bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2024–06–23
77 papers selected by
Christian Frezza, Universität zu Köln
  1. DYRK1A signalling synchronizes the mitochondrial import pathways for metabolic rewiring.
  2. Metabolic adaptation in epithelial ovarian cancer metastasis.
  3. SETD3 is a mechanosensitive enzyme that methylates actin on His-73 to regulate mitochondrial dynamics and function.
  4. Mitochondrial biology: Unique membrane remodeling from the matrix.
  5. Diet predisposes to pancreatic cancer through cellular nutrient sensing pathways.
  6. A metabolic switch orchestrated by IL-18 and the cyclic dinucleotide cGAMP programs intestinal tolerance.
  7. Mitochondria and cell death.
  8. The regulation of the apoptotic pore-An immunological tightrope walk.
  9. Spatial proteomics of skeletal muscle using thin cryosections reveals metabolic adaptation at the muscle-tendon transition zone.
  10. BMAL1-HIF2α heterodimers contribute to ccRCC.
  11. Mitoferrin2 is a synthetic lethal target for chromosome 8p deleted cancers.
  12. GABAergic disinhibition from the BNST to PNOCARC neurons promotes HFD-induced hyperphagia.
  13. Cancer-associated Histone H3 N-terminal arginine mutations disrupt PRC2 activity and impair differentiation.
  14. No single perfect mouse model of MASH.
  15. Digital telomere measurement by long-read sequencing distinguishes healthy aging from disease.
  16. Short-term cold exposure induces persistent epigenomic memory in brown fat.
  17. Nicotinamide metabolism face-off between macrophages and fibroblasts manipulates the microenvironment in gastric cancer.
  18. Non-consecutive enzyme interactions within TCA cycle supramolecular assembly regulate carbon-nitrogen metabolism.
  19. Gene regulatory networks in disease and ageing.
  20. FilamentID reveals the composition and function of metabolic enzyme polymers during gametogenesis.
  21. Spatial metabolomics in tissue injury and regeneration.
  22. Cell type-specific control and post-translational regulation of specialized metabolism: opening new avenues for plant metabolic engineering.
  23. Manipulating mitochondrial pyruvate carrier function causes metabolic remodeling in corneal myofibroblasts that ameliorates fibrosis.
  24. The initiation of mitochondrial DNA replication.
  25. Tissue-specific roles of mitochondrial unfolded protein response during obesity.
  26. Psychosocial experiences are associated with human brain mitochondrial biology.
  27. G6PD and ACSL3 are synthetic lethal partners of NF2 in Schwann cells.
  28. Deep cell phenotyping and spatial analysis of multiplexed imaging with TRACERx-PHLEX.
  29. Strand-resolved mutagenicity of DNA damage and repair.
  30. Alternative oxidase blunts pseudohypoxia and photoreceptor degeneration due to RPE mitochondrial dysfunction.
  31. PRDX6 augments selenium utilization to limit iron toxicity and ferroptosis.
  32. Orpinolide disrupts a leukemic dependency on cholesterol transport by inhibiting OSBP.
  33. Is mitochondrial morphology important for cellular physiology?
  34. PKD1 mutant clones within cirrhotic livers inhibit steatohepatitis without promoting cancer.
  35. Regulation of cellular and systemic sphingolipid homeostasis.
  36. A metabolomics pipeline highlights microbial metabolism in bloodstream infections.
  37. The SMC5/6 complex prevents genotoxicity upon APOBEC3A-mediated replication stress.
  38. Enhancing mitochondrial proteolysis alleviates alpha-synuclein-mediated cellular toxicity.
  39. Induction of DEPP1 by HIF Mediates Multiple Hallmarks of Ischemic Cardiomyopathy.
  40. Epidermal turnover in the planarian Schmidtea mediterranea involves basal cell extrusion and intestinal digestion.
  41. Dietary isoleucine content defines the metabolic and molecular response to a Western diet.
  42. High resolution long-read telomere sequencing reveals dynamic mechanisms in aging and cancer.
  43. STING orchestrates the neuronal inflammatory stress response in multiple sclerosis.
  44. Oxidative protein folding in the intermembrane space of human mitochondria.
  45. In vivo CRISPR screens reveal SCAF1 and USP15 as drivers of pancreatic cancer.
  46. Why do patients with cancer die?
  47. A druggable cascade links methionine metabolism to epigenomic reprogramming in squamous cell carcinoma.
  48. Low potassium activation of proximal mTOR/AKT signaling is mediated by Kir4.2.
  49. The methylerythritol phosphate pathway as an oxidative stress sense and response system.
  50. A MOZ-TIF2 leukemia mouse model displays KAT6-dependent H3K23 propionylation and overexpression of a set of active developmental genes.
  51. Crosstalk between degradation and bioenergetics: how autophagy and endolysosomal processes regulate energy production.
  52. Non-stem cell lineages as an alternative origin of intestinal tumorigenesis in the context of inflammation.
  53. Exploring the potential of asparagine restriction in solid cancer treatment: recent discoveries, therapeutic implications, and challenges.
  54. Metabolic regulation of misfolded protein import into mitochondria.
  55. Staphylococcal aconitase expression during iron deficiency is controlled by an sRNA-driven feedforward loop and moonlighting activity.
  56. Olfaction regulates peripheral mitophagy and mitochondrial function.
  57. Bidirectional activation of stem-like programs between metastatic cancer and alveolar type 2 cells within the niche.
  58. Targeting the sphingolipid rheostat in IDH1 mut glioma alters cholesterol homeostasis and triggers apoptosis via membrane degradation.
  59. Circadian-driven tissue specificity is constrained under caloric restricted feeding conditions.
  60. Hypoxia-induced CTCF promotes EMT in breast cancer.
  61. Lactate supports cell-autonomous ECM production to sustain metastatic behavior in prostate cancer.
  62. Protein restriction slows the development and progression of pathology in a mouse model of Alzheimer's disease.
  63. PRDX6 contributes to selenocysteine metabolism and ferroptosis resistance.
  64. NLRC5 senses NAD+ depletion, forming a PANoptosome and driving PANoptosis and inflammation.
  65. The role of polyamine metabolism in cellular function and physiology.
  66. Deoxyuridine-rich cytoplasmic DNA antagonizes STING-dependent innate immune responses and sensitizes resistant tumors to anti-PD-L1 therapy.
  67. Optimal transport for automatic alignment of untargeted metabolomic data.
  68. Optimizing the design of time-restricted eating human trials.
  69. Conserved epigenetic hallmarks of T cell aging during immunity and malignancy.
  70. Cellular senescence in normal physiology.
  71. The maintenance of oocytes in the mammalian ovary involves extreme protein longevity.
  72. Deficient brain GABA metabolism leads to widespread impairments of astrocyte and oligodendrocyte function.
  73. Channeling kynurenine.
  74. HLH-30/TFEB rewires the chaperone network to promote proteostasis under conditions of Coenzyme A and Iron-Sulfur Cluster Deficiency.
  75. Suppressed basal mitophagy drives cellular aging phenotypes that can be reversed by a p62-targeting small molecule.
  76. Age-specific and compartment-dependent changes in mitochondrial homeostasis and cytoplasmic viscosity in mouse peripheral neurons.
  77. Activation of the Keap1/Nrf2 pathway suppresses mitochondrial dysfunction, oxidative stress, and motor phenotypes in C9orf72 ALS/FTD models.
  1. Nat Commun. 2024 Jun 20. 15(1): 5265
    DYRK1A signalling synchronizes the mitochondrial import pathways for metabolic rewiring.
    Adinarayana Marada, Corvin Walter, Tamara Suhm, Sahana Shankar, Arpita Nandy, Tilman Brummer, Ines Dhaouadi, F-Nora Vögtle, Chris Meisinger.
      Mitochondria require an extensive proteome to maintain a variety of metabolic reactions, and changes in cellular demand depend on rapid adaptation of the mitochondrial protein composition. The TOM complex, the organellar entry gate for mitochondrial precursors in the outer membrane, is a target for cytosolic kinases to modulate protein influx. DYRK1A phosphorylation of the carrier import receptor TOM70 at Ser91 enables its efficient docking and thus transfer of precursor proteins to the TOM complex. Here, we probe TOM70 phosphorylation in molecular detail and find that TOM70 is not a CK2 target nor import receptor for MIC19 as previously suggested. Instead, we identify TOM20 as a MIC19 import receptor and show off-target inhibition of the DYRK1A-TOM70 axis with the clinically used CK2 inhibitor CX4945 which activates TOM20-dependent import pathways. Taken together, modulation of DYRK1A signalling adapts the central mitochondrial protein entry gate via synchronization of TOM70- and TOM20-dependent import pathways for metabolic rewiring. Thus, DYRK1A emerges as a cytosolic surveillance kinase to regulate and fine-tune mitochondrial protein biogenesis.
    DOI:  https://doi.org/10.1038/s41467-024-49611-4
  2. Biochim Biophys Acta Mol Basis Dis. 2024 Jun 18. pii: S0925-4439(24)00305-3. [Epub ahead of print]1870(7): 167312
    Metabolic adaptation in epithelial ovarian cancer metastasis.
    Mallory I Frederick, Mohamed Z Nassef, Matthew J Borrelli, Siyun Kuang, Adrian Buensuceso, Tushar More, Thekla Cordes, Patrick O'Donoghue, Trevor G Shepherd, Karsten Hiller, Ilka U Heinemann.
      Epithelial ovarian cancer (EOC) is highly lethal due to its unique metastatic characteristics. EOC spheroids enter a non-proliferative state, with hypoxic cores and reduced oncogenic signaling, all of which contribute to tumour dormancy during metastasis. We investigated the metabolomic states of EOC cells progressing through the three steps to metastasis. Metabolomes of adherent, spheroid, and re-adherent cells were validated by isotopic metabolic flux analysis and mitochondrial functional assays to identify metabolic pathways that were previously unknown to promote EOC metastasis. Although spheroids were thought to exist in a dormant state, metabolomic analysis revealed an unexpected upregulation of energy production pathways in spheroids, accompanied by increased abundance of tricarboxylic acid (TCA) cycle and electron transport chain proteins. Tracing of 13C-labelled glucose and glutamine showed increased pyruvate carboxylation and decreased glutamine anaplerosis in spheroids. Increased reductive carboxylation suggests spheroids adjust redox homeostasis by shuttling cytosolic NADPH into mitochondria via isocitrate dehydrogenase. Indeed, we observed spheroids have increased respiratory capacity and mitochondrial ATP production. Relative to adherent cells, spheroids reduced serine consumption and metabolism, processes which were reversed upon spheroid re-adherence. The data reveal a distinct metabolism in EOC spheroids that enhances energy production by the mitochondria while maintaining a dormant state with respect to growth and proliferation. The findings advance our understanding of EOC metastasis and identify the TCA cycle and mitochondrional activity as novel targets to disrupt EOC metastasis, providing new approaches to treat advanced disease.
    Keywords:  Anaplerosis; Metabolomics; Metastasis; Ovarian cancer; Oxidative phosphorylation; Serine; Spheroid; Tricarboxylic acid (TCA) cycle; electron transport chain
    DOI:  https://doi.org/10.1016/j.bbadis.2024.167312
  3. J Cell Sci. 2024 Jun 19. pii: jcs.261268. [Epub ahead of print]
    SETD3 is a mechanosensitive enzyme that methylates actin on His-73 to regulate mitochondrial dynamics and function.
    Vaibhav Deshmukh, James F Martin.
      Mitochondria, which act as sensors of metabolic homeostasis and metabolite signaling, form a dynamic intracellular network of continuously changing shape, size, and localization to respond to localized cellular energy demands. Mitochondrial dynamics and function depend on interactions with the F-actin cytoskeleton that are poorly understood. Here, we show that SET domain protein 3 (SETD3), a recently described actin histidine methyltransferase, directly methylates actin Histidine-73 and enhances F-actin polymerization on mitochondria. SETD3 is a mechano-sensitive enzyme which is localized on the outer mitochondrial membrane and promotes actin polymerization around mitochondrias. SETD3 loss of function leads to diminished F-actin around mitochondria and a decrease in mitochondrial branch length, branch number, and mitochondrial movement. Our functional analysis revealed that SETD3 is required for oxidative phosphorylation and mitochondrial complex I assembly, and function. Our data further indicate that SETD3 regulates F-actin formation around mitochondria and is essential for maintaining mitochondrial morphology, movement, and function. Finally, we discovered that SETD3 levels are regulated by ECM stiffness and regulate mitochondrial shape in response to changes in ECM stiffness. These findings provide new insight into the mechanism for F-actin polymerization around mitochondria.
    Keywords:  Cytoskeleton; Mechanotransduction; Mitochondrial dynamics; Post-translational modifications
    DOI:  https://doi.org/10.1242/jcs.261268
  4. Curr Biol. 2024 Jun 17. pii: S0960-9822(24)00608-0. [Epub ahead of print]34(12): R581-R583
    Mitochondrial biology: Unique membrane remodeling from the matrix.
    Jason A Mears.
      A new study reports the identification of a fission yeast dynamin superfamily protein, Mmc1, that self-assembles on the matrix side of the inner mitochondrial membrane and interacts with subunits of the mitochondrial contact site and cristae organizing system to maintain cristae architecture.
    DOI:  https://doi.org/10.1016/j.cub.2024.05.010
  5. FEBS Lett. 2024 Jun 17.
    Diet predisposes to pancreatic cancer through cellular nutrient sensing pathways.
    Roberta Noè, Alessandro Carrer.
      Pancreatic cancer is a lethal disease with limited effective treatments. A deeper understanding of its molecular mechanisms is crucial to reduce incidence and mortality. Epidemiological evidence suggests a link between diet and disease risk, though dietary recommendations for at-risk individuals remain debated. Here, we propose that cell-intrinsic nutrient sensing pathways respond to specific diet-derived cues to facilitate oncogenic transformation of pancreatic epithelial cells. This review explores how diet influences pancreatic cancer predisposition through nutrient sensing and downstream consequences for (pre-)cancer cell biology. We also examine experimental evidence connecting specific food intake to pancreatic cancer progression, highlighting nutrient sensing as a promising target for therapeutic development to mitigate disease risk.
    Keywords:  carbohydrates; diet; lipids; nutrient sensing; pancreatic cancer
    DOI:  https://doi.org/10.1002/1873-3468.14959
  6. Immunity. 2024 Jun 19. pii: S1074-7613(24)00305-4. [Epub ahead of print]
    A metabolic switch orchestrated by IL-18 and the cyclic dinucleotide cGAMP programs intestinal tolerance.
    Randall T Mertens, Aditya Misra, Peng Xiao, Seungbyn Baek, Joseph M Rone, Davide Mangani, Kisha N Sivanathan, Adedamola S Arojojoye, Samuel G Awuah, Insuk Lee, Guo-Ping Shi, Boryana Petrova, Jeannette R Brook, Ana C Anderson, Richard A Flavell, Naama Kanarek, Martin Hemberg, Roni Nowarski.
      Tissues are exposed to diverse inflammatory challenges that shape future inflammatory responses. While cellular metabolism regulates immune function, how metabolism programs and stabilizes immune states within tissues and tunes susceptibility to inflammation is poorly understood. Here, we describe an innate immune metabolic switch that programs long-term intestinal tolerance. Intestinal interleukin-18 (IL-18) stimulation elicited tolerogenic macrophages by preventing their proinflammatory glycolytic polarization via metabolic reprogramming to fatty acid oxidation (FAO). FAO reprogramming was triggered by IL-18 activation of SLC12A3 (NCC), leading to sodium influx, release of mitochondrial DNA, and activation of stimulator of interferon genes (STING). FAO was maintained in macrophages by a bistable switch that encoded memory of IL-18 stimulation and by intercellular positive feedback that sustained the production of macrophage-derived 2'3'-cyclic GMP-AMP (cGAMP) and epithelial-derived IL-18. Thus, a tissue-reinforced metabolic switch encodes durable immune tolerance in the gut and may enable reconstructing compromised immune tolerance in chronic inflammation.
    Keywords:  IL-18; SLC12A3; bistable circuit; cGAMP; fatty acid oxidation; immunometabolism; intestinal tolerance; macrophage; metabolic reprogramming; metabolic switch
    DOI:  https://doi.org/10.1016/j.immuni.2024.06.001
  7. Nat Cell Biol. 2024 Jun 20.
    Mitochondria and cell death.
    Hannah L Glover, Annabell Schreiner, Grant Dewson, Stephen W G Tait.
      Mitochondria are cellular factories for energy production, calcium homeostasis and iron metabolism, but they also have an unequivocal and central role in intrinsic apoptosis through the release of cytochrome c. While the subsequent activation of proteolytic caspases ensures that cell death proceeds in the absence of collateral inflammation, other phlogistic cell death pathways have been implicated in using, or engaging, mitochondria. Here we discuss the emerging complexities of intrinsic apoptosis controlled by the BCL-2 family of proteins. We highlight the emerging theory that non-lethal mitochondrial apoptotic signalling has diverse biological roles that impact cancer, innate immunity and ageing. Finally, we delineate the role of mitochondria in other forms of cell death, such as pyroptosis, ferroptosis and necroptosis, and discuss mitochondria as central hubs for the intersection and coordination of cell death signalling pathways, underscoring their potential for therapeutic manipulation.
    DOI:  https://doi.org/10.1038/s41556-024-01429-4
  8. Adv Immunol. 2024 ;pii: S0065-2776(24)00029-4. [Epub ahead of print]162 59-108
    The regulation of the apoptotic pore-An immunological tightrope walk.
    Andreas Jenner, Ana J Garcia-Saez.
      Apoptotic pore formation in mitochondria is the pivotal point for cell death during mitochondrial apoptosis. It is regulated by BCL-2 family proteins in response to various cellular stress triggers and mediates mitochondrial outer membrane permeabilization (MOMP). This allows the release of mitochondrial contents into the cytosol, which triggers rapid cell death and clearance through the activation of caspases. However, under conditions of low caspase activity, the mitochondrial contents released into the cytosol through apoptotic pores serve as inflammatory signals and activate various inflammatory responses. In this chapter, we discuss how the formation of the apoptotic pore is regulated by BCL-2 proteins as well as other cellular or mitochondrial proteins and membrane lipids. Moreover, we highlight the importance of sublethal MOMP in the regulation of mitochondrial-activated inflammation and discuss its physiological consequences in the context of pathogen infection and disease and how it can potentially be exploited therapeutically, for example to improve cancer treatment.
    Keywords:  Apoptosis; BCL-2 proteins; MOMP; Mitochondria-associated inflammation; MtDNA
    DOI:  https://doi.org/10.1016/bs.ai.2024.02.004
  9. Cell Rep. 2024 Jun 19. pii: S2211-1247(24)00702-2. [Epub ahead of print]43(7): 114374
    Spatial proteomics of skeletal muscle using thin cryosections reveals metabolic adaptation at the muscle-tendon transition zone.
    Luisa Schmidt, Michael Saynisch, Christian Hoegsbjerg, Andreas Schmidt, Abigail Mackey, Jan-Wilm Lackmann, Stefan Müller, Manuel Koch, Bent Brachvogel, Michael Kjaer, Philipp Antczak, Marcus Krüger.
      Morphological studies of skeletal muscle tissue provide insights into the architecture of muscle fibers, the surrounding cells, and the extracellular matrix (ECM). However, a spatial proteomics analysis of the skeletal muscle including the muscle-tendon transition zone is lacking. Here, we prepare cryotome muscle sections of the mouse soleus muscle and measure each slice using short liquid chromatography-mass spectrometry (LC-MS) gradients. We generate 3,000 high-resolution protein profiles that serve as the basis for a network analysis to reveal the complex architecture of the muscle-tendon junction. Among the protein profiles that increase from muscle to tendon, we find proteins related to neuronal activity, fatty acid biosynthesis, and the renin-angiotensin system (RAS). Blocking the RAS in cultured mouse tenocytes using losartan reduces the ECM synthesis. Overall, our analysis of thin cryotome sections provides a spatial proteome of skeletal muscle and reveals that the RAS acts as an additional regulator of the matrix within muscle-tendon junctions.
    Keywords:  CP: Metabolism; distance-based network; myotendinous junction; skeletal muscle; spatial proteomics
    DOI:  https://doi.org/10.1016/j.celrep.2024.114374
  10. bioRxiv. 2024 Jun 09. pii: 2024.06.07.597806. [Epub ahead of print]
    BMAL1-HIF2α heterodimers contribute to ccRCC.
    Rebecca M Mello, Diego Gomez Ceballos, Colby R Sandate, Daniel Agudelo, Celine Jouffe, Nina Henriette Uhlenhaut, Nicolas H Thomä, M Celeste Simon, Katja A Lamia.
      Circadian disruption enhances cancer risk, and many tumors exhibit disordered circadian gene expression. We show rhythmic gene expression is unexpectedly robust in clear cell renal cell carcinoma (ccRCC). Furthermore, the clock gene BMAL1 is higher in ccRCC than in healthy kidneys, unlike in other tumor types. BMAL1 is closely related to ARNT, and we show that BMAL1-HIF2α regulates a subset of HIF2α target genes in ccRCC cells. Depletion of BMAL1 reprograms HIF2α chromatin association and target gene expression and reduces ccRCC growth in culture and in xenografts. Analysis of pre-existing data reveals higher BMAL1 in patient-derived xenografts that are sensitive to growth suppression by a HIF2α antagonist (PT2399). We show that BMAL1-HIF2α is more sensitive than ARNT-HIF2α to suppression by PT2399, and increasing BMAL1 sensitizes 786O cells to growth inhibition by PT2399. Together, these findings indicate that an alternate HIF2α heterodimer containing the circadian partner BMAL1 contributes to HIF2α activity, growth, and sensitivity to HIF2α antagonist drugs in ccRCC cells.
    DOI:  https://doi.org/10.1101/2024.06.07.597806
  11. Genome Med. 2024 Jun 17. 16(1): 83
    Mitoferrin2 is a synthetic lethal target for chromosome 8p deleted cancers.
    Stephan Krieg, Thomas Rohde, Tobias Rausch, Luise Butthof, Lena Wendler-Link, Christoph Eckert, Kai Breuhahn, Bruno Galy, Jan Korbel, Maximilian Billmann, Marco Breinig, Darjus F Tschaharganeh.
       BACKGROUND: Somatic copy number alterations are a hallmark of cancer that offer unique opportunities for therapeutic exploitation. Here, we focused on the identification of specific vulnerabilities for tumors harboring chromosome 8p deletions.
    METHODS: We developed and applied an integrative analysis of The Cancer Genome Atlas (TCGA), the Cancer Dependency Map (DepMap), and the Cancer Cell Line Encyclopedia to identify chromosome 8p-specific vulnerabilities. We employ orthogonal gene targeting strategies, both in vitro and in vivo, including short hairpin RNA-mediated gene knockdown and CRISPR/Cas9-mediated gene knockout to validate vulnerabilities.
    RESULTS: We identified SLC25A28 (also known as MFRN2), as a specific vulnerability for tumors harboring chromosome 8p deletions. We demonstrate that vulnerability towards MFRN2 loss is dictated by the expression of its paralog, SLC25A37 (also known as MFRN1), which resides on chromosome 8p. In line with their function as mitochondrial iron transporters, MFRN1/2 paralog protein deficiency profoundly impaired mitochondrial respiration, induced global depletion of iron-sulfur cluster proteins, and resulted in DNA-damage and cell death. MFRN2 depletion in MFRN1-deficient tumors led to impaired growth and even tumor eradication in preclinical mouse xenograft experiments, highlighting its therapeutic potential.
    CONCLUSIONS: Our data reveal MFRN2 as a therapeutic target of chromosome 8p deleted cancers and nominate MFNR1 as the complimentary biomarker for MFRN2-directed therapies.
    Keywords:  Chromosome 8p deletion; MFRN1/2 paralog buffering; SCNAs; Synthetic lethality
    DOI:  https://doi.org/10.1186/s13073-024-01357-w
  12. Cell Rep. 2024 Jun 11. pii: S2211-1247(24)00671-5. [Epub ahead of print]43(6): 114343
    GABAergic disinhibition from the BNST to PNOCARC neurons promotes HFD-induced hyperphagia.
    Tamara Sotelo-Hitschfeld, Marielle Minère, Paul Klemm, Diba Borgmann, Daria Wnuk-Lipinski, Alexander Jais, Xianglian Jia, Svenja Corneliussen, Peter Kloppenburg, Henning Fenselau, Jens Claus Brüning.
      Activation of prepronociceptin (PNOC)-expressing neurons in the arcuate nucleus (ARC) promotes high-fat-diet (HFD)-induced hyperphagia. In turn, PNOCARC neurons can inhibit the anorexic response of proopiomelanocortin (POMC) neurons. Here, we validate the necessity of PNOCARC activity for HFD-induced inhibition of POMC neurons in mice and find that PNOCARC-neuron-dependent inhibition of POMC neurons is mediated by gamma-aminobutyric acid (GABA) release. When monitoring individual PNOCARC neuron activity via Ca2+ imaging, we find a subpopulation of PNOCARC neurons that is inhibited upon gastrointestinal calorie sensing and disinhibited upon HFD feeding. Combining retrograde rabies tracing and circuit mapping, we find that PNOC neurons from the bed nucleus of the stria terminalis (PNOCBNST) provide inhibitory input to PNOCARC neurons, and this inhibitory input is blunted upon HFD feeding. This work sheds light on how an increase in caloric content of the diet can rewire a neuronal circuit, paving the way to overconsumption and obesity development.
    Keywords:  CP: Metabolism; CP: Neuroscience
    DOI:  https://doi.org/10.1016/j.celrep.2024.114343
  13. Nat Commun. 2024 Jun 17. 15(1): 5155
    Cancer-associated Histone H3 N-terminal arginine mutations disrupt PRC2 activity and impair differentiation.
    Benjamin A Nacev, Yakshi Dabas, Matthew R Paul, Christian Pacheco, Michelle Mitchener, Yekaterina Perez, Yan Fang, Alexey A Soshnev, Douglas Barrows, Thomas Carroll, Nicholas D Socci, Samantha C St Jean, Sagarika Tiwari, Michael J Gruss, Sebastien Monette, William D Tap, Benjamin A Garcia, Tom Muir, C David Allis.
      Dysregulated epigenetic states are a hallmark of cancer and often arise from genetic alterations in epigenetic regulators. This includes missense mutations in histones, which, together with associated DNA, form nucleosome core particles. However, the oncogenic mechanisms of most histone mutations are unknown. Here, we demonstrate that cancer-associated histone mutations at arginines in the histone H3 N-terminal tail disrupt repressive chromatin domains, alter gene regulation, and dysregulate differentiation. We find that histone H3R2C and R26C mutants reduce transcriptionally repressive H3K27me3. While H3K27me3 depletion in cells expressing these mutants is exclusively observed on the minor fraction of histone tails harboring the mutations, the same mutants recurrently disrupt broad H3K27me3 domains in the chromatin context, including near developmentally regulated promoters. H3K27me3 loss leads to de-repression of differentiation pathways, with concordant effects between H3R2 and H3R26 mutants despite different proximity to the PRC2 substrate, H3K27. Functionally, H3R26C-expressing mesenchymal progenitor cells and murine embryonic stem cell-derived teratomas demonstrate impaired differentiation. Collectively, these data show that cancer-associated H3 N-terminal arginine mutations reduce PRC2 activity and disrupt chromatin-dependent developmental functions, a cancer-relevant phenotype.
    DOI:  https://doi.org/10.1038/s41467-024-49486-5
  14. Nat Metab. 2024 Jun 12.
    No single perfect mouse model of MASH.
    Russell P Goodman.
      
    DOI:  https://doi.org/10.1038/s42255-024-01052-5
  15. Nat Commun. 2024 Jun 18. 15(1): 5148
    Digital telomere measurement by long-read sequencing distinguishes healthy aging from disease.
    Santiago E Sanchez, Yuchao Gu, Yan Wang, Anudeep Golla, Annika Martin, William Shomali, Dirk Hockemeyer, Sharon A Savage, Steven E Artandi.
      Telomere length is an important biomarker of organismal aging and cellular replicative potential, but existing measurement methods are limited in resolution and accuracy. Here, we deploy digital telomere measurement (DTM) by nanopore sequencing to understand how distributions of human telomere length change with age and disease. We measure telomere attrition and de novo elongation with up to 30 bp resolution in genetically defined populations of human cells, in blood cells from healthy donors and in blood cells from patients with genetic defects in telomere maintenance. We find that human aging is accompanied by a progressive loss of long telomeres and an accumulation of shorter telomeres. In patients with defects in telomere maintenance, the accumulation of short telomeres is more pronounced and correlates with phenotypic severity. We apply machine learning to train a binary classification model that distinguishes healthy individuals from those with telomere biology disorders. This sequencing and bioinformatic pipeline will advance our understanding of telomere maintenance mechanisms and the use of telomere length as a clinical biomarker of aging and disease.
    DOI:  https://doi.org/10.1038/s41467-024-49007-4
  16. Cell Metab. 2024 Jun 12. pii: S1550-4131(24)00187-6. [Epub ahead of print]
    Short-term cold exposure induces persistent epigenomic memory in brown fat.
    Shin-Ichi Inoue, Matthew J Emmett, Hee-Woong Lim, Mohit Midha, Hannah J Richter, Isaac J Celwyn, Rashid Mehmood, Maria Chondronikola, Samuel Klein, Amy K Hauck, Mitchell A Lazar.
      Deficiency of the epigenome modulator histone deacetylase 3 (HDAC3) in brown adipose tissue (BAT) impairs the ability of mice to survive in near-freezing temperatures. Here, we report that short-term exposure to mild cold temperature (STEMCT: 15°C for 24 h) averted lethal hypothermia of mice lacking HDAC3 in BAT (HDAC3 BAT KO) exposed to 4°C. STEMCT restored the induction of the thermogenic coactivator PGC-1α along with UCP1 at 22°C, which is greatly impaired in HDAC3-deficient BAT, and deletion of either UCP1 or PGC-1α prevented the protective effect of STEMCT. Remarkably, this protection lasted for up to 7 days. Transcriptional activator C/EBPβ was induced by short-term cold exposure in mouse and human BAT and, uniquely, remained high for 7 days following STEMCT. Adeno-associated virus-mediated knockdown of BAT C/EBPβ in HDAC3 BAT KO mice erased the persistent memory of STEMCT, revealing the existence of a C/EBPβ-dependent and HDAC3-independent cold-adaptive epigenomic memory.
    Keywords:  C/EBPβ; ERRα; HDAC3; PGC-1α; UCP1; brown adipose tissue; cold memory; mitochondria; oxidative phosphorylation; thermogenesis
    DOI:  https://doi.org/10.1016/j.cmet.2024.05.011
  17. Cell Metab. 2024 Jun 12. pii: S1550-4131(24)00189-X. [Epub ahead of print]
    Nicotinamide metabolism face-off between macrophages and fibroblasts manipulates the microenvironment in gastric cancer.
    Yu Jiang, Yawen Wang, Guofeng Chen, Fei Sun, Qijing Wu, Qiong Huang, Dongqiang Zeng, Wenjun Qiu, Jiao Wang, Zhiqi Yao, Bishan Liang, Shaowei Li, Jianhua Wu, Na Huang, Yuanyuan Wang, Jingsong Chen, Xiaohui Zhai, Li Huang, Beibei Xu, Masami Yamamoto, Tetsuya Tsukamoto, Sachiyo Nomura, Wangjun Liao, Min Shi.
      Immune checkpoint blockade has led to breakthroughs in the treatment of advanced gastric cancer. However, the prominent heterogeneity in gastric cancer, notably the heterogeneity of the tumor microenvironment, highlights the idea that the antitumor response is a reflection of multifactorial interactions. Through transcriptomic analysis and dynamic plasma sample analysis, we identified a metabolic "face-off" mechanism within the tumor microenvironment, as shown by the dual prognostic significance of nicotinamide metabolism. Specifically, macrophages and fibroblasts expressing the rate-limiting enzymes nicotinamide phosphoribosyltransferase and nicotinamide N-methyltransferase, respectively, regulate the nicotinamide/1-methylnicotinamide ratio and CD8+ T cell function. Mechanistically, nicotinamide N-methyltransferase is transcriptionally activated by the NOTCH pathway transcription factor RBP-J and is further inhibited by macrophage-derived extracellular vesicles containing nicotinamide phosphoribosyltransferase via the SIRT1/NICD axis. Manipulating nicotinamide metabolism through autologous injection of extracellular vesicles restored CD8+ T cell cytotoxicity and the anti-PD-1 response in gastric cancer.
    Keywords:  crosstalk; face-off; fibroblast; gastric cancer; immune checkpoint blockade; macrophage; nicotinamide metabolism; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.cmet.2024.05.013
  18. Nat Commun. 2024 Jun 20. 15(1): 5285
    Non-consecutive enzyme interactions within TCA cycle supramolecular assembly regulate carbon-nitrogen metabolism.
    Weronika Jasinska, Mirco Dindo, Sandra M C Cordoba, Adrian W R Serohijos, Paola Laurino, Yariv Brotman, Shimon Bershtein.
      Enzymes of the central metabolism tend to assemble into transient supramolecular complexes. However, the functional significance of the interactions, particularly between enzymes catalyzing non-consecutive reactions, remains unclear. Here, by co-localizing two non-consecutive enzymes of the TCA cycle from Bacillus subtilis, malate dehydrogenase (MDH) and isocitrate dehydrogenase (ICD), in phase separated droplets we show that MDH-ICD interaction leads to enzyme agglomeration with a concomitant enhancement of ICD catalytic rate and an apparent sequestration of its reaction product, 2-oxoglutarate. Theory demonstrates that MDH-mediated clustering of ICD molecules explains the observed phenomena. In vivo analyses reveal that MDH overexpression leads to accumulation of 2-oxoglutarate and reduction of fluxes flowing through both the catabolic and anabolic branches of the carbon-nitrogen intersection occupied by 2-oxoglutarate, resulting in impeded ammonium assimilation and reduced biomass production. Our findings suggest that the MDH-ICD interaction is an important coordinator of carbon-nitrogen metabolism.
    DOI:  https://doi.org/10.1038/s41467-024-49646-7
  19. Nat Rev Nephrol. 2024 Jun 12.
    Gene regulatory networks in disease and ageing.
    Paula Unger Avila, Tsimafei Padvitski, Ana Carolina Leote, He Chen, Julio Saez-Rodriguez, Martin Kann, Andreas Beyer.
      The precise control of gene expression is required for the maintenance of cellular homeostasis and proper cellular function, and the declining control of gene expression with age is considered a major contributor to age-associated changes in cellular physiology and disease. The coordination of gene expression can be represented through models of the molecular interactions that govern gene expression levels, so-called gene regulatory networks. Gene regulatory networks can represent interactions that occur through signal transduction, those that involve regulatory transcription factors, or statistical models of gene-gene relationships based on the premise that certain sets of genes tend to be coexpressed across a range of conditions and cell types. Advances in experimental and computational technologies have enabled the inference of these networks on an unprecedented scale and at unprecedented precision. Here, we delineate different types of gene regulatory networks and their cell-biological interpretation. We describe methods for inferring such networks from large-scale, multi-omics datasets and present applications that have aided our understanding of cellular ageing and disease mechanisms.
    DOI:  https://doi.org/10.1038/s41581-024-00849-7
  20. Cell. 2024 Jun 20. pii: S0092-8674(24)00452-5. [Epub ahead of print]187(13): 3303-3318.e18
    FilamentID reveals the composition and function of metabolic enzyme polymers during gametogenesis.
    Jannik Hugener, Jingwei Xu, Rahel Wettstein, Lydia Ioannidi, Daniel Velikov, Florian Wollweber, Adrian Henggeler, Joao Matos, Martin Pilhofer.
      Gamete formation and subsequent offspring development often involve extended phases of suspended cellular development or even dormancy. How cells adapt to recover and resume growth remains poorly understood. Here, we visualized budding yeast cells undergoing meiosis by cryo-electron tomography (cryoET) and discovered elaborate filamentous assemblies decorating the nucleus, cytoplasm, and mitochondria. To determine filament composition, we developed a "filament identification" (FilamentID) workflow that combines multiscale cryoET/cryo-electron microscopy (cryoEM) analyses of partially lysed cells or organelles. FilamentID identified the mitochondrial filaments as being composed of the conserved aldehyde dehydrogenase Ald4ALDH2 and the nucleoplasmic/cytoplasmic filaments as consisting of acetyl-coenzyme A (CoA) synthetase Acs1ACSS2. Structural characterization further revealed the mechanism underlying polymerization and enabled us to genetically perturb filament formation. Acs1 polymerization facilitates the recovery of chronologically aged spores and, more generally, the cell cycle re-entry of starved cells. FilamentID is broadly applicable to characterize filaments of unknown identity in diverse cellular contexts.
    Keywords:  cellular stress; in situ structure; integrative structural biology; metabolism; method development; multiscale imaging; protein filaments; quiescence; starvation
    DOI:  https://doi.org/10.1016/j.cell.2024.04.026
  21. Curr Opin Genet Dev. 2024 Jun 19. pii: S0959-437X(24)00072-8. [Epub ahead of print]87 102223
    Spatial metabolomics in tissue injury and regeneration.
    Rosalie Gj Rietjens, Gangqi Wang, Bernard M van den Berg, Ton J Rabelink.
      Tissue homeostasis is intricately linked to cellular metabolism and metabolite exchange within the tissue microenvironment. The orchestration of adaptive cellular responses during injury and repair depends critically upon metabolic adaptation. This adaptation, in turn, shapes cell fate decisions required for the restoration of tissue homeostasis. Understanding the nuances of metabolic processes within the tissue context and comprehending the intricate communication between cells is therefore imperative for unraveling the complexity of tissue homeostasis and the processes of injury and repair. In this review, we focus on mass spectrometry imaging as an advanced platform with the potential to provide such comprehensive insights into the metabolic instruction governing tissue function. Recent advances in this technology allow to decipher the intricate metabolic networks that determine cellular behavior in the context of tissue resilience, injury, and repair. These insights not only advance our fundamental understanding of tissue biology but also hold implications for therapeutic interventions by targeting metabolic pathways critical for maintaining tissue homeostasis.
    DOI:  https://doi.org/10.1016/j.gde.2024.102223
  22. Curr Opin Plant Biol. 2024 Jun 19. pii: S1369-5266(24)00066-9. [Epub ahead of print]81 102575
    Cell type-specific control and post-translational regulation of specialized metabolism: opening new avenues for plant metabolic engineering.
    Nikolaos Ntelkis, Alain Goossens, Krešimir Šola.
      Although plant metabolic engineering enables the sustainable production of valuable metabolites with many applications, we still lack a good understanding of many multi-layered regulatory networks that govern metabolic pathways at the metabolite, protein, transcriptional and cellular level. As transcriptional regulation is better understood and often reviewed, here we highlight recent advances in the cell type-specific and post-translational regulation of plant specialized metabolism. With the advent of single-cell technologies, we are now able to characterize metabolites and their transcriptional regulators at the cellular level, which can refine our searches for missing biosynthetic enzymes and cell type-specific regulators. Post-translational regulation through enzyme inhibition, protein phosphorylation and ubiquitination are clearly evident in specialized metabolism regulation, but not frequently studied or considered in metabolic engineering efforts. Finally, we contemplate how advances in cell type-specific and post-translational regulation can be applied in metabolic engineering efforts in planta, leading to optimization of plants as metabolite production vehicles.
    Keywords:  Cell-specific regulation; Enzyme inhibition; Metabolic engineering; Post-translational regulation; Single-cell omics; Specialized metabolism
    DOI:  https://doi.org/10.1016/j.pbi.2024.102575
  23. Redox Biol. 2024 Jun 08. pii: S2213-2317(24)00213-1. [Epub ahead of print]75 103235
    Manipulating mitochondrial pyruvate carrier function causes metabolic remodeling in corneal myofibroblasts that ameliorates fibrosis.
    Kye-Im Jeon, Ankita Kumar, Paul S Brookes, Keith Nehrke, Krystel R Huxlin.
      Myofibroblasts are key cellular effectors of corneal wound healing from trauma, surgery, or infection. However, their persistent deposition of disorganized extracellular matrix can also cause corneal fibrosis and visual impairment. Recent work showed that the PPARγ agonist Troglitazone can mitigate established corneal fibrosis, and parallel in vitro data suggested this occurred through inhibition of the mitochondrial pyruvate carrier (MPC) rather than PPARγ. In addition to oxidative phosphorylation (Ox-Phos), pyruvate and other mitochondrial metabolites provide carbon for the synthesis of biological macromolecules. However, it is currently unclear how these roles selectively impact fibrosis. Here, we performed bioenergetic, metabolomic, and epigenetic analyses of corneal fibroblasts treated with TGF-β1 to stimulate myofibroblast trans-differentiation, with further addition of Troglitazone or the MPC inhibitor UK5099, to identify MPC-dependencies that may facilitate remodeling and loss of the myofibroblast phenotype. Our results show that a shift in energy metabolism is associated with, but not sufficient to drive cellular remodeling. Metabolites whose abundances were sensitive to MPC inhibition suggest that sustained carbon influx into the Krebs' cycle is prioritized over proline synthesis to fuel collagen deposition. Furthermore, increased abundance of acetyl-CoA and increased histone H3 acetylation suggest that epigenetic mechanisms downstream of metabolic remodeling may reinforce cellular phenotypes. Overall, our results highlight a novel molecular target and metabolic vulnerability that affects myofibroblast persistence in the context of corneal wounding.
    Keywords:  Cornea; Fibrosis; Metabolomics; Mitochondria; Pyruvate
    DOI:  https://doi.org/10.1016/j.redox.2024.103235
  24. Biochem Soc Trans. 2024 Jun 17. pii: BST20230952. [Epub ahead of print]
    The initiation of mitochondrial DNA replication.
    Yi Liu, Haibin Liu, Fan Zhang, Hong Xu.
      Mitochondrial DNA replication is initiated by the transcription of mitochondrial RNA polymerase (mtRNAP), as mitochondria lack a dedicated primase. However, the mechanism determining the switch between continuous transcription and premature termination to generate RNA primers for mitochondrial DNA (mtDNA) replication remains unclear. The pentatricopeptide repeat domain of mtRNAP exhibits exoribonuclease activity, which is required for the initiation of mtDNA replication in Drosophila. In this review, we explain how this exonuclease activity contributes to primer synthesis in strand-coupled mtDNA replication, and discuss how its regulation might co-ordinate mtDNA replication and transcription in both Drosophila and mammals.
    Keywords:  PPR; RNA polymerase; exonucleases; mitochondria; mtDNA; replication
    DOI:  https://doi.org/10.1042/BST20230952
  25. Obes Rev. 2024 Jun 16. e13791
    Tissue-specific roles of mitochondrial unfolded protein response during obesity.
    Fernanda S Carneiro, Carlos K Katashima, Joshua D Dodge, Dennys E Cintra, José Rodrigo Pauli, Adelino S R Da Silva, Eduardo R Ropelle.
      Obesity is a worldwide multifactorial disease caused by an imbalance in energy metabolism, increasing adiposity, weight gain, and promoting related diseases such as diabetes, cardiovascular diseases, neurodegeneration, and cancer. Recent findings have reported that metabolic stress related to obesity induces a mitochondrial stress response called mitochondrial unfolded protein response (UPRmt), a quality control pathway that occurs in a nuclear DNA-mitochondria crosstalk, causing transduction of chaperones and proteases under stress conditions. The duality of UPRmt signaling, with both beneficial and detrimental effects, acts in different contexts depending on the tissue, cell type, and physiological states, affecting the mitochondrial function and efficiency and the metabolism homeostasis during obesity, which remains not fully clarified. Therefore, this review discusses the most recent findings regarding UPRmt signaling during obesity, bringing an overview of UPRmt across different metabolic tissues.
    Keywords:  metabolism; mitochondria; mitochondrial unfolded protein response; obesity
    DOI:  https://doi.org/10.1111/obr.13791
  26. Proc Natl Acad Sci U S A. 2024 Jul 02. 121(27): e2317673121
    Psychosocial experiences are associated with human brain mitochondrial biology.
    Caroline Trumpff, Anna S Monzel, Carmen Sandi, Vilas Menon, Hans-Ulrich Klein, Masashi Fujita, Annie Lee, Vladislav A Petyuk, Cheyenne Hurst, Duc M Duong, Nicholas T Seyfried, Aliza P Wingo, Thomas S Wingo, Yanling Wang, Madhav Thambisetty, Luigi Ferrucci, David A Bennett, Philip L De Jager, Martin Picard.
      Psychosocial experiences affect brain health and aging trajectories, but the molecular pathways underlying these associations remain unclear. Normal brain function relies on energy transformation by mitochondria oxidative phosphorylation (OxPhos). Two main lines of evidence position mitochondria both as targets and drivers of psychosocial experiences. On the one hand, chronic stress exposure and mood states may alter multiple aspects of mitochondrial biology; on the other hand, functional variations in mitochondrial OxPhos capacity may alter social behavior, stress reactivity, and mood. But are psychosocial exposures and subjective experiences linked to mitochondrial biology in the human brain? By combining longitudinal antemortem assessments of psychosocial factors with postmortem brain (dorsolateral prefrontal cortex) proteomics in older adults, we find that higher well-being is linked to greater abundance of the mitochondrial OxPhos machinery, whereas higher negative mood is linked to lower OxPhos protein content. Combined, positive and negative psychosocial factors explained 18 to 25% of the variance in the abundance of OxPhos complex I, the primary biochemical entry point that energizes brain mitochondria. Moreover, interrogating mitochondrial psychobiological associations in specific neuronal and nonneuronal brain cells with single-nucleus RNA sequencing (RNA-seq) revealed strong cell-type-specific associations for positive psychosocial experiences and mitochondria in glia but opposite associations in neurons. As a result, these "mind-mitochondria" associations were masked in bulk RNA-seq, highlighting the likely underestimation of true psychobiological effect sizes in bulk brain tissues. Thus, self-reported psychosocial experiences are linked to human brain mitochondrial phenotypes.
    Keywords:  mitochondria; proteome; psychosocial factors; single cell RNA-seq; transcriptome
    DOI:  https://doi.org/10.1073/pnas.2317673121
  27. Nat Commun. 2024 Jun 15. 15(1): 5115
    G6PD and ACSL3 are synthetic lethal partners of NF2 in Schwann cells.
    Athena Kyrkou, Robert Valla, Yao Zhang, Giulia Ambrosi, Stephanie Laier, Karin Müller-Decker, Michael Boutros, Aurelio A Teleman.
      Neurofibromatosis Type II (NFII) is a genetic condition caused by loss of the NF2 gene, resulting in activation of the YAP/TAZ pathway and recurrent Schwann cell tumors, as well as meningiomas and ependymomas. Unfortunately, few pharmacological options are available for NFII. Here, we undertake a genome-wide CRISPR/Cas9 screen to search for synthetic-lethal genes that, when inhibited, cause death of NF2 mutant Schwann cells but not NF2 wildtype cells. We identify ACSL3 and G6PD as two synthetic-lethal partners for NF2, both involved in lipid biogenesis and cellular redox. We find that NF2 mutant Schwann cells are more oxidized than control cells, in part due to reduced expression of genes involved in NADPH generation such as ME1. Since G6PD and ME1 redundantly generate cytosolic NADPH, lack of either one is compatible with cell viability, but not down-regulation of both. Since genetic deficiency for G6PD is tolerated in the human population, G6PD could be a good pharmacological target for NFII.
    DOI:  https://doi.org/10.1038/s41467-024-49298-7
  28. Nat Commun. 2024 Jun 15. 15(1): 5135
    Deep cell phenotyping and spatial analysis of multiplexed imaging with TRACERx-PHLEX.
    Alastair Magness, Emma Colliver, Katey S S Enfield, Claudia Lee, Masako Shimato, Emer Daly, David A Moore, Monica Sivakumar, Karishma Valand, Dina Levi, Crispin T Hiley, Philip S Hobson, Febe van Maldegem, James L Reading, Sergio A Quezada, Julian Downward, Erik Sahai, Charles Swanton, Mihaela Angelova.
      The growing scale and dimensionality of multiplexed imaging require reproducible and comprehensive yet user-friendly computational pipelines. TRACERx-PHLEX performs deep learning-based cell segmentation (deep-imcyto), automated cell-type annotation (TYPEx) and interpretable spatial analysis (Spatial-PHLEX) as three independent but interoperable modules. PHLEX generates single-cell identities, cell densities within tissue compartments, marker positivity calls and spatial metrics such as cellular barrier scores, along with summary graphs and spatial visualisations. PHLEX was developed using imaging mass cytometry (IMC) in the TRACERx study, validated using published Co-detection by indexing (CODEX), IMC and orthogonal data and benchmarked against state-of-the-art approaches. We evaluated its use on different tissue types, tissue fixation conditions, image sizes and antibody panels. As PHLEX is an automated and containerised Nextflow pipeline, manual assessment, programming skills or pathology expertise are not essential. PHLEX offers an end-to-end solution in a growing field of highly multiplexed data and provides clinically relevant insights.
    DOI:  https://doi.org/10.1038/s41467-024-48870-5
  29. Nature. 2024 Jun;630(8017): 744-751
    Strand-resolved mutagenicity of DNA damage and repair.
    Liver Cancer Evolution Consortium
      DNA base damage is a major source of oncogenic mutations1. Such damage can produce strand-phased mutation patterns and multiallelic variation through the process of lesion segregation2. Here we exploited these properties to reveal how strand-asymmetric processes, such as replication and transcription, shape DNA damage and repair. Despite distinct mechanisms of leading and lagging strand replication3,4, we observe identical fidelity and damage tolerance for both strands. For small alkylation adducts of DNA, our results support a model in which the same translesion polymerase is recruited on-the-fly to both replication strands, starkly contrasting the strand asymmetric tolerance of bulky UV-induced adducts5. The accumulation of multiple distinct mutations at the site of persistent lesions provides the means to quantify the relative efficiency of repair processes genome wide and at single-base resolution. At multiple scales, we show DNA damage-induced mutations are largely shaped by the influence of DNA accessibility on repair efficiency, rather than gradients of DNA damage. Finally, we reveal specific genomic conditions that can actively drive oncogenic mutagenesis by corrupting the fidelity of nucleotide excision repair. These results provide insight into how strand-asymmetric mechanisms underlie the formation, tolerance and repair of DNA damage, thereby shaping cancer genome evolution.
    DOI:  https://doi.org/10.1038/s41586-024-07490-1
  30. Proc Natl Acad Sci U S A. 2024 Jun 18. 121(25): e2402384121
    Alternative oxidase blunts pseudohypoxia and photoreceptor degeneration due to RPE mitochondrial dysfunction.
    Ming Chen, Yekai Wang, Roopa Dalal, Jianhai Du, Douglas Vollrath.
      Loss of mitochondrial electron transport complex (ETC) function in the retinal pigment epithelium (RPE) in vivo results in RPE dedifferentiation and progressive photoreceptor degeneration, and has been implicated in the pathogenesis of age-related macular degeneration. Xenogenic expression of alternative oxidases in mammalian cells and tissues mitigates phenotypes arising from some mitochondrial electron transport defects, but can exacerbate others. We expressed an alternative oxidase from Ciona intestinalis (AOX) in ETC-deficient murine RPE in vivo to assess the retinal consequences of stimulating coenzyme Q oxidation and respiration without ATP generation. RPE-restricted expression of AOX in this context is surprisingly beneficial. This focused intervention mitigates RPE mTORC1 activation, dedifferentiation, hypertrophy, stress marker expression, pseudohypoxia, and aerobic glycolysis. These RPE cell autonomous changes are accompanied by increased glucose delivery to photoreceptors with attendant improvements in photoreceptor structure and function. RPE-restricted AOX expression normalizes accumulated levels of succinate and 2-hydroxyglutarate in ETC-deficient RPE, and counteracts deficiencies in numerous neural retinal metabolites. These features can be attributed to the activation of mitochondrial inner membrane flavoproteins such as succinate dehydrogenase and proline dehydrogenase, and alleviation of inhibition of 2-oxyglutarate-dependent dioxygenases such as prolyl hydroxylases and epigenetic modifiers. Our work underscores the importance to outer retinal health of coenzyme Q oxidation in the RPE and identifies a metabolic network critical for photoreceptor survival in the context of RPE mitochondrial dysfunction.
    Keywords:  alternative oxidase; coenzyme Q; mitochondrial dysfunction; retinal pigment epithelium; succinate
    DOI:  https://doi.org/10.1073/pnas.2402384121
  31. Nat Struct Mol Biol. 2024 Jun 12.
    PRDX6 augments selenium utilization to limit iron toxicity and ferroptosis.
    Hiroaki Fujita, Yu-Ki Tanaka, Seiryo Ogata, Noriyuki Suzuki, Sota Kuno, Uladzimir Barayeu, Takaaki Akaike, Yasumitsu Ogra, Kazuhiro Iwai.
      Ferroptosis is a form of regulated cell death induced by iron-dependent accumulation of lipid hydroperoxides. Selenoprotein glutathione peroxidase 4 (GPX4) suppresses ferroptosis by detoxifying lipid hydroperoxides via a catalytic selenocysteine (Sec) residue. Sec, the genetically encoded 21st amino acid, is biosynthesized from a reactive selenium donor on its cognate tRNA[Ser]Sec. It is thought that intracellular selenium must be delivered 'safely' and 'efficiently' by a carrier protein owing to its high reactivity and very low concentrations. Here, we identified peroxiredoxin 6 (PRDX6) as a novel selenoprotein synthesis factor. Loss of PRDX6 decreases the expression of selenoproteins and induces ferroptosis via a reduction in GPX4. Mechanistically, PRDX6 increases the efficiency of intracellular selenium utilization by transferring selenium between proteins within the selenocysteyl-tRNA[Ser]Sec synthesis machinery, leading to efficient synthesis of selenocysteyl-tRNA[Ser]Sec. These findings highlight previously unidentified selenium metabolic systems and provide new insights into ferroptosis.
    DOI:  https://doi.org/10.1038/s41594-024-01329-z
  32. Nat Chem Biol. 2024 Jun 21.
    Orpinolide disrupts a leukemic dependency on cholesterol transport by inhibiting OSBP.
    Marko Cigler, Hana Imrichova, Fabian Frommelt, Lucie Caramelle, Laura Depta, Andrea Rukavina, Chrysanthi Kagiou, J Thomas Hannich, Cristina Mayor-Ruiz, Giulio Superti-Furga, Sonja Sievers, Alison Forrester, Luca Laraia, Herbert Waldmann, Georg E Winter.
      Metabolic alterations in cancer precipitate in associated dependencies that can be therapeutically exploited. To meet this goal, natural product-inspired small molecules can provide a resource of invaluable chemotypes. Here, we identify orpinolide, a synthetic withanolide analog with pronounced antileukemic properties, via orthogonal chemical screening. Through multiomics profiling and genome-scale CRISPR-Cas9 screens, we identify that orpinolide disrupts Golgi homeostasis via a mechanism that requires active phosphatidylinositol 4-phosphate signaling at the endoplasmic reticulum-Golgi membrane interface. Thermal proteome profiling and genetic validation studies reveal the oxysterol-binding protein OSBP as the direct and phenotypically relevant target of orpinolide. Collectively, these data reaffirm sterol transport as a therapeutically actionable dependency in leukemia and motivate ensuing translational investigation via the probe-like compound orpinolide.
    DOI:  https://doi.org/10.1038/s41589-024-01614-4
  33. Trends Endocrinol Metab. 2024 Jun 11. pii: S1043-2760(24)00123-1. [Epub ahead of print]
    Is mitochondrial morphology important for cellular physiology?
    Timothy Wai.
      Mitochondria are double membrane-bound organelles the network morphology of which in cells is shaped by opposing events of fusion and fission executed by dynamin-like GTPases. Mutations in these genes can perturb the form and functions of mitochondria in cell and animal models of mitochondrial diseases. An expanding array of chemical, mechanical, and genetic stressors can converge on mitochondrial-shaping proteins and disrupt mitochondrial morphology. In recent years, studies aimed at disentangling the multiple roles of mitochondrial-shaping proteins beyond fission or fusion have provided insights into the homeostatic relevance of mitochondrial morphology. Here, I review the pleiotropy of mitochondrial fusion and fission proteins with the aim of understanding whether mitochondrial morphology is important for cell and tissue physiology.
    Keywords:  fission and fusion; genetic disease; mitochondrial dynamics; mitochondrial dysfunction; mitochondrial morphology
    DOI:  https://doi.org/10.1016/j.tem.2024.05.005
  34. Cell Metab. 2024 Jun 13. pii: S1550-4131(24)00191-8. [Epub ahead of print]
    PKD1 mutant clones within cirrhotic livers inhibit steatohepatitis without promoting cancer.
    Min Zhu, Yunguan Wang, Tianshi Lu, Jason Guo, Lin Li, Meng-Hsiung Hsieh, Purva Gopal, Yi Han, Naoto Fujiwara, Darren P Wallace, Alan S L Yu, Xiangyi Fang, Crystal Ransom, Sara Verschleisser, David Hsiehchen, Yujin Hoshida, Amit G Singal, Adam Yopp, Tao Wang, Hao Zhu.
      Somatic mutations in non-malignant tissues are selected for because they confer increased clonal fitness. However, it is uncertain whether these clones can benefit organ health. Here, ultra-deep targeted sequencing of 150 liver samples from 30 chronic liver disease patients revealed recurrent somatic mutations. PKD1 mutations were observed in 30% of patients, whereas they were only detected in 1.3% of hepatocellular carcinomas (HCCs). To interrogate tumor suppressor functionality, we perturbed PKD1 in two HCC cell lines and six in vivo models, in some cases showing that PKD1 loss protected against HCC, but in most cases showing no impact. However, Pkd1 haploinsufficiency accelerated regeneration after partial hepatectomy. We tested Pkd1 in fatty liver disease, showing that Pkd1 loss was protective against steatosis and glucose intolerance. Mechanistically, Pkd1 loss selectively increased mTOR signaling without SREBP-1c activation. In summary, PKD1 mutations exert adaptive functionality on the organ level without increasing transformation risk.
    Keywords:  HCC; NASH; PKD1; fatty liver; liver cancer; mTOR; somatic mutations; steatosis
    DOI:  https://doi.org/10.1016/j.cmet.2024.05.015
  35. Nat Rev Mol Cell Biol. 2024 Jun 18.
    Regulation of cellular and systemic sphingolipid homeostasis.
    Andrew Kuo, Timothy Hla.
      One hundred and fifty years ago, Johann Thudichum described sphingolipids as unusual "Sphinx-like" lipids from the brain. Today, we know that thousands of sphingolipid molecules mediate many essential functions in embryonic development and normal physiology. In addition, sphingolipid metabolism and signalling pathways are dysregulated in a wide range of pathologies, and therapeutic agents that target sphingolipids are now used to treat several human diseases. However, our understanding of sphingolipid regulation at cellular and organismal levels and their functions in developmental, physiological and pathological settings is rudimentary. In this Review, we discuss recent advances in sphingolipid pathways in different organelles, how secreted sphingolipid mediators modulate physiology and disease, progress in sphingolipid-targeted therapeutic and diagnostic research, and the trans-cellular sphingolipid metabolic networks between microbiota and mammals. Advances in sphingolipid biology have led to a deeper understanding of mammalian physiology and may lead to progress in the management of many diseases.
    DOI:  https://doi.org/10.1038/s41580-024-00742-y
  36. Cell. 2024 Jun 11. pii: S0092-8674(24)00579-8. [Epub ahead of print]
    A metabolomics pipeline highlights microbial metabolism in bloodstream infections.
    Jared R Mayers, Jack Varon, Ruixuan R Zhou, Martin Daniel-Ivad, Courtney Beaulieu, Amrisha Bholse, Nathaniel R Glasser, Franziska M Lichtenauer, Julie Ng, Mayra Pinilla Vera, Curtis Huttenhower, Mark A Perrella, Clary B Clish, Sihai D Zhao, Rebecca M Baron, Emily P Balskus.
      The growth of antimicrobial resistance (AMR) highlights an urgent need to identify bacterial pathogenic functions that may be targets for clinical intervention. Although severe infections profoundly alter host metabolism, prior studies have largely ignored microbial metabolism in this context. Here, we describe an iterative, comparative metabolomics pipeline to uncover microbial metabolic features in the complex setting of a host and apply it to investigate gram-negative bloodstream infection (BSI) in patients. We find elevated levels of bacterially derived acetylated polyamines during BSI and discover the enzyme responsible for their production (SpeG). Blocking SpeG activity reduces bacterial proliferation and slows pathogenesis. Reduction of SpeG activity also enhances bacterial membrane permeability and increases intracellular antibiotic accumulation, allowing us to overcome AMR in culture and in vivo. This study highlights how tools to study pathogen metabolism in the natural context of infection can reveal and prioritize therapeutic strategies for addressing challenging infections.
    Keywords:  N-acetylputrescine; antibiotic resistance; diacetylspermidine; metabolomics; polyamine/diamine acetyltransferase; polyamines; sepsis
    DOI:  https://doi.org/10.1016/j.cell.2024.05.035
  37. EMBO J. 2024 Jun 17.
    The SMC5/6 complex prevents genotoxicity upon APOBEC3A-mediated replication stress.
    Dylan F Fingerman, David R O'Leary, Ava R Hansen, Thi Tran, Brooke R Harris, Rachel A DeWeerd, Katharina E Hayer, Jiayi Fan, Emily Chen, Mithila Tennakoon, Alice Meroni, Julia H Szeto, Jessica Devenport, Danielle LaVigne, Matthew D Weitzman, Ophir Shalem, Jeffrey Bednarski, Alessandro Vindigni, Xiaolan Zhao, Abby M Green.
      Mutational patterns caused by APOBEC3 cytidine deaminase activity are evident throughout human cancer genomes. In particular, the APOBEC3A family member is a potent genotoxin that causes substantial DNA damage in experimental systems and human tumors. However, the mechanisms that ensure genome stability in cells with active APOBEC3A are unknown. Through an unbiased genome-wide screen, we define the Structural Maintenance of Chromosomes 5/6 (SMC5/6) complex as essential for cell viability when APOBEC3A is active. We observe an absence of APOBEC3A mutagenesis in human tumors with SMC5/6 dysfunction, consistent with synthetic lethality. Cancer cells depleted of SMC5/6 incur substantial genome damage from APOBEC3A activity during DNA replication. Further, APOBEC3A activity results in replication tract lengthening which is dependent on PrimPol, consistent with re-initiation of DNA synthesis downstream of APOBEC3A-induced lesions. Loss of SMC5/6 abrogates elongated replication tracts and increases DNA breaks upon APOBEC3A activity. Our findings indicate that replication fork lengthening reflects a DNA damage response to APOBEC3A activity that promotes genome stability in an SMC5/6-dependent manner. Therefore, SMC5/6 presents a potential therapeutic vulnerability in tumors with active APOBEC3A.
    Keywords:  Cancer Mutagenesis; Cytidine Deaminase; Genome Integrity; Mutational Signatures; Replication Stress
    DOI:  https://doi.org/10.1038/s44318-024-00137-x
  38. NPJ Parkinsons Dis. 2024 Jun 21. 10(1): 120
    Enhancing mitochondrial proteolysis alleviates alpha-synuclein-mediated cellular toxicity.
    Xi Zhang, Linhao Ruan, Hu Wang, Jin Zhu, Taibo Li, Gordon Sun, Yi Dong, Yuhao Wang, Gil Berreby, Ashley Shay, Rong Chen, Sreekumar Ramachandran, Valina L Dawson, Ted M Dawson, Rong Li.
      Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by mitochondrial dysfunction and accumulation of alpha-synuclein (α-Syn)-containing protein aggregates known as Lewy bodies (LB). Here, we investigated the entry of α-Syn into mitochondria to cause mitochondrial dysfunction and loss of cellular fitness in vivo. We show that α-Syn expressed in yeast and human cells is constitutively imported into mitochondria. In a transgenic mouse model, the level of endogenous α-Syn accumulation in mitochondria of dopaminergic neurons and microglia increases with age. The imported α-Syn is degraded by conserved mitochondrial proteases, most notably NLN and PITRM1 (Prd1 and Cym1 in yeast, respectively). α-Syn in the mitochondrial matrix that is not degraded interacts with respiratory chain complexes, leading to loss of mitochondrial DNA (mtDNA), mitochondrial membrane potential and cellular fitness decline. Importantly, enhancing mitochondrial proteolysis by increasing levels of specific proteases alleviated these defects in yeast, human cells, and a PD model of mouse primary neurons. Together, our results provide a direct link between α-synuclein-mediated cellular toxicity and its import into mitochondria and reveal potential therapeutic targets for the treatment of α-synucleinopathies.
    DOI:  https://doi.org/10.1038/s41531-024-00733-y
  39. Circulation. 2024 Jun 17.
    Induction of DEPP1 by HIF Mediates Multiple Hallmarks of Ischemic Cardiomyopathy.
    Gregory A Wyant, Qinqin Jiang, Madhu Singh, Shariq Qayyum, Clara Levrero, Bradley A Maron, William G Kaelin.
       BACKGROUND: HIF (hypoxia inducible factor) regulates many aspects of cardiac function. We and others previously showed that chronic HIF activation in the heart in mouse models phenocopies multiple features of ischemic cardiomyopathy in humans, including mitochondrial loss, lipid accumulation, and systolic cardiac dysfunction. In some settings, HIF also causes the loss of peroxisomes. How, mechanistically, HIF promotes cardiac dysfunction is an open question.
    METHODS: We used mice lacking cardiac pVHL (von Hippel-Lindau protein) to investigate how chronic HIF activation causes multiple features of ischemic cardiomyopathy, such as autophagy induction and lipid accumulation. We performed immunoblot assays, RNA sequencing, mitochondrial and peroxisomal autophagy flux measurements, and live cell imaging on hearts and isolated cardiomyocytes. We used CRISPR-Cas9 gene editing in mice to validate a novel mediator of cardiac dysfunction in the setting of chronic HIF activation.
    RESULTS: We identify a previously unknown pathway by which cardiac HIF activation promotes the loss of mitochondria and peroxisomes. We found that DEPP1 (decidual protein induced by progesterone 1) is induced under hypoxia in a HIF-dependent manner and localizes inside mitochondria. DEPP1 is both necessary and sufficient for hypoxia-induced autophagy and triglyceride accumulation in cardiomyocytes ex vivo. DEPP1 loss increases cardiomyocyte survival in the setting of chronic HIF activation ex vivo, and whole-body Depp1 loss decreases cardiac dysfunction in hearts with chronic HIF activation caused by VHL loss in vivo.
    CONCLUSIONS: Our findings identify DEPP1 as a key component in the cardiac remodeling that occurs with chronic ischemia.
    Keywords:  DEPP1; HIF; VHL; autophagy; cardiomyocyte; hypoxia; mitochondria; peroxisome
    DOI:  https://doi.org/10.1161/CIRCULATIONAHA.123.066628
  40. Cell Rep. 2024 Jun 11. pii: S2211-1247(24)00633-8. [Epub ahead of print] 114305
    Epidermal turnover in the planarian Schmidtea mediterranea involves basal cell extrusion and intestinal digestion.
    Jun-Ru Lee, Tobias Boothe, Clemens Mauksch, Albert Thommen, Jochen C Rink.
      Planarian flatworms undergo continuous internal turnover, wherein old cells are replaced by the division progeny of adult pluripotent stem cells (neoblasts). How cell turnover is carried out at the organismal level remains an intriguing question in planarians and other systems. While previous studies have predominantly focused on neoblast proliferation, little is known about the processes that mediate cell loss during tissue homeostasis. Here, we use the planarian epidermis as a model to study the mechanisms of cell removal. We established a covalent dye-labeling assay and image analysis pipeline to quantify the cell turnover rate in the planarian epidermis. Our findings indicate that the ventral epidermis is highly dynamic and epidermal cells undergo internalization via basal extrusion, followed by a relocation toward the intestine and ultimately digestion by intestinal phagocytes. Overall, our study reveals a complex homeostatic process of cell clearance that may generally allow planarians to catabolize their own cells.
    Keywords:  CP: Developmental biology; Planaria; basal extrusion; cell clearance; cell turnover; epidermis; live imaging; march of death; phagocytes; schmidtea mediterranea
    DOI:  https://doi.org/10.1016/j.celrep.2024.114305
  41. bioRxiv. 2024 Jun 03. pii: 2024.05.30.596340. [Epub ahead of print]
    Dietary isoleucine content defines the metabolic and molecular response to a Western diet.
    Michaela E Trautman, Cara L Green, Michael R MacArthur, Krittisak Chaiyakul, Yasmine H Alam, Chung-Yang Yeh, Reji Babygirija, Isabella James, Michael Gilpin, Esther Zelenovskiy, Madelyn Green, Ryan N Marshall, Michelle M Sonsalla, Victoria Flores, Judith A Simcox, Irene M Ong, Kristen C Malecki, Cholsoon Jang, Dudley W Lamming.
      The amino acid composition of the diet has recently emerged as a critical regulator of metabolic health. Consumption of the branched-chain amino acid isoleucine is positively correlated with body mass index in humans, and reducing dietary levels of isoleucine rapidly improves the metabolic health of diet-induced obese male C57BL/6J mice. However, it is unknown how sex, strain, and dietary isoleucine intake may interact to impact the response to a Western Diet (WD). Here, we find that although the magnitude of the effect varies by sex and strain, reducing dietary levels of isoleucine protects C57BL/6J and DBA/2J mice of both sexes from the deleterious metabolic effects of a WD, while increasing dietary levels of isoleucine impairs aspects of metabolic health. Despite broadly positive responses across all sexes and strains to reduced isoleucine, the molecular response of each sex and strain is highly distinctive. Using a multi-omics approach, we identify a core sex- and strain-independent molecular response to dietary isoleucine, and identify mega-clusters of differentially expressed hepatic genes, metabolites, and lipids associated with each phenotype. Intriguingly, the metabolic effects of reduced isoleucine in mice are not associated with FGF21 - and we find that in humans plasma FGF21 levels are likewise not associated with dietary levels of isoleucine. Finally, we find that foods contain a range of isoleucine levels, and that consumption of dietary isoleucine is lower in humans with healthy eating habits. Our results demonstrate that the dietary level of isoleucine is critical in the metabolic and molecular response to a WD, and suggest that lowering dietary levels of isoleucine may be an innovative and translatable strategy to protect from the negative metabolic consequences of a WD.
    DOI:  https://doi.org/10.1101/2024.05.30.596340
  42. Nat Commun. 2024 Jun 18. 15(1): 5149
    High resolution long-read telomere sequencing reveals dynamic mechanisms in aging and cancer.
    Tobias T Schmidt, Carly Tyer, Preeyesh Rughani, Candy Haggblom, Jeffrey R Jones, Xiaoguang Dai, Kelly A Frazer, Fred H Gage, Sissel Juul, Scott Hickey, Jan Karlseder.
      Telomeres are the protective nucleoprotein structures at the end of linear eukaryotic chromosomes. Telomeres' repetitive nature and length have traditionally challenged the precise assessment of the composition and length of individual human telomeres. Here, we present Telo-seq to resolve bulk, chromosome arm-specific and allele-specific human telomere lengths using Oxford Nanopore Technologies' native long-read sequencing. Telo-seq resolves telomere shortening in five population doubling increments and reveals intrasample, chromosome arm-specific, allele-specific telomere length heterogeneity. Telo-seq can reliably discriminate between telomerase- and ALT-positive cancer cell lines. Thus, Telo-seq is a tool to study telomere biology during development, aging, and cancer at unprecedented resolution.
    DOI:  https://doi.org/10.1038/s41467-024-48917-7
  43. Cell. 2024 Jun 07. pii: S0092-8674(24)00576-2. [Epub ahead of print]
    STING orchestrates the neuronal inflammatory stress response in multiple sclerosis.
    Marcel S Woo, Christina Mayer, Lars Binkle-Ladisch, Jana K Sonner, Sina C Rosenkranz, Artem Shaposhnykov, Nicola Rothammer, Volodymyr Tsvilovskyy, Svenja M Lorenz, Lukas Raich, Lukas C Bal, Vanessa Vieira, Ingrid Wagner, Simone Bauer, Markus Glatzel, Marcus Conrad, Doron Merkler, Marc Freichel, Manuel A Friese.
      Inflammation-induced neurodegeneration is a defining feature of multiple sclerosis (MS), yet the underlying mechanisms remain unclear. By dissecting the neuronal inflammatory stress response, we discovered that neurons in MS and its mouse model induce the stimulator of interferon genes (STING). However, activation of neuronal STING requires its detachment from the stromal interaction molecule 1 (STIM1), a process triggered by glutamate excitotoxicity. This detachment initiates non-canonical STING signaling, which leads to autophagic degradation of glutathione peroxidase 4 (GPX4), essential for neuronal redox homeostasis and thereby inducing ferroptosis. Both genetic and pharmacological interventions that target STING in neurons protect against inflammation-induced neurodegeneration. Our findings position STING as a central regulator of the detrimental neuronal inflammatory stress response, integrating inflammation with glutamate signaling to cause neuronal cell death, and present it as a tractable target for treating neurodegeneration in MS.
    Keywords:  STING; calcium signaling; cell death; excitotoxicity; ferroptosis; multiple sclerosis; neurodegeneration; neuroinflammation
    DOI:  https://doi.org/10.1016/j.cell.2024.05.031
  44. FEBS Open Bio. 2024 Jun 12.
    Oxidative protein folding in the intermembrane space of human mitochondria.
    Christine Zarges, Jan Riemer.
      The mitochondrial intermembrane space hosts a machinery for oxidative protein folding, the mitochondrial disulfide relay. This machinery imports a large number of soluble proteins into the compartment, where they are retained through oxidative folding. Additionally, the disulfide relay enhances the stability of many proteins by forming disulfide bonds. In this review, we describe the mitochondrial disulfide relay in human cells, its components, and their coordinated collaboration in mechanistic detail. We also discuss the human pathologies associated with defects in this machinery and its protein substrates, providing a comprehensive overview of its biological importance and implications for health.
    Keywords:  ALR; IMS; MIA40; mitochondria; oxidative protein folding; protein import
    DOI:  https://doi.org/10.1002/2211-5463.13839
  45. Nat Commun. 2024 Jun 20. 15(1): 5266
    In vivo CRISPR screens reveal SCAF1 and USP15 as drivers of pancreatic cancer.
    Sebastien Martinez, Shifei Wu, Michael Geuenich, Ahmad Malik, Ramona Weber, Tristan Woo, Amy Zhang, Gun Ho Jang, Dzana Dervovic, Khalid N Al-Zahrani, Ricky Tsai, Nassima Fodil, Philippe Gros, Steven Gallinger, G Gregory Neely, Faiyaz Notta, Ataman Sendoel, Kieran Campbell, Ulrich Elling, Daniel Schramek.
      Functionally characterizing the genetic alterations that drive pancreatic cancer is a prerequisite for precision medicine. Here, we perform somatic CRISPR/Cas9 mutagenesis screens to assess the transforming potential of 125 recurrently mutated pancreatic cancer genes, which revealed USP15 and SCAF1 as pancreatic tumor suppressors. Mechanistically, we find that USP15 functions in a haploinsufficient manner and that loss of USP15 or SCAF1 leads to reduced inflammatory TNFα, TGF-β and IL6 responses and increased sensitivity to PARP inhibition and Gemcitabine. Furthermore, we find that loss of SCAF1 leads to the formation of a truncated, inactive USP15 isoform at the expense of full-length USP15, functionally coupling SCAF1 and USP15. Notably, USP15 and SCAF1 alterations are observed in 31% of pancreatic cancer patients. Our results highlight the utility of in vivo CRISPR screens to integrate human cancer genomics and mouse modeling for the discovery of cancer driver genes with potential prognostic and therapeutic implications.
    DOI:  https://doi.org/10.1038/s41467-024-49450-3
  46. Nat Rev Cancer. 2024 Jun 19.
    Why do patients with cancer die?
    Adrienne Boire, Katy Burke, Thomas R Cox, Theresa Guise, Mariam Jamal-Hanjani, Tobias Janowitz, Rosandra Kaplan, Rebecca Lee, Charles Swanton, Matthew G Vander Heiden, Erik Sahai.
      Cancer is a major cause of global mortality, both in affluent countries and increasingly in developing nations. Many patients with cancer experience reduced life expectancy and have metastatic disease at the time of death. However, the more precise causes of mortality and patient deterioration before death remain poorly understood. This scarcity of information, particularly the lack of mechanistic insights, presents a challenge for the development of novel treatment strategies to improve the quality of, and potentially extend, life for patients with late-stage cancer. In addition, earlier deployment of existing strategies to prolong quality of life is highly desirable. In this Roadmap, we review the proximal causes of mortality in patients with cancer and discuss current knowledge about the interconnections between mechanisms that contribute to mortality, before finally proposing new and improved avenues for data collection, research and the development of treatment strategies that may improve quality of life for patients.
    DOI:  https://doi.org/10.1038/s41568-024-00708-4
  47. Proc Natl Acad Sci U S A. 2024 Jun 25. 121(26): e2320835121
    A druggable cascade links methionine metabolism to epigenomic reprogramming in squamous cell carcinoma.
    Chehyun Nam, Li-Yan Li, Qian Yang, Benjamin Ziman, Hua Zhao, Boyan Hu, Casey Collet, Pei Jing, Qifang Lei, Li-Yan Xu, En-Min Li, H Phillip Koeffler, Uttam K Sinha, De-Chen Lin.
      Upper aerodigestive squamous cell carcinoma (UASCC) is a common and aggressive malignancy with few effective therapeutic options. Here, we investigate amino acid metabolism in this cancer, surprisingly noting that UASCC exhibits the highest methionine level across all human cancers, driven by its transporter LAT1. We show that LAT1 is also expressed at the highest level in UASCC, transcriptionally activated by UASCC-specific promoter and enhancers, which are directly coregulated by SCC master regulators TP63/KLF5/SREBF1. Unexpectedly, unbiased bioinformatic screen identifies EZH2 as the most significant target downstream of the LAT1-methionine pathway, directly linking methionine metabolism to epigenomic reprogramming. Importantly, this cascade is indispensable for the survival and proliferation of UASCC patient-derived tumor organoids. In addition, LAT1 expression is closely associated with cellular sensitivity to inhibition of the LAT1-methionine-EZH2 axis. Notably, this unique LAT1-methionine-EZH2 cascade can be targeted effectively by either pharmacological approaches or dietary intervention in vivo. In summary, this work maps a unique mechanistic cross talk between epigenomic reprogramming with methionine metabolism, establishes its biological significance in the biology of UASCC, and identifies a unique tumor-specific vulnerability which can be exploited both pharmacologically and dietarily.
    Keywords:  LAT1; UASCC; cancer metabolism; epigenomics; methionine
    DOI:  https://doi.org/10.1073/pnas.2320835121
  48. Nat Commun. 2024 Jun 17. 15(1): 5144
    Low potassium activation of proximal mTOR/AKT signaling is mediated by Kir4.2.
    Yahua Zhang, Fabian Bock, Mohammed Ferdaus, Juan Pablo Arroyo, Kristie L Rose, Purvi Patel, Jerod S Denton, Eric Delpire, Alan M Weinstein, Ming-Zhi Zhang, Raymond C Harris, Andrew S Terker.
      The renal epithelium is sensitive to changes in blood potassium (K+). We identify the basolateral K+ channel, Kir4.2, as a mediator of the proximal tubule response to K+ deficiency. Mice lacking Kir4.2 have a compensated baseline phenotype whereby they increase their distal transport burden to maintain homeostasis. Upon dietary K+ depletion, knockout animals decompensate as evidenced by increased urinary K+ excretion and development of a proximal renal tubular acidosis. Potassium wasting is not proximal in origin but is caused by higher ENaC activity and depends upon increased distal sodium delivery. Three-dimensional imaging reveals Kir4.2 knockouts fail to undergo proximal tubule expansion, while the distal convoluted tubule response is exaggerated. AKT signaling mediates the dietary K+ response, which is blunted in Kir4.2 knockouts. Lastly, we demonstrate in isolated tubules that AKT phosphorylation in response to low K+ depends upon mTORC2 activation by secondary changes in Cl- transport. Data support a proximal role for cell Cl- which, as it does along the distal nephron, responds to K+ changes to activate kinase signaling.
    DOI:  https://doi.org/10.1038/s41467-024-49562-w
  49. Nat Commun. 2024 Jun 21. 15(1): 5303
    The methylerythritol phosphate pathway as an oxidative stress sense and response system.
    Jordi Perez-Gil, James Behrendorff, Andrew Douw, Claudia E Vickers.
      The methylerythritol phosphate (MEP) pathway is responsible for biosynthesis of the precursors of isoprenoid compounds in eubacteria and plastids. It is a metabolic alternative to the well-known mevalonate pathway for isoprenoid production found in archaea and eukaryotes. Recently, a role for the MEP pathway in oxidative stress detection, signalling, and response has been identified. This role is executed in part through the unusual cyclic intermediate, methylerythritol cyclodiphosphate (MEcDP). We postulate that this response is triggered through the oxygen sensitivity of the MEP pathway's terminal iron-sulfur (Fe-S) cluster enzymes. MEcDP is the substrate of IspG, the first Fe-S cluster enzyme in the pathway; it accumulates under oxidative stress conditions and acts as a signalling molecule. It may also act as an antioxidant. Furthermore, evidence is emerging for a broader and highly nuanced role of the MEP pathway in oxidative stress responses, implemented through a complex system of differential regulation and sensitivity at numerous nodes in the pathway. Here, we explore the evidence for such a role (including the contribution of the Fe-S cluster enzymes and different pathway metabolites, especially MEcDP), the evolutionary implications, and the many questions remaining about the behaviour of the MEP pathway in the presence of oxidative stress.
    DOI:  https://doi.org/10.1038/s41467-024-49483-8
  50. Proc Natl Acad Sci U S A. 2024 Jun 25. 121(26): e2405905121
    A MOZ-TIF2 leukemia mouse model displays KAT6-dependent H3K23 propionylation and overexpression of a set of active developmental genes.
    Anne E Smolko, Daniel W Sullivan, Sarah Naomi Olsen, Hyuckjoon Kang, Samuel D Whedon, Jonathan B Baell, Philip A Cole, Scott A Armstrong, Mitzi I Kuroda.
      Aberrant regulation of chromatin modifiers is a common occurrence across many cancer types, and a key priority is to determine how specific alterations of these proteins, often enzymes, can be targeted therapeutically. MOZ, a histone acyltransferase, is recurrently fused to coactivators CBP, p300, and TIF2 in cases of acute myeloid leukemia (AML). Using either pharmacological inhibition or targeted protein degradation in a mouse model for MOZ-TIF2-driven leukemia, we show that KAT6 (MOZ/MORF) enzymatic activity and the MOZ-TIF2 protein are necessary for indefinite proliferation in cell culture. MOZ-TIF2 directly regulates a small subset of genes encoding developmental transcription factors, augmenting their high expression. Furthermore, transcription levels in MOZ-TIF2 cells positively correlate with enrichment of histone H3 propionylation at lysine 23 (H3K23pr), a recently appreciated histone acylation associated with gene activation. Unexpectedly, we also show that MOZ-TIF2 and MLL-AF9 regulate transcription of unique gene sets, and their cellular models exhibit distinct sensitivities to multiple small-molecule inhibitors directed against AML pathways. This is despite the shared genetic pathways of wild-type MOZ and MLL. Overall, our data provide insight into how aberrant regulation of MOZ contributes to leukemogenesis. We anticipate that these experiments will inform future work identifying targeted therapies in the treatment of AML and other diseases involving MOZ-induced transcriptional dysregulation.
    Keywords:  AML; KAT6; MOZ; propionylation
    DOI:  https://doi.org/10.1073/pnas.2405905121
  51. Neural Regen Res. 2025 Mar 01. 20(3): 671-681
    Crosstalk between degradation and bioenergetics: how autophagy and endolysosomal processes regulate energy production.
    Angelid Pabon, Jagannatham Naidu Bhupana, Ching-On Wong.
      Cells undergo metabolic reprogramming to adapt to changes in nutrient availability, cellular activity, and transitions in cell states. The balance between glycolysis and mitochondrial respiration is crucial for energy production, and metabolic reprogramming stipulates a shift in such balance to optimize both bioenergetic efficiency and anabolic requirements. Failure in switching bioenergetic dependence can lead to maladaptation and pathogenesis. While cellular degradation is known to recycle precursor molecules for anabolism, its potential role in regulating energy production remains less explored. The bioenergetic switch between glycolysis and mitochondrial respiration involves transcription factors and organelle homeostasis, which are both regulated by the cellular degradation pathways. A growing body of studies has demonstrated that both stem cells and differentiated cells exhibit bioenergetic switch upon perturbations of autophagic activity or endolysosomal processes. Here, we highlighted the current understanding of the interplay between degradation processes, specifically autophagy and endolysosomes, transcription factors, endolysosomal signaling, and mitochondrial homeostasis in shaping cellular bioenergetics. This review aims to summarize the relationship between degradation processes and bioenergetics, providing a foundation for future research to unveil deeper mechanistic insights into bioenergetic regulation.
    DOI:  https://doi.org/10.4103/NRR.NRR-D-23-02095
  52. Nat Genet. 2024 Jun 20.
    Non-stem cell lineages as an alternative origin of intestinal tumorigenesis in the context of inflammation.
    Mathijs P Verhagen, Rosalie Joosten, Mark Schmitt, Niko Välimäki, Andrea Sacchetti, Kristiina Rajamäki, Jiahn Choi, Paola Procopio, Sara Silva, Berdine van der Steen, Thierry P P van den Bosch, Danielle Seinstra, Annemarie C de Vries, Michail Doukas, Leonard H Augenlicht, Lauri A Aaltonen, Riccardo Fodde.
      According to conventional views, colon cancer originates from stem cells. However, inflammation, a key risk factor for colon cancer, has been shown to suppress intestinal stemness. Here, we used Paneth cells as a model to assess the capacity of differentiated lineages to trigger tumorigenesis in the context of inflammation in mice. Upon inflammation, Paneth cell-specific Apc mutations led to intestinal tumors reminiscent not only of those arising in patients with inflammatory bowel disease, but also of a larger fraction of human sporadic colon cancers. The latter is possibly because of the inflammatory consequences of western-style dietary habits, a major colon cancer risk factor. Machine learning methods designed to predict the cell-of-origin of cancer from patient-derived tumor samples confirmed that, in a substantial fraction of sporadic cases, the origins of colon cancer reside in secretory lineages and not in stem cells.
    DOI:  https://doi.org/10.1038/s41588-024-01801-y
  53. Med Oncol. 2024 Jun 15. 41(7): 176
    Exploring the potential of asparagine restriction in solid cancer treatment: recent discoveries, therapeutic implications, and challenges.
    Marina Gabriel Fontes, Carolina Silva, William Henry Roldán, Gisele Monteiro.
      Asparagine is a non-essential amino acid crucial for protein biosynthesis and function, and therefore cell maintenance and growth. Furthermore, this amino acid has an important role in regulating several metabolic pathways, such as tricarboxylic acid cycle and the urea cycle. When compared to normal cells, tumor cells typically present a higher demand for asparagine, making it a compelling target for therapy. In this review article, we investigate different facets of asparagine bioavailability intricate role in malignant tumors raised from solid organs. We take a comprehensive look at asparagine synthetase expression and regulation in cancer, including the impact on tumor growth and metastasis. Moreover, we explore asparagine depletion through L-asparaginase as a potential therapeutic method for aggressive solid tumors, approaching different formulations of the enzyme and combinatory therapies. In summary, here we delve into studies about endogenous and exogenous asparagine availability in solid cancers, analyzing therapeutic implications and future challenges.
    Keywords:  Amino acid deprivation; Biopharmaceutical; Cancer metabolism; Metastasis
    DOI:  https://doi.org/10.1007/s12032-024-02424-3
  54. Elife. 2024 Jun 20. pii: RP87518. [Epub ahead of print]12
    Metabolic regulation of misfolded protein import into mitochondria.
    Yuhao Wang, Linhao Ruan, Jin Zhu, Xi Zhang, Alexander Chih-Chieh Chang, Alexis Tomaszewski, Rong Li.
      Mitochondria are the cellular energy hub and central target of metabolic regulation. Mitochondria also facilitate proteostasis through pathways such as the 'mitochondria as guardian in cytosol' (MAGIC) whereby cytosolic misfolded proteins (MPs) are imported into and degraded inside mitochondria. In this study, a genome-wide screen in Saccharomyces cerevisiae uncovered that Snf1, the yeast AMP-activated protein kinase (AMPK), inhibits the import of MPs into mitochondria while promoting mitochondrial biogenesis under glucose starvation. We show that this inhibition requires a downstream transcription factor regulating mitochondrial gene expression and is likely to be conferred through substrate competition and mitochondrial import channel selectivity. We further show that Snf1/AMPK activation protects mitochondrial fitness in yeast and human cells under stress induced by MPs such as those associated with neurodegenerative diseases.
    Keywords:  AMPK; MAGIC; S. cerevisiae; cell biology; human; metabolism; misfolded protein; mitochondria; protein import; proteostasis
    DOI:  https://doi.org/10.7554/eLife.87518
  55. Nucleic Acids Res. 2024 Jun 13. pii: gkae506. [Epub ahead of print]
    Staphylococcal aconitase expression during iron deficiency is controlled by an sRNA-driven feedforward loop and moonlighting activity.
    Maxime Barrault, Svetlana Chabelskaya, Rodrigo H Coronel-Tellez, Claire Toffano-Nioche, Eric Jacquet, Philippe Bouloc.
      Pathogenic bacteria employ complex systems to cope with metal ion shortage conditions and propagate in the host. IsrR is a regulatory RNA (sRNA) whose activity is decisive for optimum Staphylococcus aureus fitness upon iron starvation and for full virulence. IsrR down-regulates several genes encoding iron-containing enzymes to spare iron for essential processes. Here, we report that IsrR regulates the tricarboxylic acid (TCA) cycle by controlling aconitase (CitB), an iron-sulfur cluster-containing enzyme, and its transcriptional regulator, CcpE. This IsrR-dependent dual-regulatory mechanism provides an RNA-driven feedforward loop, underscoring the tight control required to prevent aconitase expression. Beyond its canonical enzymatic role, aconitase becomes an RNA-binding protein with regulatory activity in iron-deprived conditions, a feature that is conserved in S. aureus. Aconitase not only negatively regulates its own expression, but also impacts the enzymes involved in both its substrate supply and product utilization. This moonlighting activity concurrently upregulates pyruvate carboxylase expression, allowing it to compensate for the TCA cycle deficiency associated with iron scarcity. These results highlight the cascade of complex posttranscriptional regulations controlling S. aureus central metabolism in response to iron deficiency.
    DOI:  https://doi.org/10.1093/nar/gkae506
  56. Sci Adv. 2024 Jun 21. 10(25): eadn0014
    Olfaction regulates peripheral mitophagy and mitochondrial function.
    Julian G Dishart, Corinne L Pender, Koning Shen, Hanlin Zhang, Megan Ly, Madison B Webb, Andrew Dillin.
      The central nervous system coordinates peripheral cellular stress responses, including the unfolded protein response of the mitochondria (UPRMT); however, the contexts for which this regulatory capability evolved are unknown. UPRMT is up-regulated upon pathogenic infection and in metabolic flux, and the olfactory nervous system has been shown to regulate pathogen resistance and peripheral metabolic activity. Therefore, we asked whether the olfactory nervous system in Caenorhabditis elegans controls the UPRMT cell nonautonomously. We found that silencing a single inhibitory olfactory neuron pair, AWC, led to robust induction of UPRMT and reduction of oxidative phosphorylation dependent on serotonin signaling and parkin-mediated mitophagy. Further, AWC ablation confers resistance to the pathogenic bacteria Pseudomonas aeruginosa partially dependent on the UPRMT transcription factor atfs-1 and fully dependent on mitophagy machinery. These data illustrate a role for the olfactory nervous system in regulating whole-organism mitochondrial dynamics, perhaps in preparation for postprandial metabolic stress or pathogenic infection.
    DOI:  https://doi.org/10.1126/sciadv.adn0014
  57. Dev Cell. 2024 May 31. pii: S1534-5807(24)00338-1. [Epub ahead of print]
    Bidirectional activation of stem-like programs between metastatic cancer and alveolar type 2 cells within the niche.
    Felipe S Rodrigues, Adam Karoutas, Stefanie Ruhland, Nicolas Rabas, Tatiana Rizou, Stefania Di Blasio, Rute M M Ferreira, Victoria L Bridgeman, Robert Goldstone, Miriam L Sopena, Joo-Hyeon Lee, Luigi Ombrato, Ilaria Malanchi.
      A key step for metastatic outgrowth involves the generation of a deeply altered microenvironment (niche) that supports the malignant behavior of cancer cells. The complexity of the metastatic niche has posed a significant challenge in elucidating the underlying programs driving its origin. Here, by focusing on early stages of breast cancer metastasis to the lung in mice, we describe a cancer-dependent chromatin remodeling and activation of developmental programs in alveolar type 2 (AT2) cells within the niche. We show that metastatic cells can prime AT2 cells into a reprogrammed multilineage state. In turn, this cancer-induced reprogramming of AT2 cells promoted stem-like features in cancer cells and enhanced their initiation capacity. In conclusion, we propose the concept of "reflected stemness" as an early phenomenon during metastatic niche initiation, wherein metastatic cells reprogram the local tissue into a stem-like state that enhances intrinsic cancer-initiating potential, creating a positive feedback loop where tumorigenic programs are amplified.
    Keywords:  Metastasis; Sox9; alveolar type 2 cells; breast cancer; lung stem cells; metastasis-initiating cells; metastatic niche; multilineage state; tissue reprogramming
    DOI:  https://doi.org/10.1016/j.devcel.2024.05.020
  58. bioRxiv. 2024 Apr 27. pii: 2024.04.26.591321. [Epub ahead of print]
    Targeting the sphingolipid rheostat in IDH1 mut glioma alters cholesterol homeostasis and triggers apoptosis via membrane degradation.
    Tyrone Dowdy, Helena Muley Vilamu, Adrian Lita, Aiguo Li, Tomohiro Yamasaki, Lumin Zhang, Raj Chari, Hua Song, Meili Zhang, Wei Zhang, Nicole Briceno, Dionne Davis, Mark R Gilbert, Mioara Larion.
      The cross-regulation of metabolism and trafficking is not well understood for the vital sphingolipids and cholesterol constituents of cellular compartments. While reports are starting to surface on how sphingolipids like sphingomyelin (SM) dysregulate cholesterol levels in different cellular compartments (Jiang et al., 2022), limited research is available on the mechanisms driving the relationship between sphingolipids and cholesterol homeostasis, or its biological implications. Previously, we have identified sphingolipid metabolism as a unique vulnerability for IDH1 mut gliomas via a rational drug design. Herein, we show how modulating sphingolipid levels affects cholesterol homeostasis in brain tumors. However, we unexpectedly discovered for the first time that C17 sphingosine and NDMS addition to cancer cells alters cholesterol homeostasis by impacting its cellular synthesis, uptake, and efflux leading to a net decrease in cholesterol levels and inducing apoptosis. Our results reflect a reverse correlation between the levels of sphingosines, NDMS, and unesterified, free cholesterol in the cells. We show that increasing sphingosine and NDMS (a sphingosine analog) levels alter not only the trafficking of cholesterol between membranes but also the efflux and synthesis of cholesterol. We also demonstrate that despite the effort to remove free cholesterol by ABCA1-mediated efflux or by suppressing machinery for the influx (LDLR) and biosynthetic pathway (HMGCR), apoptosis is inevitable for IDH1 mut glioma cells. This is the first study that shows how altering sphingosine levels directly affects cholesterol homeostasis in cancer cells and can be used to manipulate this relationship to induce apoptosis in IDH1 mut gliomas.
    DOI:  https://doi.org/10.1101/2024.04.26.591321
  59. Commun Biol. 2024 Jun 20. 7(1): 752
    Circadian-driven tissue specificity is constrained under caloric restricted feeding conditions.
    Renrui Chen, Ziang Zhang, Junjie Ma, Bing Liu, Zhengyun Huang, Ganlu Hu, Ju Huang, Ying Xu, Guang-Zhong Wang.
      Tissue specificity is a fundamental property of an organ that affects numerous biological processes, including aging and longevity, and is regulated by the circadian clock. However, the distinction between circadian-affected tissue specificity and other tissue specificities remains poorly understood. Here, using multi-omics data on circadian rhythms in mice, we discovered that approximately 35% of tissue-specific genes are directly affected by circadian regulation. These circadian-affected tissue-specific genes have higher expression levels and are associated with metabolism in hepatocytes. They also exhibit specific features in long-reads sequencing data. Notably, these genes are associated with aging and longevity at both the gene level and at the network module level. The expression of these genes oscillates in response to caloric restricted feeding regimens, which have been demonstrated to promote longevity. In addition, aging and longevity genes are disrupted in various circadian disorders. Our study indicates that the modulation of circadian-affected tissue specificity is essential for understanding the circadian mechanisms that regulate aging and longevity at the genomic level.
    DOI:  https://doi.org/10.1038/s42003-024-06421-0
  60. Cell Rep. 2024 Jun 18. pii: S2211-1247(24)00695-8. [Epub ahead of print]43(7): 114367
    Hypoxia-induced CTCF promotes EMT in breast cancer.
    Parik Kakani, Shruti Ganesh Dhamdhere, Deepak Pant, Rushikesh Joshi, Jharna Mishra, Atul Samaiya, Sanjeev Shukla.
      Cancer cells experiencing hypoxic stress employ epithelial-mesenchymal transition (EMT) to undergo metastasis through rewiring of the chromatin landscape, epigenetics, and importantly, gene expression. Here, we showed that hypoxia modulates the epigenetic landscape on CTCF promoter and upregulates its expression. Hypoxia-driven epigenetic regulation, specifically DNA demethylation mediated by TET2, is a prerequisite for CTCF induction. Mechanistically, in hypoxic conditions, Hypoxia-inducible factor 1-alpha (HIF1α) binds to the unmethylated CTCF promoter, causing transcriptional upregulation. Further, we uncover the pivotal role of CTCF in promoting EMT as loss of CTCF abrogated invasiveness of hypoxic breast cancer cells. These findings highlight the functional contribution of HIF1α-CTCF axis in promoting EMT in hypoxic breast cancer cells. Lastly, CTCF expression is alleviated and the potential for EMT is diminished when the HIF1α binding is particularly disrupted through the dCas9-DNMT3A system-mediated maintenance of DNA methylation on the CTCF promoter. This axis may offer a unique therapeutic target in breast cancer.
    Keywords:  CP: Cancer; CP: Molecular biology; CRISPR-dCas9-mediated editing; CTCF; EMT; breast cancer; epigenetics; hypoxia
    DOI:  https://doi.org/10.1016/j.celrep.2024.114367
  61. EMBO Rep. 2024 Jun 21.
    Lactate supports cell-autonomous ECM production to sustain metastatic behavior in prostate cancer.
    Luigi Ippolito, Assia Duatti, Marta Iozzo, Giuseppina Comito, Elisa Pardella, Nicla Lorito, Marina Bacci, Erica Pranzini, Alice Santi, Giada Sandrini, Carlo V Catapano, Sergio Serni, Pietro Spatafora, Andrea Morandi, Elisa Giannoni, Paola Chiarugi.
      Extracellular matrix (ECM) is a major component of the tumor environment, promoting the establishment of a pro-invasive behavior. Such environment is supported by both tumor- and stromal-derived metabolites, particularly lactate. In prostate cancer (PCa), cancer-associated fibroblasts (CAFs) are major contributors of secreted lactate, able to impact on metabolic and transcriptional regulation in cancer cells. Here, we describe a mechanism by which CAF-secreted lactate promotes in PCa cells the expression of genes coding for the collagen family. Lactate-exploiting PCa cells rely on increased α-ketoglutarate (α-KG) which activates the α-KG-dependent collagen prolyl-4-hydroxylase (P4HA1) to support collagen hydroxylation. De novo synthetized collagen plays a signaling role by activating discoidin domain receptor 1 (DDR1), supporting stem-like and invasive features of PCa cells. Inhibition of lactate-induced collagen hydroxylation and DDR1 activation reduces the metastatic colonization of PCa cells. Overall, these results provide a new understanding of the link between collagen remodeling/signaling and the nutrient environment exploited by PCa.
    Keywords:  CAFs; Collagen Hydroxylation; Collagen Signaling; Lactate Metabolism
    DOI:  https://doi.org/10.1038/s44319-024-00180-z
  62. Nat Commun. 2024 Jun 18. 15(1): 5217
    Protein restriction slows the development and progression of pathology in a mouse model of Alzheimer's disease.
    Reji Babygirija, Michelle M Sonsalla, Jericha Mill, Isabella James, Jessica H Han, Cara L Green, Mariah F Calubag, Gina Wade, Anna Tobon, John Michael, Michaela M Trautman, Ryan Matoska, Chung-Yang Yeh, Isaac Grunow, Heidi H Pak, Michael J Rigby, Dominique A Baldwin, Natalie M Niemi, John M Denu, Luigi Puglielli, Judith Simcox, Dudley W Lamming.
      Dietary protein is a critical regulator of metabolic health and aging. Low protein diets are associated with healthy aging in humans, and dietary protein restriction extends the lifespan and healthspan of mice. In this study, we examined the effect of protein restriction (PR) on metabolic health and the development and progression of Alzheimer's disease (AD) in the 3xTg mouse model of AD. Here, we show that PR promotes leanness and glycemic control in 3xTg mice, specifically rescuing the glucose intolerance of 3xTg females. PR induces sex-specific alterations in circulating and brain metabolites, downregulating sphingolipid subclasses in 3xTg females. PR also reduces AD pathology and mTORC1 activity, increases autophagy, and improves the cognition of 3xTg mice. Finally, PR improves the survival of 3xTg mice. Our results suggest that PR or pharmaceutical interventions that mimic the effects of this diet may hold promise as a treatment for AD.
    DOI:  https://doi.org/10.1038/s41467-024-49589-z
  63. bioRxiv. 2024 Jun 06. pii: 2024.06.04.597364. [Epub ahead of print]
    PRDX6 contributes to selenocysteine metabolism and ferroptosis resistance.
    Zhiyi Chen, Alex Inague, Kamini Kaushal, Gholamreza Fazeli, Thamara N Xavier da Silva, Ancely Ferreira Dos Santos, Tasneem Cheytan, Florencio Porto Freitas, Umut Yildiz, Lucas Gasparello Viviani, Rodrigo Santiago Lima, Mikaela Peglow Pinz, Isadora Medeiros, Thiago Geronimo Pires Alegria, Railmara Pereira da Silva, Larissa Regina Diniz, Simon Weinzweig, Judith Klein-Seetharaman, Andreas Trumpp, Adriana Manas, Robert Hondal, Matthias Fischer, Christoph Bartenhagen, Briana K Shimada, Lucia A Seale, Marietta Fabiano, Ulrich Schweizer, Luis E Netto, Flavia Carla Meotti, Hamed Alborzinia, Sayuri Miyamoto, Jose Pedro Friedmann Angeli.
      Selenocysteine (Sec) metabolism is crucial for cellular function and ferroptosis prevention and has traditionally been thought to begin with the uptake of the Sec carrier selenoprotein P (SELENOP). Following uptake, Sec released from SELENOP undergoes metabolisation via selenocysteine lyase (SCLY), producing selenide, a substrate used by selenophosphate synthetase 2 (SEPHS2), which provides the essential selenium donor - selenophosphate - for the biosynthesis of the selenocysteine tRNA. Here, we report the discovery of an alternative pathway mediating Sec metabolisation that is independent of SCLY and mediated by peroxiredoxin 6 (PRDX6). Mechanistically, we demonstrate that PRDX6 can readily react with selenide and interact with SEPHS2, potentially acting as a selenium delivery system. Moreover, we demonstrate the presence and functional significance of this alternative route in cancer cells where we reveal a notable association between elevated expression of PRDX6 with a highly aggressive neuroblastoma subtype. Altogether, our study sheds light on a previously unrecognized aspect of Sec metabolism and its implications in ferroptosis, offering new avenues for therapeutic exploitation.
    DOI:  https://doi.org/10.1101/2024.06.04.597364
  64. Cell. 2024 Jun 11. pii: S0092-8674(24)00578-6. [Epub ahead of print]
    NLRC5 senses NAD+ depletion, forming a PANoptosome and driving PANoptosis and inflammation.
    Balamurugan Sundaram, Nagakannan Pandian, Hee Jin Kim, Hadia M Abdelaal, Raghvendra Mall, Omkar Indari, Roman Sarkar, Rebecca E Tweedell, Emily Q Alonzo, Jonathon Klein, Shondra M Pruett-Miller, Peter Vogel, Thirumala-Devi Kanneganti.
      NLRs constitute a large, highly conserved family of cytosolic pattern recognition receptors that are central to health and disease, making them key therapeutic targets. NLRC5 is an enigmatic NLR with mutations associated with inflammatory and infectious diseases, but little is known about its function as an innate immune sensor and cell death regulator. Therefore, we screened for NLRC5's role in response to infections, PAMPs, DAMPs, and cytokines. We identified that NLRC5 acts as an innate immune sensor to drive inflammatory cell death, PANoptosis, in response to specific ligands, including PAMP/heme and heme/cytokine combinations. NLRC5 interacted with NLRP12 and PANoptosome components to form a cell death complex, suggesting an NLR network forms similar to those in plants. Mechanistically, TLR signaling and NAD+ levels regulated NLRC5 expression and ROS production to control cell death. Furthermore, NLRC5-deficient mice were protected in hemolytic and inflammatory models, suggesting that NLRC5 could be a potential therapeutic target.
    Keywords:  ASC; DAMP; NLRC5; NLRP12; NLRP3; PAMP; PANoptosis; RIPK3; ROS; TLRs; TNF; apoptosis; caspase; colitis; heme; hemophagocytic lymphohistiocytosis; inflammasome; inflammatory cell death; necroptosis; pyroptosis
    DOI:  https://doi.org/10.1016/j.cell.2024.05.034
  65. Am J Physiol Cell Physiol. 2024 Jun 17.
    The role of polyamine metabolism in cellular function and physiology.
    Ryan S Schibalski, Anastasia S Shulha, Betty Tsao, Oleg Palygin, Daria V Ilatovskaya.
      Polyamines are molecules with multiple amino groups that are essential for cellular function. The major polyamines are putrescine, spermidine, spermine, and cadaverine. Polyamines are important for posttranscriptional regulation, autophagy, programmed cell death, proliferation, redox homeostasis, and ion channel function; their levels are tightly controlled. High levels of polyamines are associated with proliferative pathologies such as cancer, while low polyamine levels are observed in aging, and elevated polyamine turnover enhances oxidative stress. Polyamine metabolism is implicated in a variety of pathophysiological processes in the nervous, immune, and cardiovascular systems. Currently, manipulating polyamine levels is under investigation as a potential preventive treatment in several pathologies, including aging, ischemia/reperfusion injury, pulmonary hypertension, and cancer. Although polyamines have been implicated in a plethora of intracellular mechanisms, our understanding of these processes remains incomplete and is a topic of ongoing investigations. Here, we discuss the regulation and cellular functions of polyamines, their role in physiology and pathology, and emphasize the current gaps in knowledge and potential future research directions.
    Keywords:  Cellular function; Pathophysiology; Physiology; Polyamines; Sex differences
    DOI:  https://doi.org/10.1152/ajpcell.00074.2024
  66. bioRxiv. 2024 Apr 05. pii: 2024.04.04.588079. [Epub ahead of print]
    Deoxyuridine-rich cytoplasmic DNA antagonizes STING-dependent innate immune responses and sensitizes resistant tumors to anti-PD-L1 therapy.
    Pinakin Pandya, Frank P Vendetti, Joseph El-Ghoubaira, Sudipta Pathak, Joshua J Deppas, Reyna Jones, Anthony V Columbus, Yunqi Zhang, Daniel Ivanov, Ziyu Huang, Kate M MacDonald, Shane M Harding, Raquel Buj, Katherine M Aird, Jan H Beumer, Robert W Sobol, Christopher J Bakkenist.
      DNA damage and cytoplasmic DNA induce type-1 interferon (IFN-1) and potentiate responses to immune checkpoint inhibitors. Our prior work found that inhibitors of the DNA damage response kinase ATR (ATRi) induce IFN-1 and deoxyuridine (dU) incorporation by DNA polymerases, akin to antimetabolites. Whether and how dU incorporation is required for ATRi-induced IFN-1 signaling is not known. Here, we show that ATRi-dependent IFN-1 responses require uracil DNA glycosylase (UNG)-initiated base excision repair and STING. Quantitative analyses of nine distinct nucleosides reveals that ATRi induce dU incorporation more rapidly in UNG wild-type than knockout cells, and that induction of IFN-1 is associated with futile cycles of repair. While ATRi induce similar numbers of micronuclei in UNG wild-type and knockout cells, dU containing micronuclei and cytoplasmic DNA are increased in knockout cells. Surprisingly, DNA fragments containing dU block STING-dependent induction of IFN-1, MHC-1, and PD-L1. Furthermore, UNG knockout sensitizes cells to IFN-γ in vitro , and potentiates responses to anti-PD-L1 in resistant tumors in vivo . These data demonstrate an unexpected and specific role for dU-rich DNA in suppressing STING-dependent IFN-1 responses, and show that UNG-deficient tumors have a heightened response to immune checkpoint inhibitors.
    STATEMENT OF SIGNIFICANCE: Antimetabolites disrupt nucleotide pools and increase dU incorporation by DNA polymerases. We show that unrepaired dU potentiates responses to checkpoint inhibitors in mouse models of cancer. Patients with low tumor UNG may respond to antimetabolites combined with checkpoint inhibitors, and patients with high tumor UNG may respond to UNG inhibitors combined with checkpoint inhibitors.
    DOI:  https://doi.org/10.1101/2024.04.04.588079
  67. Elife. 2024 Jun 18. pii: RP91597. [Epub ahead of print]12
    Optimal transport for automatic alignment of untargeted metabolomic data.
    Marie Breeur, George Stepaniants, Pekka Keski-Rahkonen, Philippe Rigollet, Vivian Viallon.
      Untargeted metabolomic profiling through liquid chromatography-mass spectrometry (LC-MS) measures a vast array of metabolites within biospecimens, advancing drug development, disease diagnosis, and risk prediction. However, the low throughput of LC-MS poses a major challenge for biomarker discovery, annotation, and experimental comparison, necessitating the merging of multiple datasets. Current data pooling methods encounter practical limitations due to their vulnerability to data variations and hyperparameter dependence. Here, we introduce GromovMatcher, a flexible and user-friendly algorithm that automatically combines LC-MS datasets using optimal transport. By capitalizing on feature intensity correlation structures, GromovMatcher delivers superior alignment accuracy and robustness compared to existing approaches. This algorithm scales to thousands of features requiring minimal hyperparameter tuning. Manually curated datasets for validating alignment algorithms are limited in the field of untargeted metabolomics, and hence we develop a dataset split procedure to generate pairs of validation datasets to test the alignments produced by GromovMatcher and other methods. Applying our method to experimental patient studies of liver and pancreatic cancer, we discover shared metabolic features related to patient alcohol intake, demonstrating how GromovMatcher facilitates the search for biomarkers associated with lifestyle risk factors linked to several cancer types.
    Keywords:  Gromov-Wasserstein; LC-MS; cancer biology; cancer metabolism; computational biology; data integration; human; optimal transport; systems biology; untargeted metabolomics
    DOI:  https://doi.org/10.7554/eLife.91597
  68. Nat Metab. 2024 Jun 21.
    Optimizing the design of time-restricted eating human trials.
    Krista A Varady, Lisa S Chow.
      
    DOI:  https://doi.org/10.1038/s42255-024-01073-0
  69. Nat Aging. 2024 Jun 12.
    Conserved epigenetic hallmarks of T cell aging during immunity and malignancy.
    Tian Mi, Andrew G Soerens, Shanta Alli, Tae Gun Kang, Anoop Babu Vasandan, Zhaoming Wang, Vaiva Vezys, Shunsuke Kimura, Ilaria Iacobucci, Stephen B Baylin, Peter A Jones, Christopher Hiner, April Mueller, Harris Goldstein, Charles G Mullighan, Caitlin C Zebley, David Masopust, Ben Youngblood.
      Chronological aging correlates with epigenetic modifications at specific loci, calibrated to species lifespan. Such 'epigenetic clocks' appear conserved among mammals, but whether they are cell autonomous and restricted by maximal organismal lifespan remains unknown. We used a multilifetime murine model of repeat vaccination and memory T cell transplantation to test whether epigenetic aging tracks with cellular replication and if such clocks continue 'counting' beyond species lifespan. Here we found that memory T cell epigenetic clocks tick independently of host age and continue through four lifetimes. Instead of recording chronological time, T cells recorded proliferative experience through modification of cell cycle regulatory genes. Applying this epigenetic profile across a range of human T cell contexts, we found that naive T cells appeared 'young' regardless of organism age, while in pediatric patients, T cell acute lymphoblastic leukemia appeared to have epigenetically aged for up to 200 years. Thus, T cell epigenetic clocks measure replicative history and can continue to accumulate well-beyond organismal lifespan.
    DOI:  https://doi.org/10.1038/s43587-024-00649-5
  70. Science. 2024 Jun 21. 384(6702): 1300-1301
    Cellular senescence in normal physiology.
    João Pedro de Magalhães.
      Long associated with aging, senescent cells can promote health and have physiological roles.
    DOI:  https://doi.org/10.1126/science.adj7050
  71. Nat Cell Biol. 2024 Jun 20.
    The maintenance of oocytes in the mammalian ovary involves extreme protein longevity.
    Katarina Harasimov, Rebecca L Gorry, Luisa M Welp, Sarah Mae Penir, Yehor Horokhovskyi, Shiya Cheng, Katsuyoshi Takaoka, Alexandra Stützer, Ann-Sophie Frombach, Ana Lisa Taylor Tavares, Monika Raabe, Sara Haag, Debojit Saha, Katharina Grewe, Vera Schipper, Silvio O Rizzoli, Henning Urlaub, Juliane Liepe, Melina Schuh.
      Women are born with all of their oocytes. The oocyte proteome must be maintained with minimal damage throughout the woman's reproductive life, and hence for decades. Here we report that oocyte and ovarian proteostasis involves extreme protein longevity. Mouse ovaries had more extremely long-lived proteins than other tissues, including brain. These long-lived proteins had diverse functions, including in mitochondria, the cytoskeleton, chromatin and proteostasis. The stable proteins resided not only in oocytes but also in long-lived ovarian somatic cells. Our data suggest that mammals increase protein longevity and enhance proteostasis by chaperones and cellular antioxidants to maintain the female germline for long periods. Indeed, protein aggregation in oocytes did not increase with age and proteasome activity did not decay. However, increasing protein longevity cannot fully block female germline senescence. Large-scale proteome profiling of ~8,890 proteins revealed a decline in many long-lived proteins of the proteostasis network in the aging ovary, accompanied by massive proteome remodeling, which eventually leads to female fertility decline.
    DOI:  https://doi.org/10.1038/s41556-024-01442-7
  72. Glia. 2024 Jun 20.
    Deficient brain GABA metabolism leads to widespread impairments of astrocyte and oligodendrocyte function.
    Jens V Andersen, Oana C Marian, Filippa L Qvist, Emil W Westi, Blanca I Aldana, Arne Schousboe, Anthony S Don, Niels H Skotte, Petrine Wellendorph.
      The neurometabolic disorder succinic semialdehyde dehydrogenase (SSADH) deficiency leads to great neurochemical imbalances and severe neurological manifestations. The cause of the disease is loss of function of the enzyme SSADH, leading to impaired metabolism of the principal inhibitory neurotransmitter GABA. Despite the known identity of the enzymatic deficit, the underlying pathology of SSADH deficiency remains unclear. To uncover new mechanisms of the disease, we performed an untargeted integrative analysis of cerebral protein expression, functional metabolism, and lipid composition in a genetic mouse model of SSADH deficiency (ALDH5A1 knockout mice). Our proteomic analysis revealed a clear regional vulnerability, as protein alterations primarily manifested in the hippocampus and cerebral cortex of the ALDH5A1 knockout mice. These regions displayed aberrant expression of proteins linked to amino acid homeostasis, mitochondria, glial function, and myelination. Stable isotope tracing in acutely isolated brain slices demonstrated an overall maintained oxidative metabolism of glucose, but a selective decrease in astrocyte metabolic activity in the cerebral cortex of ALDH5A1 knockout mice. In contrast, an elevated capacity of oxidative glutamine metabolism was observed in the ALDH5A1 knockout brain, which may serve as a neuronal compensation of impaired astrocyte glutamine provision. In addition to reduced expression of critical oligodendrocyte proteins, a severe depletion of myelin-enriched sphingolipids was found in the brains of ALDH5A1 knockout mice, suggesting degeneration of myelin. Altogether, our study highlights that impaired astrocyte and oligodendrocyte function is intimately linked to SSADH deficiency pathology, suggesting that selective targeting of glial cells may hold therapeutic potential in this disease.
    Keywords:  SSADH deficiency; brain energy metabolism; glia; glutamate/GABA‐glutamine cycle; myelin
    DOI:  https://doi.org/10.1002/glia.24585
  73. Nat Chem Biol. 2024 Jun 19.
    Channeling kynurenine.
    Mollie I Sweeney, David M Tobin.
      
    DOI:  https://doi.org/10.1038/s41589-024-01643-z
  74. bioRxiv. 2024 Jun 06. pii: 2024.06.05.597553. [Epub ahead of print]
    HLH-30/TFEB rewires the chaperone network to promote proteostasis under conditions of Coenzyme A and Iron-Sulfur Cluster Deficiency.
    Rewayd Shalash, Mor Levi-Ferber, Henrik von Chrzanowski, Mohammad Khaled Atrash, Yaron Shav-Tal, Sivan Henis-Korenblit.
      The maintenance of a properly folded proteome is critical for cellular function and organismal health, and its age-dependent collapse is associated with a wide range of diseases. Here, we find that despite the central role of Coenzyme A as a molecular cofactor in hundreds of cellular reactions, limiting Coenzyme A levels in C. elegans and in human cells, by inhibiting the conserved pantothenate kinase, promotes proteostasis. Impairment of the cytosolic iron-sulfur clusters formation pathway, which depends on Coenzyme A, similarly promotes proteostasis and acts in the same pathway. Proteostasis improvement by Coenzyme A/iron-sulfur cluster deficiencies are dependent on the conserved HLH-30/TFEB transcription factor. Strikingly, under these conditions, HLH-30 promotes proteostasis by potentiating the expression of select chaperone genes providing a chaperone-mediated proteostasis shield, rather than by its established role as an autophagy and lysosome biogenesis promoting factor. This reflects the versatile nature of this conserved transcription factor, that can transcriptionally activate a wide range of protein quality control mechanisms, including chaperones and stress response genes alongside autophagy and lysosome biogenesis genes. These results highlight TFEB as a key proteostasis-promoting transcription factor and underscore it and its upstream regulators as potential therapeutic targets in proteostasis-related diseases.
    DOI:  https://doi.org/10.1101/2024.06.05.597553
  75. Dev Cell. 2024 May 20. pii: S1534-5807(24)00295-8. [Epub ahead of print]
    Suppressed basal mitophagy drives cellular aging phenotypes that can be reversed by a p62-targeting small molecule.
    George Kelly, Tetsushi Kataura, Johan Panek, Gailing Ma, Hanna Salmonowicz, Ashley Davis, Hannah Kendall, Charlotte Brookes, Daniel Moscoh Ayine-Tora, Peter Banks, Glyn Nelson, Laura Dobby, Patricia R Pitrez, Laura Booth, Lydia Costello, Gavin D Richardson, Penny Lovat, Stefan Przyborski, Lino Ferreira, Laura Greaves, Karolina Szczepanowska, Thomas von Zglinicki, Satomi Miwa, Max Brown, Michael Flagler, John E Oblong, Charles C Bascom, Bernadette Carroll, Jóhannes Reynisson, Viktor I Korolchuk.
      Selective degradation of damaged mitochondria by autophagy (mitophagy) is proposed to play an important role in cellular homeostasis. However, the molecular mechanisms and the requirement of mitochondrial quality control by mitophagy for cellular physiology are poorly understood. Here, we demonstrated that primary human cells maintain highly active basal mitophagy initiated by mitochondrial superoxide signaling. Mitophagy was found to be mediated by PINK1/Parkin-dependent pathway involving p62 as a selective autophagy receptor (SAR). Importantly, this pathway was suppressed upon the induction of cellular senescence and in naturally aged cells, leading to a robust shutdown of mitophagy. Inhibition of mitophagy in proliferating cells was sufficient to trigger the senescence program, while reactivation of mitophagy was necessary for the anti-senescence effects of NAD precursors or rapamycin. Furthermore, reactivation of mitophagy by a p62-targeting small molecule rescued markers of cellular aging, which establishes mitochondrial quality control as a promising target for anti-aging interventions.
    Keywords:  PINK1; Parkin; aging; autophagy; mitophagy; nicotinamide; nicotinamide riboside; p62; rapamycin; redox; senescence
    DOI:  https://doi.org/10.1016/j.devcel.2024.04.020
  76. Aging Cell. 2024 Jun 17. e14250
    Age-specific and compartment-dependent changes in mitochondrial homeostasis and cytoplasmic viscosity in mouse peripheral neurons.
    James N Sleigh, Francesca Mattedi, Sandy Richter, Emily Annuario, Kristal Ng, I Emilie Steinmark, Iveta Ivanova, István L Darabán, Parth P Joshi, Elena R Rhymes, Shirwa Awale, Gokhan Yahioglu, Jacqueline C Mitchell, Klaus Suhling, Giampietro Schiavo, Alessio Vagnoni.
      Mitochondria are dynamic bioenergetic hubs that become compromised with age. In neurons, declining mitochondrial axonal transport has been associated with reduced cellular health. However, it is still unclear to what extent the decline of mitochondrial transport and function observed during ageing are coupled, and if somal and axonal mitochondria display compartment-specific features that make them more susceptible to the ageing process. It is also not known whether the biophysical state of the cytoplasm, thought to affect many cellular functions, changes with age to impact mitochondrial trafficking and homeostasis. Focusing on the mouse peripheral nervous system, we show that age-dependent decline in mitochondrial trafficking is accompanied by reduction of mitochondrial membrane potential and intramitochondrial viscosity, but not calcium buffering, in both somal and axonal mitochondria. Intriguingly, we observe a specific increase in cytoplasmic viscosity in the neuronal cell body, where mitochondria are most polarised, which correlates with decreased cytoplasmic diffusiveness. Increasing cytoplasmic crowding in the somatic compartment of DRG neurons grown in microfluidic chambers reduces mitochondrial axonal trafficking, suggesting a mechanistic link between the regulation of cytoplasmic viscosity and mitochondrial dynamics. Our work provides a reference for studying the relationship between neuronal mitochondrial homeostasis and the viscoelasticity of the cytoplasm in a compartment-dependent manner during ageing.
    Keywords:  FLIM; TR‐FAIM; advanced microscopy; ageing; axonal transport; crowding and viscosity; mice; mitochondria
    DOI:  https://doi.org/10.1111/acel.14250
  77. Life Sci Alliance. 2024 Sep;pii: e202402853. [Epub ahead of print]7(9):
    Activation of the Keap1/Nrf2 pathway suppresses mitochondrial dysfunction, oxidative stress, and motor phenotypes in C9orf72 ALS/FTD models.
    Wing Hei Au, Leonor Miller-Fleming, Alvaro Sanchez-Martinez, James Ak Lee, Madeleine J Twyning, Hiran A Prag, Laura Raik, Scott P Allen, Pamela J Shaw, Laura Ferraiuolo, Heather Mortiboys, Alexander J Whitworth.
      Mitochondrial dysfunction is a common feature of C9orf72 amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD); however, it remains unclear whether this is a cause or consequence of the pathogenic process. Analysing multiple aspects of mitochondrial biology across several Drosophila models of C9orf72-ALS/FTD, we found morphology, oxidative stress, and mitophagy are commonly affected, which correlated with progressive loss of locomotor performance. Notably, only genetic manipulations that reversed the oxidative stress levels were also able to rescue C9orf72 locomotor deficits, supporting a causative link between mitochondrial dysfunction, oxidative stress, and behavioural phenotypes. Targeting the key antioxidant Keap1/Nrf2 pathway, we found that genetic reduction of Keap1 or pharmacological inhibition by dimethyl fumarate significantly rescued the C9orf72-related oxidative stress and motor deficits. Finally, mitochondrial ROS levels were also elevated in C9orf72 patient-derived iNeurons and were effectively suppressed by dimethyl fumarate treatment. These results indicate that mitochondrial oxidative stress is an important mechanistic contributor to C9orf72 pathogenesis, affecting multiple aspects of mitochondrial function and turnover. Targeting the Keap1/Nrf2 signalling pathway to combat oxidative stress represents a therapeutic strategy for C9orf72-related ALS/FTD.
    DOI:  https://doi.org/10.26508/lsa.202402853
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