. 2024 Jul 05. 14(13): e5028
    Analysis and Quantification of the Mitochondrial-ER Lipidome.
    Alexis R Diaz-Vegas, Anthony S Don, James G Burchfield.
      Mitochondria are vital organelles essential for cellular functions, but their lipid composition and response to stressors are not fully understood. Recent advancements in lipidomics reveal insights into lipid functions, especially their roles in metabolic perturbations and diseases. Previous methods have focused on the protein composition of mitochondria and mitochondrial-associated membranes. The advantage of our technique is that it combines organelle isolation with targeted lipidomics, offering new insights into the composition and dynamics of these organelles in pathological conditions. We developed a mitochondria isolation protocol for L6 myotubes, enabling lipidomics analysis of specific organelles without interference from other cellular compartments. This approach offers a unique opportunity to dissect lipid dynamics within mitochondria and their associated ER compartments under cellular stress. Key features • Analysis and quantification of lipids in mitochondria-ER fraction through liquid chromatography-tandem mass spectrometry-based lipidomics (LC-MS/MS lipidomics). • LC-MS/MS lipidomics provide precise and unbiased information on the lipid composition in in vitro systems. • LC-MS/MS lipidomics facilitates the identification of lipid signatures in mammalian cells.
    Keywords:  Cardiolipin; Ceramides; Endoplasmic reticulum; Lipidomics; Mitochondria; Subcellular fractionation
    DOI:  https://doi.org/10.21769/BioProtoc.5028
  47. Cold Spring Harb Perspect Med. 2024 Jul 15. pii: a041551. [Epub ahead of print]
    Imaging Tumor Metabolism.
    Thomas Ruan, Kayvan R Keshari.
      Molecular imaging-the mapping of molecular and cellular processes in vivo-has the unique capability to interrogate cancer metabolism in its spatial contexts. This work describes the usage of the two most developed modalities for imaging metabolism in vivo: positron emission tomography (PET) and magnetic resonance (MR). These techniques can be used to probe glycolysis, glutamine metabolism, anabolic metabolism, redox state, hypoxia, and extracellular acidification. This review aims to provide an overview of the strengths and limitations of currently available molecular imaging strategies.
    DOI:  https://doi.org/10.1101/cshperspect.a041551
  48. bioRxiv. 2024 Jul 01. pii: 2024.06.27.601041. [Epub ahead of print]
    Sulfur Amino Acid Restriction Enhances Exercise Capacity in Mice by Boosting Fat Oxidation in Muscle.
    Charlotte G Mann, Michael R MacArthur, Jing Zhang, Songlin Gong, Jenna E AbuSalim, Craig J Hunter, Wenyun Lu, Thomas Agius, Alban Longchamp, Florent Allagnat, Joshua Rabinowitz, James R Mitchell, Katrien De Bock, Sarah J Mitchell.
      Dietary restriction of the sulfur-containing amino acids methionine and cysteine (SAAR) improves body composition, enhances insulin sensitivity, and extends lifespan; benefits seen also with endurance exercise. Yet, the impact of SAAR on skeletal muscle remains largely unexplored. Here we demonstrate that one week of SAAR in sedentary, young, male mice increases endurance exercise capacity. Indirect calorimetry showed that SAAR increased lipid oxidation at rest and delayed the onset of carbohydrate utilization during exercise. Transcriptomic analysis revealed increased expression of genes involved in fatty acid catabolism especially in glycolytic muscle following SAAR. These findings were functionally supported by increased fatty acid circulatory turnover flux and muscle β-oxidation. Reducing lipid uptake from circulation through endothelial cell (EC)-specific CD36 deletion attenuated the running phenotype. Mechanistically, VEGF-signaling inhibition prevented exercise increases following SAAR, without affecting angiogenesis, implicating noncanonical VEGF signaling and EC CD36-dependent fatty acid transport in regulating exercise capacity by influencing muscle substrate availability.
    DOI:  https://doi.org/10.1101/2024.06.27.601041
  49. Science. 2024 Jul 19. 385(6706): eadm9238
    The human mitochondrial mRNA structurome reveals mechanisms of gene expression.
    J Conor Moran, Amir Brivanlou, Michele Brischigliaro, Flavia Fontanesi, Silvi Rouskin, Antoni Barrientos.
      The human mitochondrial genome encodes crucial oxidative phosphorylation system proteins, pivotal for aerobic energy transduction. They are translated from nine monocistronic and two bicistronic transcripts whose native structures remain unexplored, posing a gap in understanding mitochondrial gene expression. In this work, we devised the mitochondrial dimethyl sulfate mutational profiling with sequencing (mitoDMS-MaPseq) method and applied detection of RNA folding ensembles using expectation-maximization (DREEM) clustering to unravel the native mitochondrial messenger RNA (mt-mRNA) structurome in wild-type (WT) and leucine-rich pentatricopeptide repeat-containing protein (LRPPRC)-deficient cells. Our findings elucidate LRPPRC's role as a holdase contributing to maintaining mt-mRNA folding and efficient translation. mt-mRNA structural insights in WT mitochondria, coupled with metabolic labeling, unveil potential mRNA-programmed translational pausing and a distinct programmed ribosomal frameshifting mechanism. Our data define a critical layer of mitochondrial gene expression regulation. These mt-mRNA folding maps provide a reference for studying mt-mRNA structures in diverse physiological and pathological contexts.
    DOI:  https://doi.org/10.1126/science.adm9238
  50. Nat Cell Biol. 2024 Jul 15.
    Zeb1 mediates EMT/plasticity-associated ferroptosis sensitivity in cancer cells by regulating lipogenic enzyme expression and phospholipid composition.
    Annemarie Schwab, Zhigang Rao, Jie Zhang, André Gollowitzer, Katharina Siebenkäs, Nino Bindel, Elisabetta D'Avanzo, Ruthger van Roey, Yussuf Hajjaj, Ece Özel, Isabell Armstark, Leonhard Bereuter, Fengting Su, Julia Grander, Ehsan Bonyadi Rad, Arwin Groenewoud, Felix B Engel, George W Bell, Whitney S Henry, José Pedro Friedmann Angeli, Marc P Stemmler, Simone Brabletz, Andreas Koeberle, Thomas Brabletz.
      Therapy resistance and metastasis, the most fatal steps in cancer, are often triggered by a (partial) activation of the epithelial-mesenchymal transition (EMT) programme. A mesenchymal phenotype predisposes to ferroptosis, a cell death pathway exerted by an iron and oxygen-radical-mediated peroxidation of phospholipids containing polyunsaturated fatty acids. We here show that various forms of EMT activation, including TGFβ stimulation and acquired therapy resistance, increase ferroptosis susceptibility in cancer cells, which depends on the EMT transcription factor Zeb1. We demonstrate that Zeb1 increases the ratio of phospholipids containing pro-ferroptotic polyunsaturated fatty acids over cyto-protective monounsaturated fatty acids by modulating the differential expression of the underlying crucial enzymes stearoyl-Co-A desaturase 1 (SCD), fatty acid synthase (FASN), fatty acid desaturase 2 (FADS2), elongation of very long-chain fatty acid 5 (ELOVL5) and long-chain acyl-CoA synthetase 4 (ACSL4). Pharmacological inhibition of selected lipogenic enzymes (SCD and FADS2) allows the manipulation of ferroptosis sensitivity preferentially in high-Zeb1-expressing cancer cells. Our data are of potential translational relevance and suggest a combination of ferroptosis activators and SCD inhibitors for the treatment of aggressive cancers expressing high Zeb1.
    DOI:  https://doi.org/10.1038/s41556-024-01464-1
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