bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2024–09–01
53 papers selected by
Christian Frezza, Universität zu Köln
  1. Lactate helps cancer cells resist chemotherapy.
  2. The glycolytic metabolite methylglyoxal covalently inactivates the NLRP3 inflammasome.
  3. Serine and glycine physiology reversibly modulate retinal and peripheral nerve function.
  4. P53-dependent hypusination of eIF5A affects mitochondrial translation and senescence immune surveillance.
  5. The unique catalytic properties of PSAT1 mediate metabolic adaptation to glutamine blockade.
  6. Mitochondrial membrane lipids in the regulation of bioenergetic flux.
  7. Mitochondrial translation is the primary determinant of secondary mitochondrial complex I deficiencies.
  8. Mapping spatial organization and genetic cell-state regulators to target immune evasion in ovarian cancer.
  9. Affinity war: PSAT1 outcompetes the rest.
  10. A brief guide to studying extracellular vesicle function in the context of metabolism.
  11. INF2-mediated actin polymerization at ER-organelle contacts regulates organelle size and movement.
  12. Amino acid metabolism in kidney health and disease.
  13. Aberrant mitochondrial DNA synthesis in macrophages exacerbates inflammation and atherosclerosis.
  14. Hydrogen sulfide coordinates glucose metabolism switch through destabilizing tetrameric pyruvate kinase M2.
  15. A nutrigeroscience approach: Dietary macronutrients and cellular senescence.
  16. Release of mitochondrial dsRNA into the cytosol is a key driver of the inflammatory phenotype of senescent cells.
  17. Drp1 depletion protects against ferroptotic cell death by preserving mitochondrial integrity and redox homeostasis.
  18. A cell state-specific metabolic vulnerability to GPX4-dependent ferroptosis in glioblastoma.
  19. MYC Induces Oncogenic Stress through RNA Decay and Ribonucleotide Catabolism in Breast Cancer.
  20. APOBEC3C-mediated NF-κB activation enhances clear cell renal cell carcinoma progression.
  21. Mitochondrial calcium uniporter channel gatekeeping in cardiovascular disease.
  22. Feeding into cardiometabolic health.
  23. Conjoint analysis of succinylome and phosphorylome reveals imbalanced HDAC phosphorylation-driven succinylayion dynamic contibutes to lung cancer.
  24. ACMSD inhibition corrects fibrosis, inflammation, and DNA damage in MASLD/MASH.
  25. PHF6 cooperates with SWI/SNF complexes to facilitate transcriptional progression.
  26. Developmental signals control chromosome segregation fidelity during pluripotency and neurogenesis by modulating replicative stress.
  27. Glucose-1,6-bisphosphate: A new gatekeeper of cerebral mitochondrial pyruvate uptake.
  28. Tumour Microenvironment-Like Conditions Alter Pancreatic Cancer Cell Metabolism and Behaviour.
  29. Cell-specific expression of key mitochondrial enzymes limits OXPHOS in astrocytes of the adult human neocortex and hippocampal formation.
  30. Renal L-2-hydroxyglutarate dehydrogenase activity promotes hypoxia tolerance and mitochondrial metabolism in Drosophila melanogaster.
  31. EWS-WT1 fusion isoforms establish oncogenic programs and therapeutic vulnerabilities in desmoplastic small round cell tumors.
  32. Animal and bacterial viruses share conserved mechanisms of immune evasion.
  33. Nuclear ATP-citrate lyase regulates chromatin-dependent activation and maintenance of the myofibroblast gene program.
  34. METI: deep profiling of tumor ecosystems by integrating cell morphology and spatial transcriptomics.
  35. Exploring the heterogeneous targets of metabolic aging at single-cell resolution.
  36. Thyroid hormone remodels cortex to coordinate body-wide metabolism and exploration.
  37. An economic demand-based framework for prioritization strategies in response to transient amino acid limitations.
  38. Lysosomal membrane contact sites: Integrative hubs for cellular communication and homeostasis.
  39. Mitochondrial serine catabolism safeguards maintenance of the hematopoietic stem cell pool in homeostasis and injury.
  40. Infection-induced peripheral mitochondria fission drives ER encapsulations and inter-mitochondria contacts that rescue bioenergetics.
  41. Spatially clustered type I interferon responses at injury borderzones.
  42. Metabolite signaling in the heart.
  43. Context-dependent roles of mitochondrial LONP1 in orchestrating the balance between airway progenitor versus progeny cells.
  44. Stearoyl-CoA desaturase inhibition is toxic to acute myeloid leukemia displaying high levels of the de novo fatty acid biosynthesis and desaturation.
  45. The Fanconi anemia pathway induces chromothripsis and ecDNA-driven cancer drug resistance.
  46. Structural basis for allosteric regulation of human phosphofructokinase-1.
  47. Loss-of-function mutations in Dnmt3a and Tet2 lead to accelerated atherosclerosis and concordant macrophage phenotypes.
  48. Cytosine methylation flags mitochondrial RNA for degradation.
  49. Mitochondrial heterogeneity and crosstalk in aging: Time for a paradigm shift?
  50. From resonance to chaos by modulating spatiotemporal patterns through a synthetic optogenetic oscillator.
  51. Impact of oxytosis on the cross-talk of mTORC with mitochondrial proteins in drug-resistant cancer stem cells.
  52. NaCl enhances CD8+ T cell effector functions in cancer immunotherapy.
  53. ZBP1 links mtDNA instability to sustained IFN-I responses and cardiomyopathy.
  1. Nature. 2024 Aug 23.
    Lactate helps cancer cells resist chemotherapy.
      
    Keywords:  Cancer; Metabolism
    DOI:  https://doi.org/10.1038/d41586-024-02731-9
  2. Cell Rep. 2024 Aug 27. pii: S2211-1247(24)01039-8. [Epub ahead of print]43(9): 114688
    The glycolytic metabolite methylglyoxal covalently inactivates the NLRP3 inflammasome.
    Caroline Stanton, Chavin Buasakdi, Jie Sun, Ian Levitan, Prerona Bora, Sergei Kutseikin, R Luke Wiseman, Michael J Bollong.
      The NLRP3 inflammasome promotes inflammation in disease, yet the full repertoire of mechanisms regulating its activity is not well delineated. Among established regulatory mechanisms, covalent modification of NLRP3 has emerged as a common route for the pharmacological inactivation of this protein. Here, we show that inhibition of the glycolytic enzyme phosphoglycerate kinase 1 (PGK1) results in the accumulation of methylglyoxal, a reactive metabolite whose increased levels decrease NLRP3 assembly and inflammatory signaling in cells. We find that methylglyoxal inactivates NLRP3 via a non-enzymatic, covalent-crosslinking-based mechanism, promoting inter- and intraprotein MICA (methyl imidazole crosslink between cysteine and arginine) posttranslational linkages within NLRP3. This work establishes NLRP3 as capable of sensing a host of electrophilic chemicals, both exogenous small molecules and endogenous reactive metabolites, and suggests a mechanism by which glycolytic flux can moderate the activation status of a central inflammatory signaling pathway.
    Keywords:  CP: Immunology; CP: Metabolism; MICA modification; NLRP3; PGK1; covalent; glycolysis; inflammasome; inflammation; methylglyoxal
    DOI:  https://doi.org/10.1016/j.celrep.2024.114688
  3. Cell Metab. 2024 Aug 21. pii: S1550-4131(24)00323-1. [Epub ahead of print]
    Serine and glycine physiology reversibly modulate retinal and peripheral nerve function.
    Esther W Lim, Regis J Fallon, Caleb Bates, Yoichiro Ideguchi, Takayuki Nagasaki, Michal K Handzlik, Emeline Joulia, Roberto Bonelli, Courtney R Green, Brendan R E Ansell, Maki Kitano, Ilham Polis, Amanda J Roberts, Furuya Shigeki, Rando Allikmets, Martina Wallace, Martin Friedlander, Christian M Metallo, Marin L Gantner.
      Metabolic homeostasis is maintained by redundant pathways to ensure adequate nutrient supply during fasting and other stresses. These pathways are regulated locally in tissues and systemically via the liver, kidney, and circulation. Here, we characterize how serine, glycine, and one-carbon (SGOC) metabolism fluxes across the eye, liver, and kidney sustain retinal amino acid levels and function. Individuals with macular telangiectasia (MacTel), an age-related retinal disease with reduced circulating serine and glycine, carrying deleterious alleles in SGOC metabolic enzymes exhibit an exaggerated reduction in circulating serine. A Phgdh+/- mouse model of this haploinsufficiency experiences accelerated retinal defects upon dietary serine/glycine restriction, highlighting how otherwise silent haploinsufficiencies can impact retinal health. We demonstrate that serine-associated retinopathy and peripheral neuropathy are reversible, as both are restored in mice upon serine supplementation. These data provide molecular insights into the genetic and metabolic drivers of neuro-retinal dysfunction while highlighting therapeutic opportunities to ameliorate this pathogenesis.
    Keywords:  MacTel; PHGDH; glycine; glycine cleavage; one-carbon metabolism; retina metabolism; serine; serine supplementation; sphingolipids; stable-isotope tracing
    DOI:  https://doi.org/10.1016/j.cmet.2024.07.021
  4. Nat Commun. 2024 Aug 28. 15(1): 7458
    P53-dependent hypusination of eIF5A affects mitochondrial translation and senescence immune surveillance.
    Xiangli Jiang, Ali Hyder Baig, Giuliana Palazzo, Rossella Del Pizzo, Toman Bortecen, Sven Groessl, Esther A Zaal, Cinthia Claudia Amaya Ramirez, Alexander Kowar, Daniela Aviles-Huerta, Celia R Berkers, Wilhelm Palm, Darjus Tschaharganeh, Jeroen Krijgsveld, Fabricio Loayza-Puch.
      Cellular senescence is characterized by a permanent growth arrest and is associated with tissue aging and cancer. Senescent cells secrete a number of different cytokines referred to as the senescence-associated secretory phenotype (SASP), which impacts the surrounding tissue and immune response. Here, we find that senescent cells exhibit higher rates of protein synthesis compared to proliferating cells and identify eIF5A as a crucial regulator of this process. Polyamine metabolism and hypusination of eIF5A play a pivotal role in sustaining elevated levels of protein synthesis in senescent cells. Mechanistically, we identify a p53-dependent program in senescent cells that maintains hypusination levels of eIF5A. Finally, we demonstrate that functional eIF5A is required for synthesizing mitochondrial ribosomal proteins and monitoring the immune clearance of premalignant senescent cells in vivo. Our findings establish an important role of protein synthesis during cellular senescence and suggest a link between eIF5A, polyamine metabolism, and senescence immune surveillance.
    DOI:  https://doi.org/10.1038/s41467-024-51901-w
  5. Nat Metab. 2024 Aug;6(8): 1529-1548
    The unique catalytic properties of PSAT1 mediate metabolic adaptation to glutamine blockade.
    Yijian Qiu, Olivia T Stamatatos, Qingting Hu, Jed Ruiter Swain, Suzanne Russo, Ava Sann, Ana S H Costa, Sara Violante, David L Spector, Justin R Cross, Michael J Lukey.
      Cultured cancer cells frequently rely on the consumption of glutamine and its subsequent hydrolysis by glutaminase (GLS). However, this metabolic addiction can be lost in the tumour microenvironment, rendering GLS inhibitors ineffective in the clinic. Here we show that glutamine-addicted breast cancer cells adapt to chronic glutamine starvation, or GLS inhibition, via AMPK-mediated upregulation of the serine synthesis pathway (SSP). In this context, the key product of the SSP is not serine, but α-ketoglutarate (α-KG). Mechanistically, we find that phosphoserine aminotransferase 1 (PSAT1) has a unique capacity for sustained α-KG production when glutamate is depleted. Breast cancer cells with resistance to glutamine starvation or GLS inhibition are highly dependent on SSP-supplied α-KG. Accordingly, inhibition of the SSP prevents adaptation to glutamine blockade, resulting in a potent drug synergism that suppresses breast tumour growth. These findings highlight how metabolic redundancy can be context dependent, with the catalytic properties of different metabolic enzymes that act on the same substrate determining which pathways can support tumour growth in a particular nutrient environment. This, in turn, has practical consequences for therapies targeting cancer metabolism.
    DOI:  https://doi.org/10.1038/s42255-024-01104-w
  6. Cell Metab. 2024 Aug 13. pii: S1550-4131(24)00326-7. [Epub ahead of print]
    Mitochondrial membrane lipids in the regulation of bioenergetic flux.
    Stephen Thomas Decker, Katsuhiko Funai.
      Oxidative phosphorylation (OXPHOS) occurs through and across the inner mitochondrial membrane (IMM). Mitochondrial membranes contain a distinct lipid composition, aided by lipid biosynthetic machinery localized in the IMM and class-specific lipid transporters that limit lipid traffic in and out of mitochondria. This unique lipid composition appears to be essential for functions of mitochondria, particularly OXPHOS, by its effects on direct lipid-to-protein interactions, membrane properties, and cristae ultrastructure. This review highlights the biological significance of mitochondrial lipids, with a particular spotlight on the role of lipids in mitochondrial bioenergetics. We describe pathways for the biosynthesis of mitochondrial lipids and provide evidence for their roles in physiology, their implications in human disease, and the mechanisms by which they regulate mitochondrial bioenergetics.
    Keywords:  bioenergetics; mitochondria; phospholipids
    DOI:  https://doi.org/10.1016/j.cmet.2024.07.024
  7. iScience. 2024 Aug 16. 27(8): 110560
    Mitochondrial translation is the primary determinant of secondary mitochondrial complex I deficiencies.
    Kristýna Čunátová, Marek Vrbacký, Guillermo Puertas-Frias, Lukáš Alán, Marie Vanišová, María José Saucedo-Rodríguez, Josef Houštěk, Erika Fernández-Vizarra, Jiří Neužil, Alena Pecinová, Petr Pecina, Tomáš Mráček.
      Individual complexes of the mitochondrial oxidative phosphorylation system (OXPHOS) are not linked solely by their function; they also share dependencies at the maintenance/assembly level, where one complex depends on the presence of a different individual complex. Despite the relevance of this "interdependence" behavior for mitochondrial diseases, its true nature remains elusive. To understand the mechanism that can explain this phenomenon, we examined the consequences of the aberration of different OXPHOS complexes in human cells. We demonstrate here that the complete disruption of each of the OXPHOS complexes resulted in a decrease in the complex I (cI) level and that the major reason for this is linked to the downregulation of mitochondrial ribosomal proteins. We conclude that the secondary cI defect is due to mitochondrial protein synthesis attenuation, while the responsible signaling pathways could differ based on the origin of the OXPHOS defect.
    Keywords:  Biochemistry; Cell biology; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2024.110560
  8. Nat Immunol. 2024 Aug 23.
    Mapping spatial organization and genetic cell-state regulators to target immune evasion in ovarian cancer.
    Christine Yiwen Yeh, Karmen Aguirre, Olivia Laveroni, Subin Kim, Aihui Wang, Brooke Liang, Xiaoming Zhang, Lucy M Han, Raeline Valbuena, Michael C Bassik, Young-Min Kim, Sylvia K Plevritis, Michael P Snyder, Brooke E Howitt, Livnat Jerby.
      The drivers of immune evasion are not entirely clear, limiting the success of cancer immunotherapies. Here we applied single-cell spatial and perturbational transcriptomics to delineate immune evasion in high-grade serous tubo-ovarian cancer. To this end, we first mapped the spatial organization of high-grade serous tubo-ovarian cancer by profiling more than 2.5 million cells in situ in 130 tumors from 94 patients. This revealed a malignant cell state that reflects tumor genetics and is predictive of T cell and natural killer cell infiltration levels and response to immune checkpoint blockade. We then performed Perturb-seq screens and identified genetic perturbations-including knockout of PTPN1 and ACTR8-that trigger this malignant cell state. Finally, we show that these perturbations, as well as a PTPN1/PTPN2 inhibitor, sensitize ovarian cancer cells to T cell and natural killer cell cytotoxicity, as predicted. This study thus identifies ways to study and target immune evasion by linking genetic variation, cell-state regulators and spatial biology.
    DOI:  https://doi.org/10.1038/s41590-024-01943-5
  9. Nat Metab. 2024 Aug;6(8): 1429-1430
    Affinity war: PSAT1 outcompetes the rest.
    Richard Possemato.
      
    DOI:  https://doi.org/10.1038/s42255-024-01096-7
  10. Nat Metab. 2024 Aug 26.
    A brief guide to studying extracellular vesicle function in the context of metabolism.
    Daniel Stephen Lark, Kerstin Stemmer, Wei Ying, Clair Crewe.
      
    DOI:  https://doi.org/10.1038/s42255-024-01112-w
  11. Res Sq. 2024 Aug 16. pii: rs.3.rs-4720604. [Epub ahead of print]
    INF2-mediated actin polymerization at ER-organelle contacts regulates organelle size and movement.
    Cara R Schiavon, Yuning Wang, Jasmine W Feng, Stephanie Garrett, Tsung-Chang Sung, Yelena Dayn, Chunxin Wang, Richard J Youle, Omar A Quintero-Carmona, Gerald S Shadel, Uri Manor.
      Proper regulation of organelle dynamics and inter-organelle contacts is critical for cellular health and function. Both the endoplasmic reticulum (ER) and actin cytoskeleton are known to regulate organelle dynamics, but how, when, and where these two subcellular components are coordinated to control organelle dynamics remains unclear. Here, we show that ER-associated actin consistently marks mitochondrial, endosomal, and lysosomal fission sites. We also show that actin polymerization by the ER-anchored isoform of the formin protein INF2 is a key regulator of the morphology and mobility of these organelles. Together, our findings establish a mechanism by which INF2-mediated polymerization of ER-associated actin at ER-organelle contacts regulates organelle dynamics.
    DOI:  https://doi.org/10.21203/rs.3.rs-4720604/v1
  12. Nat Rev Nephrol. 2024 Aug 28.
    Amino acid metabolism in kidney health and disease.
    Martine G E Knol, Vera C Wulfmeyer, Roman-Ulrich Müller, Markus M Rinschen.
      Amino acids form peptides and proteins and are therefore considered the main building blocks of life. The kidney has an important but under-appreciated role in the synthesis, degradation, filtration, reabsorption and excretion of amino acids, acting to retain useful metabolites while excreting potentially harmful and waste products from amino acid metabolism. A complex network of kidney transporters and enzymes guides these processes and moderates the competing concentrations of various metabolites and amino acid products. Kidney amino acid metabolism contributes to gluconeogenesis, nitrogen clearance, acid-base metabolism and provision of fuel for tricarboxylic acid cycle and urea cycle intermediates, and is thus a central hub for homeostasis. Conversely, kidney disease affects the levels and metabolism of a variety of amino acids. Here, we review the metabolic role of the kidney in amino acid metabolism and describe how different diseases of the kidney lead to aberrations in amino acid metabolism. Improved understanding of the metabolic and communication routes that are affected by disease could provide new mechanistic insights into the pathogenesis of kidney diseases and potentially enable targeted dietary or pharmacological interventions.
    DOI:  https://doi.org/10.1038/s41581-024-00872-8
  13. Nat Commun. 2024 Aug 26. 15(1): 7337
    Aberrant mitochondrial DNA synthesis in macrophages exacerbates inflammation and atherosclerosis.
    Niranjana Natarajan, Jonathan Florentin, Ebin Johny, Hanxi Xiao, Scott Patrick O'Neil, Liqun Lei, Jixing Shen, Lee Ohayon, Aaron R Johnson, Krithika Rao, Xiaoyun Li, Yanwu Zhao, Yingze Zhang, Sina Tavakoli, Sruti Shiva, Jishnu Das, Partha Dutta.
      There is a large body of evidence that cellular metabolism governs inflammation, and that inflammation contributes to the progression of atherosclerosis. However, whether mitochondrial DNA synthesis affects macrophage function and atherosclerosis pathology is not fully understood. Here we show, by transcriptomic analyzes of plaque macrophages, spatial single cell transcriptomics of atherosclerotic plaques, and functional experiments, that mitochondrial DNA (mtDNA) synthesis in atherosclerotic plaque macrophages are triggered by vascular cell adhesion molecule 1 (VCAM-1) under inflammatory conditions in both humans and mice. Mechanistically, VCAM-1 activates C/EBPα, which binds to the promoters of key mitochondrial biogenesis genes - Cmpk2 and Pgc1a. Increased CMPK2 and PGC-1α expression triggers mtDNA synthesis, which activates STING-mediated inflammation. Consistently, atherosclerosis and inflammation are less severe in Apoe-/- mice lacking Vcam1 in macrophages. Downregulation of macrophage-specific VCAM-1 in vivo leads to decreased expression of LYZ1 and FCOR, involved in STING signalling. Finally, VCAM-1 expression in human carotid plaque macrophages correlates with necrotic core area, mitochondrial volume, and oxidative damage to DNA. Collectively, our study highlights the importance of macrophage VCAM-1 in inflammation and atherogenesis pathology and proposes a self-acerbating pathway involving increased mtDNA synthesis.
    DOI:  https://doi.org/10.1038/s41467-024-51780-1
  14. Nat Commun. 2024 Aug 29. 15(1): 7463
    Hydrogen sulfide coordinates glucose metabolism switch through destabilizing tetrameric pyruvate kinase M2.
    Rong-Hsuan Wang, Pin-Ru Chen, Yue-Ting Chen, Yi-Chang Chen, Yu-Hsin Chu, Chia-Chen Chien, Po-Chen Chien, Shao-Yun Lo, Zhong-Liang Wang, Min-Chen Tsou, Ssu-Yu Chen, Guang-Shen Chiu, Wen-Ling Chen, Yi-Hsuan Wu, Lily Hui-Ching Wang, Wen-Ching Wang, Shu-Yi Lin, Hsing-Jien Kung, Lu-Hai Wang, Hui-Chun Cheng, Kai-Ti Lin.
      Most cancer cells reprogram their glucose metabolic pathway from oxidative phosphorylation to aerobic glycolysis for energy production. By reducing enzyme activity of pyruvate kinase M2 (PKM2), cancer cells attain a greater fraction of glycolytic metabolites for macromolecule synthesis needed for rapid proliferation. Here we demonstrate that hydrogen sulfide (H2S) destabilizes the PKM2 tetramer into monomer/dimer through sulfhydration at cysteines, notably at C326, leading to reduced PKM2 enzyme activity and increased PKM2-mediated transcriptional activation. Blocking PKM2 sulfhydration at C326 through amino acid mutation stabilizes the PKM2 tetramer and crystal structure further revealing the tetramer organization of PKM2-C326S. The PKM2-C326S mutant in cancer cells rewires glucose metabolism to mitochondrial respiration, significantly inhibiting tumor growth. In this work, we demonstrate that PKM2 sulfhydration by H2S inactivates PKM2 activity to promote tumorigenesis and inhibiting this process could be a potential therapeutic approach for targeting cancer metabolism.
    DOI:  https://doi.org/10.1038/s41467-024-51875-9
  15. Cell Metab. 2024 Aug 15. pii: S1550-4131(24)00327-9. [Epub ahead of print]
    A nutrigeroscience approach: Dietary macronutrients and cellular senescence.
    Mariah F Calubag, Paul D Robbins, Dudley W Lamming.
      Cellular senescence, a process in which a cell exits the cell cycle in response to stressors, is one of the hallmarks of aging. Senescence and the senescence-associated secretory phenotype (SASP)-a heterogeneous set of secreted factors that disrupt tissue homeostasis and promote the accumulation of senescent cells-reprogram metabolism and can lead to metabolic dysfunction. Dietary interventions have long been studied as methods to combat age-associated metabolic dysfunction, promote health, and increase lifespan. A growing body of literature suggests that senescence is responsive to diet, both to calories and specific dietary macronutrients, and that the metabolic benefits of dietary interventions may arise in part through reducing senescence. Here, we review what is currently known about dietary macronutrients' effect on senescence and the SASP, the nutrient-responsive molecular mechanisms that may mediate these effects, and the potential for these findings to inform the development of a nutrigeroscience approach to healthy aging.
    Keywords:  branched-chain amino acids; cellular senescence; healthspan; macronutrients; nutrigeroscience; protein; senescence-associated secretory phenotype
    DOI:  https://doi.org/10.1016/j.cmet.2024.07.025
  16. Nat Commun. 2024 Aug 27. 15(1): 7378
    Release of mitochondrial dsRNA into the cytosol is a key driver of the inflammatory phenotype of senescent cells.
    Vanessa López-Polo, Mate Maus, Emmanouil Zacharioudakis, Miguel Lafarga, Camille Stephan-Otto Attolini, Francisco D M Marques, Marta Kovatcheva, Evripidis Gavathiotis, Manuel Serrano.
      The escape of mitochondrial double-stranded dsRNA (mt-dsRNA) into the cytosol has been recently linked to a number of inflammatory diseases. Here, we report that the release of mt-dsRNA into the cytosol is a general feature of senescent cells and a critical driver of their inflammatory secretome, known as senescence-associated secretory phenotype (SASP). Inhibition of the mitochondrial RNA polymerase, the dsRNA sensors RIGI and MDA5, or the master inflammatory signaling protein MAVS, all result in reduced expression of the SASP, while broadly preserving other hallmarks of senescence. Moreover, senescent cells are hypersensitized to mt-dsRNA-driven inflammation due to their reduced levels of PNPT1 and ADAR1, two proteins critical for mitigating the accumulation of mt-dsRNA and the inflammatory potency of dsRNA, respectively. We find that mitofusin MFN1, but not MFN2, is important for the activation of the mt-dsRNA/MAVS/SASP axis and, accordingly, genetic or pharmacologic MFN1 inhibition attenuates the SASP. Finally, we report that senescent cells within fibrotic and aged tissues present dsRNA foci, and inhibition of mitochondrial RNA polymerase reduces systemic inflammation associated to senescence. In conclusion, we uncover the mt-dsRNA/MAVS/MFN1 axis as a key driver of the SASP and we identify novel therapeutic strategies for senescence-associated diseases.
    DOI:  https://doi.org/10.1038/s41467-024-51363-0
  17. Cell Death Dis. 2024 Aug 27. 15(8): 626
    Drp1 depletion protects against ferroptotic cell death by preserving mitochondrial integrity and redox homeostasis.
    Stephan Tang, Anneke Fuß, Zohreh Fattahi, Carsten Culmsee.
      Mitochondria are highly dynamic organelles which undergo constant fusion and fission as part of the mitochondrial quality control. In genetic diseases and age-related neurodegenerative disorders, altered mitochondrial fission-fusion dynamics have been linked to impaired mitochondrial quality control, disrupted organelle integrity and function, thereby promoting neural dysfunction and death. The key enzyme regulating mitochondrial fission is the GTPase Dynamin-related Protein 1 (Drp1), which is also considered as a key player in mitochondrial pathways of regulated cell death. In particular, increasing evidence suggests a role for impaired mitochondrial dynamics and integrity in ferroptosis, which is an iron-dependent oxidative cell death pathway with relevance in neurodegeneration. In this study, we demonstrate that CRISPR/Cas9-mediated genetic depletion of Drp1 exerted protective effects against oxidative cell death by ferroptosis through preserved mitochondrial integrity and maintained redox homeostasis. Knockout of Drp1 resulted in mitochondrial elongation, attenuated ferroptosis-mediated impairment of mitochondrial membrane potential, and stabilized iron trafficking and intracellular iron storage. In addition, Drp1 deficiency exerted metabolic effects, with reduced basal and maximal mitochondrial respiration and a metabolic shift towards glycolysis. These metabolic effects further alleviated the mitochondrial contribution to detrimental ROS production thereby significantly enhancing neural cell resilience against ferroptosis. Taken together, this study highlights the key role of Drp1 in mitochondrial pathways of ferroptosis and expose the regulator of mitochondrial dynamics as a potential therapeutic target in neurological diseases involving oxidative dysregulation.
    DOI:  https://doi.org/10.1038/s41419-024-07015-8
  18. EMBO J. 2024 Aug 27.
    A cell state-specific metabolic vulnerability to GPX4-dependent ferroptosis in glioblastoma.
    Matei A Banu, Athanassios Dovas, Michael G Argenziano, Wenting Zhao, Colin P Sperring, Henar Cuervo Grajal, Zhouzerui Liu, Dominique Mo Higgins, Misha Amini, Brianna Pereira, Ling F Ye, Aayushi Mahajan, Nelson Humala, Julia L Furnari, Pavan S Upadhyayula, Fereshteh Zandkarimi, Trang Tt Nguyen, Damian Teasley, Peter B Wu, Li Hai, Charles Karan, Tyrone Dowdy, Aida Razavilar, Markus D Siegelin, Jan Kitajewski, Mioara Larion, Jeffrey N Bruce, Brent R Stockwell, Peter A Sims, Peter Canoll.
      Glioma cells hijack developmental programs to control cell state. Here, we uncover a glioma cell state-specific metabolic liability that can be therapeutically targeted. To model cell conditions at brain tumor inception, we generated genetically engineered murine gliomas, with deletion of p53 alone (p53) or with constitutively active Notch signaling (N1IC), a pathway critical in controlling astrocyte differentiation during brain development. N1IC tumors harbored quiescent astrocyte-like transformed cell populations while p53 tumors were predominantly comprised of proliferating progenitor-like cell states. Further, N1IC transformed cells exhibited increased mitochondrial lipid peroxidation, high ROS production and depletion of reduced glutathione. This altered mitochondrial phenotype rendered the astrocyte-like, quiescent populations more sensitive to pharmacologic or genetic inhibition of the lipid hydroperoxidase GPX4 and induction of ferroptosis. Treatment of patient-derived early-passage cell lines and glioma slice cultures generated from surgical samples with a GPX4 inhibitor induced selective depletion of quiescent astrocyte-like glioma cell populations with similar metabolic profiles. Collectively, these findings reveal a specific therapeutic vulnerability to ferroptosis linked to mitochondrial redox imbalance in a subpopulation of quiescent astrocyte-like glioma cells resistant to standard forms of treatment.
    Keywords:  Astrocytic; Ferroptosis; Glioma; Mitochondrial-metabolism; Quiescent
    DOI:  https://doi.org/10.1038/s44318-024-00176-4
  19. Cancer Discov. 2024 Aug 28. OF1-OF18
    MYC Induces Oncogenic Stress through RNA Decay and Ribonucleotide Catabolism in Breast Cancer.
    Jitendra K Meena, Jarey H Wang, Nicholas J Neill, Dianne Keough, Nagireddy Putluri, Panagiotis Katsonis, Amanda M Koire, Hyemin Lee, Elizabeth A Bowling, Siddhartha Tyagi, Mayra Orellana, Rocio Dominguez-Vidaña, Heyuan Li, Kenneth Eagle, Charles Danan, Hsiang-Ching Chung, Andrew D Yang, William Wu, Sarah J Kurley, Brian M Ho, Joseph R Zoeller, Calla M Olson, Kristen L Meerbrey, Olivier Lichtarge, Arun Sreekumar, Clifford C Dacso, Luke W Guddat, Dominik Rejman, Dana Hocková, Zlatko Janeba, Lukas M Simon, Charles Y Lin, Monica C Pillon, Thomas F Westbrook.
      Upregulation of MYC is a hallmark of cancer, wherein MYC drives oncogenic gene expression and elevates total RNA synthesis across cancer cell transcriptomes. Although this transcriptional anabolism fuels cancer growth and survival, the consequences and metabolic stresses induced by excess cellular RNA are poorly understood. Herein, we discover that RNA degradation and downstream ribonucleotide catabolism is a novel mechanism of MYC-induced cancer cell death. Combining genetics and metabolomics, we find that MYC increases RNA decay through the cytoplasmic exosome, resulting in the accumulation of cytotoxic RNA catabolites and reactive oxygen species. Notably, tumor-derived exosome mutations abrogate MYC-induced cell death, suggesting excess RNA decay may be toxic to human cancers. In agreement, purine salvage acts as a compensatory pathway that mitigates MYC-induced ribonucleotide catabolism, and inhibitors of purine salvage impair MYC+ tumor progression. Together, these data suggest that MYC-induced RNA decay is an oncogenic stress that can be exploited therapeutically. Significance: MYC is the most common oncogenic driver of poor-prognosis cancers but has been recalcitrant to therapeutic inhibition. We discovered a new vulnerability in MYC+ cancer where MYC induces cell death through excess RNA decay. Therapeutics that exacerbate downstream ribonucleotide catabolism provide a therapeutically tractable approach to TNBC (Triple-negative Breast Cancer) and other MYC-driven cancers.
    DOI:  https://doi.org/10.1158/2159-8290.CD-22-0649
  20. Mol Oncol. 2024 Aug 26.
    APOBEC3C-mediated NF-κB activation enhances clear cell renal cell carcinoma progression.
    Nora Hase, Danny Misiak, Helge Taubert, Stefan Hüttelmaier, Michael Gekle, Marcel Köhn.
      Renowned as the predominant form of kidney cancer, clear cell renal cell carcinoma (ccRCC) exhibits susceptibility to immunotherapies due to its specific expression profile as well as notable immune cell infiltration. Despite this, effectively treating metastatic ccRCC remains a significant challenge, necessitating a more profound comprehension of the underlying molecular mechanisms governing its progression. Here, we unveil that the enhanced expression of the RNA-binding protein DNA dC → dU-editing enzyme APOBEC-3C (APOBEC3C; also known as A3C) in ccRCC tissue and ccRCC-derived cell lines serves as a catalyst for tumor growth by amplifying nuclear factor-kappa B (NF-κB) activity. By employing RNA-sequencing and cell-based assays in ccRCC-derived cell lines, we determined that A3C is a stress-responsive factor and crucial for cell survival. Furthermore, we identified that A3C binds and potentially stabilizes messenger RNAs (mRNAs) encoding positive regulators of the NF-κB pathway. Upon A3C depletion, essential subunits of the NF-κB family are abnormally restrained in the cytoplasm, leading to deregulation of NF-κB target genes. Our study illuminates the pivotal role of A3C in promoting ccRCC tumor development, positioning it as a prospective target for future therapeutic strategies.
    Keywords:  APOBEC3C; NF‐κB; RBP; ccRCC
    DOI:  https://doi.org/10.1002/1878-0261.13721
  21. Nat Cardiovasc Res. 2024 May;3(5): 500-514
    Mitochondrial calcium uniporter channel gatekeeping in cardiovascular disease.
    Tyler L Stevens, Henry M Cohen, Joanne F Garbincius, John W Elrod.
      The mitochondrial calcium (mCa2+) uniporter channel (mtCU) resides at the inner mitochondrial membrane and is required for Ca2+ to enter the mitochondrial matrix. The mtCU is essential for cellular function, as mCa2+ regulates metabolism, bioenergetics, signaling pathways and cell death. mCa2+ uptake is primarily regulated by the MICU family (MICU1, MICU2, MICU3), EF-hand-containing Ca2+-sensing proteins, which respond to cytosolic Ca2+ concentrations to modulate mtCU activity. Considering that mitochondrial function and Ca2+ signaling are ubiquitously disrupted in cardiovascular disease, mtCU function has been a hot area of investigation for the last decade. Here we provide an in-depth review of MICU-mediated regulation of mtCU structure and function, as well as potential mtCU-independent functions of these proteins. We detail their role in cardiac physiology and cardiovascular disease by highlighting the phenotypes of different mutant animal models, with an emphasis on therapeutic potential and targets of interest in this pathway.
    DOI:  https://doi.org/10.1038/s44161-024-00463-7
  22. Nat Metab. 2024 Aug;6(8): 1419
    Feeding into cardiometabolic health.
      
    DOI:  https://doi.org/10.1038/s42255-024-01123-7
  23. Brief Bioinform. 2024 Jul 25. pii: bbae415. [Epub ahead of print]25(5):
    Conjoint analysis of succinylome and phosphorylome reveals imbalanced HDAC phosphorylation-driven succinylayion dynamic contibutes to lung cancer.
    Yifan Guo, Haoyu Wen, Zongwei Chen, Mengxia Jiao, Yuchen Zhang, Di Ge, Ronghua Liu, Jie Gu.
      Cancerous genetic mutations result in a complex and comprehensive post-translational modification (PTM) dynamics, in which protein succinylation is well known for its ability to reprogram cell metabolism and is involved in the malignant evolution. Little is known about the regulatory interactions between succinylation and other PTMs in the PTM network. Here, we developed a conjoint analysis and systematic clustering method to explore the intermodification communications between succinylome and phosphorylome from eight lung cancer patients. We found that the intermodification coorperation in both parallel and series. Besides directly participating in metabolism pathways, some phosphosites out of mitochondria were identified as an upstream regulatory modification directing succinylome dynamics in cancer metabolism reprogramming. Phosphorylated activation of histone deacetylase (HDAC) in lung cancer resulted in the removal of acetylation and favored the occurrence of succinylation modification of mitochondrial proteins. These results suggest a tandem regulation between succinylation and phosphorylation in the PTM network and provide HDAC-related targets for intervening mitochondrial succinylation and cancer metabolism reprogramming.
    Keywords:  lung cancer; metabolism; phosphorylation; proteome; succinylation
    DOI:  https://doi.org/10.1093/bib/bbae415
  24. J Hepatol. 2024 Aug 22. pii: S0168-8278(24)02484-X. [Epub ahead of print]
    ACMSD inhibition corrects fibrosis, inflammation, and DNA damage in MASLD/MASH.
    Yasmine J Liu, Masaki Kimura, Xiaoxu Li, Jonathan Sulc, Qi Wang, Sandra Rodríguez-López, Angelique M L Scantlebery, Keno Strotjohann, Hector Gallart-Ayala, Archana Vijayakumar, Robert P Myers, Julijana Ivanisevic, Riekelt H Houtkooper, G Mani Subramanian, Takanori Takebe, Johan Auwerx.
       BACKGROUND & AIMS: Recent findings reveal the importance of tryptophan-initiated de novo nicotinamide adenine dinucleotide (NAD+) synthesis in the liver, a process previously considered secondary to biosynthesis from nicotinamide. The enzyme α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD), primarily expressed in liver and kidney, acts as a modulator of de novo NAD+ synthesis. Boosting NAD+ levels has previously demonstrated remarkable metabolic benefits in mouse models. In this study, we aimed to investigate the therapeutic implications of ACMSD inhibition in the treatment of metabolic dysfunction-associated steatotic liver disease/steatohepatitis (MASLD/MASH).
    METHODS: In vitro experiments were conducted in primary rodent hepatocytes, Huh7 human liver carcinoma cells and iPSC-derived human liver organoids (HLOs). C57BL/6J male mice were fed a western-style diet and housed at thermoneutrality to recapitulate key aspects of MASLD/MASH. Pharmacological ACMSD inhibition was given therapeutically, following disease onset. Steatohepatitis HLO models were used to assess the DNA damage responses by ACMSD inhibition in human contexts.
    RESULTS: Inhibiting ACMSD with a novel specific pharmacological inhibitor promotes de novo NAD+ synthesis and reduces DNA damage ex vivo, in vivo, and in HLO models. In mouse models of MASLD/MASH, de novo NAD+ biosynthesis is suppressed, and transcriptomic DNA damage signatures correlate with disease severity; in humans, Mendelian randomization-based genetic analysis suggests a notable impact of genomic stress on liver disease susceptibility. Therapeutic inhibition of ACMSD in mice increases liver NAD+ and reverses MASLD/MASH, mitigating fibrosis, inflammation, and DNA damage, as were observed in HLO models of steatohepatitis.
    CONCLUSIONS: Our findings highlight the benefits of ACMSD inhibition to enhance hepatic NAD+ levels and enable genomic protection, underscoring its therapeutic potential in MASLD/MASH.
    IMPACT AND IMPLICATIONS: Enhancing NAD+ levels has shown remarkable health benefits in mouse models of MASLD/MASH, yet liver-specific NAD+ boosting strategies remain underexplored. Here, we present a novel pharmacological approach to enhance liver NAD+de novo synthesis by inhibiting ACMSD, an enzyme highly expressed in the liver. Inhibiting ACMSD increases NAD+ levels, enhances mitochondrial respiration, and maintains genomic stability in hepatocytes ex vivo and in vivo. These molecular benefits prevent disease progression in both mouse and human liver organoid models of steatohepatitis. Our preclinical study identifies ACMSD as a promising target for MASLD/MASH management and lays the groundwork for developing ACMSD inhibitors as a clinical treatment.
    Keywords:  ACMSD; DNA repair; MASLD/MASH; Mendelian randomization; NAD(+); human liver organoids
    DOI:  https://doi.org/10.1016/j.jhep.2024.08.009
  25. Nat Commun. 2024 Aug 24. 15(1): 7303
    PHF6 cooperates with SWI/SNF complexes to facilitate transcriptional progression.
    Priya Mittal, Jacquelyn A Myers, Raymond D Carter, Sandi Radko-Juettner, Hayden A Malone, Wojciech Rosikiewicz, Alexis N Robertson, Zhexin Zhu, Ishwarya V Narayanan, Baranda S Hansen, Meadow Parrish, Natarajan V Bhanu, Robert J Mobley, Jerold E Rehg, Beisi Xu, Yiannis Drosos, Shondra M Pruett-Miller, Mats Ljungman, Benjamin A Garcia, Gang Wu, Janet F Partridge, Charles W M Roberts.
      Genes encoding subunits of SWI/SNF (BAF) chromatin remodeling complexes are mutated in nearly 25% of cancers. To gain insight into the mechanisms by which SWI/SNF mutations drive cancer, we contributed ten rhabdoid tumor (RT) cell lines mutant for SWI/SNF subunit SMARCB1 to a genome-scale CRISPR-Cas9 depletion screen performed across 896 cell lines. We identify PHF6 as specifically essential for RT cell survival and demonstrate that dependency on Phf6 extends to Smarcb1-deficient cancers in vivo. As mutations in either SWI/SNF or PHF6 can cause the neurodevelopmental disorder Coffin-Siris syndrome, our findings of a dependency suggest a previously unrecognized functional link. We demonstrate that PHF6 co-localizes with SWI/SNF complexes at promoters, where it is essential for maintenance of an active chromatin state. We show that in the absence of SMARCB1, PHF6 loss disrupts the recruitment and stability of residual SWI/SNF complex members, collectively resulting in the loss of active chromatin at promoters and stalling of RNA Polymerase II progression. Our work establishes a mechanistic basis for the shared syndromic features of SWI/SNF and PHF6 mutations in CSS and the basis for selective dependency on PHF6 in SMARCB1-mutant cancers.
    DOI:  https://doi.org/10.1038/s41467-024-51566-5
  26. Nat Commun. 2024 Aug 28. 15(1): 7404
    Developmental signals control chromosome segregation fidelity during pluripotency and neurogenesis by modulating replicative stress.
    Anchel de Jaime-Soguero, Janina Hattemer, Anja Bufe, Alexander Haas, Jeroen van den Berg, Vincent van Batenburg, Biswajit Das, Barbara di Marco, Stefania Androulaki, Nicolas Böhly, Jonathan J M Landry, Brigitte Schoell, Viviane S Rosa, Laura Villacorta, Yagmur Baskan, Marleen Trapp, Vladimir Benes, Andrei Chabes, Marta Shahbazi, Anna Jauch, Ulrike Engel, Annarita Patrizi, Rocio Sotillo, Alexander van Oudenaarden, Josephine Bageritz, Julieta Alfonso, Holger Bastians, Sergio P Acebrón.
      Human development relies on the correct replication, maintenance and segregation of our genetic blueprints. How these processes are monitored across embryonic lineages, and why genomic mosaicism varies during development remain unknown. Using pluripotent stem cells, we identify that several patterning signals-including WNT, BMP, and FGF-converge into the modulation of DNA replication stress and damage during S-phase, which in turn controls chromosome segregation fidelity in mitosis. We show that the WNT and BMP signals protect from excessive origin firing, DNA damage and chromosome missegregation derived from stalled forks in pluripotency. Cell signalling control of chromosome segregation declines during lineage specification into the three germ layers, but re-emerges in neural progenitors. In particular, we find that the neurogenic factor FGF2 induces DNA replication stress-mediated chromosome missegregation during the onset of neurogenesis, which could provide a rationale for the elevated chromosomal mosaicism of the developing brain. Our results highlight roles for morphogens and cellular identity in genome maintenance that contribute to somatic mosaicism during mammalian development.
    DOI:  https://doi.org/10.1038/s41467-024-51821-9
  27. Mol Metab. 2024 Aug 24. pii: S2212-8778(24)00149-2. [Epub ahead of print] 102018
    Glucose-1,6-bisphosphate: A new gatekeeper of cerebral mitochondrial pyruvate uptake.
    Motahareh Solina Safari, Priska Woerl, Carolin Garmsiri, Dido Weber, Marcel Kwiatkowski, Madlen Hotze, Louisa Kuenkel, Luisa Lang, Matthias Erlacher, Ellen Gelpi, Johannes A Hainfellner, Gottfried Baier, Gabriele Baier-Bitterlich, Stephanie Zur Nedden.
       OBJECTIVE: Glucose-1,6-bisphosphate (G-1,6-BP), a byproduct of glycolysis that is synthesized by phosphoglucomutase 2 like 1 (PGM2L1), is particularly abundant in neurons. G-1,6-BP is sensitive to the glycolytic flux, due to its dependence on 1,3-bisphosphoglycerate as phosphate donor, and the energy state, due to its degradation by inosine monophosphate-activated phosphomannomutase 1. Since the exact role of this metabolite remains unclear, our aim was to elucidate the specific function of G-1,6-BP in the brain.
    METHODS: The effect of PGM2L1 on neuronal post-ischemic viability was assessed by siRNA-mediated knockdown of PGM2L1 in primary mouse neurons. Acute mouse brain slices were used to correlate the reduction in G-1,6-BP upon ischemia to changes in carbon metabolism by 13C6-glucose tracing. A drug affinity responsive target stability assay was used to test if G-1,6-BP interacts with the mitochondrial pyruvate carrier (MPC) subunits in mouse brain protein extracts. Human embryonic kidney cells expressing a MPC bioluminescence resonance energy transfer sensor were used to analyze how PGM2L1 overexpression affects MPC activity. The effect of G-1,6-BP on mitochondrial pyruvate uptake and oxygen consumption rates was analyzed in isolated mouse brain mitochondria. PGM2L1 and a predicted upstream kinase were overexpressed in a human neuroblastoma cell line and G-1,6-BP levels were measured.
    RESULTS: We found that G-1,6-BP in mouse brain slices was quickly degraded upon ischemia and reperfusion. Knockdown of PGM2L1 in mouse neurons reduced post-ischemic viability, indicating that PGM2L1 plays a neuroprotective role. The reduction in G-1,6-BP upon ischemia was not accompanied by alterations in glycolytic rates but we did see a reduced 13C6-glucose incorporation into citrate, suggesting a potential role in mitochondrial pyruvate uptake or metabolism. Indeed, G-1,6-BP interacted with both MPC subunits and overexpression of PGM2L1 increased MPC activity. G-1,6-BP, at concentrations found in the brain, enhanced mitochondrial pyruvate uptake and pyruvate-induced oxygen consumption rates. Overexpression of a predicted upstream kinase inhibited PGM2L1 activity, showing that besides metabolism, also signaling pathways can regulate G-1,6-BP levels.
    CONCLUSIONS: We provide evidence that G-1,6-BP positively regulates mitochondrial pyruvate uptake and post-ischemic neuronal viability. These compelling data reveal a novel mechanism by which neurons can couple glycolysis-derived pyruvate to the tricarboxylic acid cycle. This process is sensitive to the glycolytic flux, the cell's energetic state, and upstream signaling cascades, offering many regulatory means to fine-tune this critical metabolic step.
    Keywords:  Energy metabolism; Glucose-1,6-bisphosphate; Ischemia; Mitochondrial pyruvate carrier; Phosphoglucomutase 2 like 1; Protein kinase N1
    DOI:  https://doi.org/10.1016/j.molmet.2024.102018
  28. Am J Physiol Cell Physiol. 2024 Aug 26.
    Tumour Microenvironment-Like Conditions Alter Pancreatic Cancer Cell Metabolism and Behaviour.
    Georgina Louise Gardner, Jeffrey Alan Stuart.
      The tumour microenvironment is complex and dynamic, characterized by poor vascularization, limited nutrient availability, hypoxia, and an acidic pH. This environment plays a critical role in driving cancer progression. However, standard cell culture conditions used to study cancer cell biology in vitro fail to replicate the in vivo environment of tumours. Recently, 'physiological' cell culture media that closely resemble human plasma have been developed (e.g., Plasmax, HPLM), along with more frequent adoption of physiological oxygen conditions (1-8% O2). Nonetheless, further refinement of tumour-specific culture conditions may be needed. In this study, we describe the development of a Tumour Microenvironment Medium (TMEM) based on murine pancreatic ductal adenocarcinoma (PDAC) tumour interstitial fluid. Using RNA-sequencing, we show that murine PDAC cells (KPCY) cultured in tumour-like conditions (TMEM, pH 7.0, 1.5% O2) exhibit profound differences in gene expression compared to plasma-like conditions (Mouse Plasma Medium, pH 7.4, 5% O2). Specifically, the expression of genes and pathways associated with cell migration, biosynthesis, angiogenesis, and epithelial-to-mesenchymal transition were altered, suggesting tumour-like conditions promote metastatic phenotypes and metabolic remodeling. Using functional assays to validate RNA-seq data, we confirmed increased motility at 1.5%O2/TMEM, despite reduced cell proliferation. Moreover, a hallmark shift to glycolytic metabolism was identified via measurement of glucose uptake/lactate production and mitochondrial respiration. Taken together, these findings demonstrate that growth in 1.5%O2/TMEM alters several biological responses in ways relevant to cancer biology, and more closely models hallmark cancerous phenotypes in culture. This highlights the importance of establishing tumour microenvironment-like conditions in standard cancer research.
    Keywords:  Cell Culture; Metabolism; Oxygen; Physiological Media; Tumour Mircoenvironment
    DOI:  https://doi.org/10.1152/ajpcell.00452.2024
  29. Commun Biol. 2024 Aug 24. 7(1): 1045
    Cell-specific expression of key mitochondrial enzymes limits OXPHOS in astrocytes of the adult human neocortex and hippocampal formation.
    Arpád Dobolyi, Melinda Cservenák, Attila G Bagó, Chun Chen, Anna Stepanova, Krisztina Paal, Jeonghyoun Lee, Miklós Palkovits, Gavin Hudson, Christos Chinopoulos.
      The astrocyte-to-neuron lactate shuttle model entails that, upon glutamatergic neurotransmission, glycolytically derived pyruvate in astrocytes is mainly converted to lactate instead of being entirely catabolized in mitochondria. The mechanism of this metabolic rewiring and its occurrence in human brain are unclear. Here by using immunohistochemistry (4 brains) and imaging mass cytometry (8 brains) we show that astrocytes of the adult human neocortex and hippocampal formation express barely detectable amounts of mitochondrial proteins critical for performing oxidative phosphorylation (OXPHOS). These data are corroborated by queries of transcriptomes (107 brains) of neuronal versus non-neuronal cells fetched from the Allen Institute for Brain Science for genes coding for a much larger repertoire of entities contributing to OXPHOS, showing that human non-neuronal elements barely expressed mRNAs coding for such proteins. With less OXPHOS, human brain astrocytes are thus bound to produce more lactate to avoid interruption of glycolysis.
    DOI:  https://doi.org/10.1038/s42003-024-06751-z
  30. Mol Metab. 2024 Aug 23. pii: S2212-8778(24)00144-3. [Epub ahead of print] 102013
    Renal L-2-hydroxyglutarate dehydrogenase activity promotes hypoxia tolerance and mitochondrial metabolism in Drosophila melanogaster.
    Nader H Mahmoudzadeh, Yasaman Heidarian, Jason P Tourigny, Alexander J Fitt, Katherine Beebe, Hongde Li, Arthur Luhur, Kasun Buddika, Liam Mungcal, Anirban Kundu, Robert A Policastro, Garrett J Brinkley, Gabriel E Zentner, Travis Nemkov, Robert Pepin, Geetanjali Chawla, Sunil Sudarshan, Aylin R Rodan, Angelo D'Alessandro, Jason M Tennessen.
      The mitochondrial enzyme L-2-hydroxyglutarate dehydrogenase (L2HGDH) regulates the abundance of L-2-hydroxyglutarate (L-2HG), a potent signaling metabolite capable of influencing chromatin architecture, mitochondrial metabolism, and cell fate decisions. Loss of L2hgdh activity in humans induces ectopic L-2HG accumulation, resulting in neurodevelopmental defects, altered immune cell function, and enhanced growth of clear cell renal cell carcinomas. To better understand the molecular mechanisms that underlie these disease pathologies, we used the fruit fly Drosophila melanogaster to investigate the endogenous functions of L2hgdh. Our studies revealed that while L2hgdh is not essential for growth or viability under standard culture conditions, L2hgdh mutants are hypersensitive to hypoxia and expire during the reoxygenation phase with severe disruptions of mitochondrial metabolism. Moreover, we find that the fly renal system (Malpighian tubules; MTs) is a key site of L2hgdh activity, as L2hgdh mutants that express a rescuing transgene within the MTs survive hypoxia treatment and exhibit normal levels of mitochondrial metabolites. We also demonstrate that even under normoxic conditions, L2hgdh mutant MTs experience significant metabolic stress and are sensitized to aberrant growth upon Egfr activation. Overall, our findings present a model in which renal L2hgdh activity limits systemic L-2HG accumulation, thus indirectly regulating the balance between glycolytic and mitochondrial metabolism, enabling successful recovery from hypoxia exposure, and ensuring renal tissue integrity.
    Keywords:  Drosophila; L-2-hydroxyglutarate; L2hgdh oncometabolite; hypoxia
    DOI:  https://doi.org/10.1016/j.molmet.2024.102013
  31. Nat Commun. 2024 Aug 28. 15(1): 7460
    EWS-WT1 fusion isoforms establish oncogenic programs and therapeutic vulnerabilities in desmoplastic small round cell tumors.
    Gaylor Boulay, Liliane C Broye, Rui Dong, Sowmya Iyer, Rajendran Sanalkumar, Yu-Hang Xing, Rémi Buisson, Shruthi Rengarajan, Beverly Naigles, Benoît Duc, Angela Volorio, Mary E Awad, Raffaele Renella, Ivan Chebib, G Petur Nielsen, Edwin Choy, Gregory M Cote, Lee Zou, Igor Letovanec, Ivan Stamenkovic, Miguel N Rivera, Nicolò Riggi.
      EWS fusion oncoproteins underlie several human malignancies including Desmoplastic Small Round Cell Tumor (DSRCT), an aggressive cancer driven by EWS-WT1 fusion proteins. Here we combine chromatin occupancy and 3D profiles to identify EWS-WT1-dependent gene regulation networks and target genes. We show that EWS-WT1 is a powerful chromatin activator controlling an oncogenic gene expression program that characterizes primary tumors. Similar to wild type WT1, EWS-WT1 has two isoforms that differ in their DNA binding domain and we find that they have distinct DNA binding profiles and are both required to generate viable tumors that resemble primary DSRCT. Finally, we identify candidate EWS-WT1 target genes with potential therapeutic implications, including CCND1, whose inhibition by the clinically-approved drug Palbociclib leads to marked tumor burden decrease in DSRCT PDXs in vivo. Taken together, our studies identify gene regulation programs and therapeutic vulnerabilities in DSRCT and provide a mechanistic understanding of the complex oncogenic activity of EWS-WT1.
    DOI:  https://doi.org/10.1038/s41467-024-51851-3
  32. Cell. 2024 Aug 23. pii: S0092-8674(24)00889-4. [Epub ahead of print]
    Animal and bacterial viruses share conserved mechanisms of immune evasion.
    Samuel J Hobbs, Jason Nomburg, Jennifer A Doudna, Philip J Kranzusch.
      Animal and bacterial cells sense and defend against viral infections using evolutionarily conserved antiviral signaling pathways. Here, we show that viruses overcome host signaling using mechanisms of immune evasion that are directly shared across the eukaryotic and prokaryotic kingdoms of life. Structures of animal poxvirus proteins that inhibit host cGAS-STING signaling demonstrate architectural and catalytic active-site homology shared with bacteriophage Acb1 proteins, which inactivate CBASS anti-phage defense. In bacteria, phage Acb1 proteins are viral enzymes that degrade host cyclic nucleotide immune signals. Structural comparisons of poxvirus protein-2'3'-cGAMP and phage Acb1-3'3'-cGAMP complexes reveal a universal mechanism of host nucleotide immune signal degradation and explain kingdom-specific additions that enable viral adaptation. Chimeric bacteriophages confirm that animal poxvirus proteins are sufficient to evade immune signaling in bacteria. Our findings identify a mechanism of immune evasion conserved between animal and bacterial viruses and define shared rules that explain host-virus interactions across multiple kingdoms of life.
    Keywords:  CBASS; antiviral immunity; cGAS; cGLR; cyclic nucleotide; immune evasion; poxvirus
    DOI:  https://doi.org/10.1016/j.cell.2024.07.057
  33. Nat Cardiovasc Res. 2024 Jul;3(7): 869-882
    Nuclear ATP-citrate lyase regulates chromatin-dependent activation and maintenance of the myofibroblast gene program.
    Michael P Lazaropoulos, Andrew A Gibb, Douglas J Chapski, Abheya A Nair, Allison N Reiter, Rajika Roy, Deborah M Eaton, Kenneth C Bedi, Kenneth B Margulies, Kathryn E Wellen, Conchi Estarás, Thomas M Vondriska, John W Elrod.
      Differentiation of cardiac fibroblasts to myofibroblasts is necessary for matrix remodeling and fibrosis in heart failure. We previously reported that mitochondrial calcium signaling drives α-ketoglutarate-dependent histone demethylation, promoting myofibroblast formation. Here we investigate the role of ATP-citrate lyase (ACLY), a key enzyme for acetyl-CoA biosynthesis, in histone acetylation regulating myofibroblast fate and persistence in cardiac fibrosis. We show that inactivation of ACLY prevents myofibroblast differentiation and reverses myofibroblasts towards quiescence. Genetic deletion of Acly in post-activated myofibroblasts prevents fibrosis and preserves cardiac function in pressure-overload heart failure. TGFβ stimulation enhances ACLY nuclear localization and ACLY-SMAD2/3 interaction, and increases H3K27ac at fibrotic gene loci. Pharmacological inhibition of ACLY or forced nuclear expression of a dominant-negative ACLY mutant prevents myofibroblast formation and H3K27ac. Our data indicate that nuclear ACLY activity is necessary for myofibroblast differentiation and persistence by maintaining histone acetylation at TGFβ-induced myofibroblast genes. These findings provide targets to prevent and reverse pathological fibrosis.
    DOI:  https://doi.org/10.1038/s44161-024-00502-3
  34. Nat Commun. 2024 Aug 25. 15(1): 7312
    METI: deep profiling of tumor ecosystems by integrating cell morphology and spatial transcriptomics.
    Jiahui Jiang, Yunhe Liu, Jiangjiang Qin, Jianfeng Chen, Jingjing Wu, Melissa P Pizzi, Rossana Lazcano, Kohei Yamashita, Zhiyuan Xu, Guangsheng Pei, Kyung Serk Cho, Yanshuo Chu, Ansam Sinjab, Fuduan Peng, Xinmiao Yan, Guangchun Han, Ruiping Wang, Enyu Dai, Yibo Dai, Bogdan A Czerniak, Andrew Futreal, Anirban Maitra, Alexander Lazar, Humam Kadara, Amir A Jazaeri, Xiangdong Cheng, Jaffer Ajani, Jianjun Gao, Jian Hu, Linghua Wang.
      Recent advances in spatial transcriptomics (ST) techniques provide valuable insights into cellular interactions within the tumor microenvironment (TME). However, most analytical tools lack consideration of histological features and rely on matched single-cell RNA sequencing data, limiting their effectiveness in TME studies. To address this, we introduce the Morphology-Enhanced Spatial Transcriptome Analysis Integrator (METI), an end-to-end framework that maps cancer cells and TME components, stratifies cell types and states, and analyzes cell co-localization. By integrating spatial transcriptomics, cell morphology, and curated gene signatures, METI enhances our understanding of the molecular landscape and cellular interactions within the tissue. We evaluate the performance of METI on ST data generated from various tumor tissues, including gastric, lung, and bladder cancers, as well as premalignant tissues. We also conduct a quantitative comparison of METI with existing clustering and cell deconvolution tools, demonstrating METI's robust and consistent performance.
    DOI:  https://doi.org/10.1038/s41467-024-51708-9
  35. Trends Endocrinol Metab. 2024 Aug 23. pii: S1043-2760(24)00190-5. [Epub ahead of print]
    Exploring the heterogeneous targets of metabolic aging at single-cell resolution.
    Shuhui Sun, Mengmeng Jiang, Shuai Ma, Jie Ren, Guang-Hui Liu.
      Our limited understanding of metabolic aging poses major challenges to comprehending the diverse cellular alterations that contribute to age-related decline, and to devising targeted interventions. This review provides insights into the heterogeneous nature of cellular metabolism during aging and its response to interventions, with a specific focus on cellular heterogeneity and its implications. By synthesizing recent findings using single-cell approaches, we explored the vulnerabilities of distinct cell types and key metabolic pathways. Delving into the cell type-specific alterations underlying the efficacy of systemic interventions, we also discuss the complexity of integrating single-cell data and advocate for leveraging computational tools and artificial intelligence to harness the full potential of these data, develop effective strategies against metabolic aging, and promote healthy aging.
    Keywords:  aging; heterogeneity; intervention; metabolism; single-cell
    DOI:  https://doi.org/10.1016/j.tem.2024.07.009
  36. Cell. 2024 Aug 19. pii: S0092-8674(24)00835-3. [Epub ahead of print]
    Thyroid hormone remodels cortex to coordinate body-wide metabolism and exploration.
    Daniel R Hochbaum, Lauren Hulshof, Amanda Urke, Wengang Wang, Alexandra C Dubinsky, Hannah C Farnsworth, Richard Hakim, Sherry Lin, Giona Kleinberg, Keiramarie Robertson, Canaria Park, Alyssa Solberg, Yechan Yang, Caroline Baynard, Naeem M Nadaf, Celia C Beron, Allison E Girasole, Lynne Chantranupong, Marissa D Cortopassi, Shannon Prouty, Ludwig Geistlinger, Alexander S Banks, Thomas S Scanlan, Sandeep Robert Datta, Michael E Greenberg, Gabriella L Boulting, Evan Z Macosko, Bernardo L Sabatini.
      Animals adapt to environmental conditions by modifying the function of their internal organs, including the brain. To be adaptive, alterations in behavior must be coordinated with the functional state of organs throughout the body. Here, we find that thyroid hormone-a regulator of metabolism in many peripheral organs-directly activates cell-type-specific transcriptional programs in the frontal cortex of adult male mice. These programs are enriched for axon-guidance genes in glutamatergic projection neurons, synaptic regulatory genes in both astrocytes and neurons, and pro-myelination factors in oligodendrocytes, suggesting widespread plasticity of cortical circuits. Indeed, whole-cell electrophysiology revealed that thyroid hormone alters excitatory and inhibitory synaptic transmission, an effect that requires thyroid hormone-induced gene regulatory programs in presynaptic neurons. Furthermore, thyroid hormone action in the frontal cortex regulates innate exploratory behaviors and causally promotes exploratory decision-making. Thus, thyroid hormone acts directly on the cerebral cortex in males to coordinate exploratory behaviors with whole-body metabolic state.
    Keywords:  body-brain coordination; exploration; metabolism; neuroscience; synaptic plasticity; thyroid hormone; transcriptionally regulated behavior
    DOI:  https://doi.org/10.1016/j.cell.2024.07.041
  37. Nat Commun. 2024 Aug 23. 15(1): 7254
    An economic demand-based framework for prioritization strategies in response to transient amino acid limitations.
    Ritu Gupta, Swagata Adhikary, Nidhi Dalpatraj, Sunil Laxman.
      Cells contain disparate amounts of distinct amino acids, each of which has different metabolic and chemical origins, but the supply cost vs demand requirements of each is unclear. Here, using yeast we quantify the restoration-responses after disrupting amino acid supply, and uncover a hierarchically prioritized restoration strategy for distinct amino acids. We comprehensively calculate individual amino acid biosynthetic supply costs, quantify total demand for an amino acid, and estimate cumulative supply/demand requirements for each amino acid. Through this, we discover that the restoration priority is driven by the gross demand for an amino acid, which is itself coupled to low supply costs for that amino acid. Demand from metabolic requirements dominate the demand-pulls for an amino acid, as exemplified by the largest restoration response upon disrupting arginine supply. Collectively, this demand-driven framework that drives the amino acid economy can identify novel amino acid responses, and help design metabolic engineering applications.
    DOI:  https://doi.org/10.1038/s41467-024-51769-w
  38. Curr Top Membr. 2024 ;pii: S1063-5823(24)00020-6. [Epub ahead of print]93 85-116
    Lysosomal membrane contact sites: Integrative hubs for cellular communication and homeostasis.
    Sumit Bandyopadhyay, Daniel Adebayo, Eseiwi Obaseki, Hanaa Hariri.
      Lysosomes are more than just cellular recycling bins; they play a crucial role in regulating key cellular functions. Proper lysosomal function is essential for growth pathway regulation, cell proliferation, and metabolic homeostasis. Impaired lysosomal function is associated with lipid storage disorders and neurodegenerative diseases. Lysosomes form extensive and dynamic close contacts with the membranes of other organelles, including the endoplasmic reticulum, mitochondria, peroxisomes, and lipid droplets. These membrane contacts sites (MCSs) are vital for many lysosomal functions. In this chapter, we will explore lysosomal MCSs focusing on the machinery that mediates these contacts, how they are regulated, and their functional implications on physiology and pathology.
    Keywords:  Lipid homeostasis; Lysosomes; Membrane contact sites; Nutrient sensing; Organelles communication
    DOI:  https://doi.org/10.1016/bs.ctm.2024.07.001
  39. Cell Stem Cell. 2024 Aug 21. pii: S1934-5909(24)00285-6. [Epub ahead of print]
    Mitochondrial serine catabolism safeguards maintenance of the hematopoietic stem cell pool in homeostasis and injury.
    Changhong Du, Chaonan Liu, Kuan Yu, Shuzhen Zhang, Zeyu Fu, Xinliang Chen, Weinian Liao, Jun Chen, Yimin Zhang, Xinmiao Wang, Mo Chen, Fang Chen, Mingqiang Shen, Cheng Wang, Shilei Chen, Song Wang, Junping Wang.
      Hematopoietic stem cells (HSCs) employ a very unique metabolic pattern to maintain themselves, while the spectrum of their metabolic adaptations remains incompletely understood. Here, we uncover a distinct and heterogeneous serine metabolism within HSCs and identify mouse HSCs as a serine auxotroph whose maintenance relies on exogenous serine and the ensuing mitochondrial serine catabolism driven by the hydroxymethyltransferase 2 (SHMT2)-methylene-tetrahydrofolate dehydrogenase 2 (MTHFD2) axis. Mitochondrial serine catabolism primarily feeds NAD(P)H generation to maintain redox balance and thereby diminishes ferroptosis susceptibility of HSCs. Dietary serine deficiency, or genetic or pharmacological inhibition of the SHMT2-MTHFD2 axis, increases ferroptosis susceptibility of HSCs, leading to impaired maintenance of the HSC pool. Moreover, exogenous serine protects HSCs from irradiation-induced myelosuppressive injury by fueling mitochondrial serine catabolism to mitigate ferroptosis. These findings reframe the canonical view of serine from a nonessential amino acid to an essential niche metabolite for HSC pool maintenance.
    Keywords:  NADPH; SHMT2; ferroptosis; hematopoietic stem cell; heterogeneity; ionizing radiation; mitochondrial serine catabolism; myelosuppressive injury
    DOI:  https://doi.org/10.1016/j.stem.2024.07.009
  40. Nat Commun. 2024 Aug 27. 15(1): 7352
    Infection-induced peripheral mitochondria fission drives ER encapsulations and inter-mitochondria contacts that rescue bioenergetics.
    William A Hofstadter, Katelyn C Cook, Elene Tsopurashvili, Robert Gebauer, Vojtěch Pražák, Emily A Machala, Ji Woo Park, Kay Grünewald, Emmanuelle R J Quemin, Ileana M Cristea.
      The dynamic regulation of mitochondria shape via fission and fusion is critical for cellular responses to stimuli. In homeostatic cells, two modes of mitochondrial fission, midzone and peripheral, provide a decision fork between either proliferation or clearance of mitochondria. However, the relationship between specific mitochondria shapes and functions remains unclear in many biological contexts. While commonly associated with decreased bioenergetics, fragmented mitochondria paradoxically exhibit elevated respiration in several disease states, including infection with the prevalent pathogen human cytomegalovirus (HCMV) and metastatic melanoma. Here, incorporating super-resolution microscopy with mass spectrometry and metabolic assays, we use HCMV infection to establish a molecular mechanism for maintaining respiration within a fragmented mitochondria population. We establish that HCMV induces fragmentation through peripheral mitochondrial fission coupled with suppression of mitochondria fusion. Unlike uninfected cells, the progeny of peripheral fission enter mitochondria-ER encapsulations (MENCs) where they are protected from degradation and bioenergetically stabilized during infection. MENCs also stabilize pro-viral inter-mitochondria contacts (IMCs), which electrochemically link mitochondria and promote respiration. Demonstrating a broader relevance, we show that the fragmented mitochondria within metastatic melanoma cells also form MENCs. Our findings establish a mechanism where mitochondria fragmentation can promote increased respiration, a feature relevant in the context of human diseases.
    DOI:  https://doi.org/10.1038/s41467-024-51680-4
  41. Nature. 2024 Aug 28.
    Spatially clustered type I interferon responses at injury borderzones.
    V K Ninh, D M Calcagno, J D Yu, B Zhang, N Taghdiri, R Sehgal, J M Mesfin, C J Chen, K Kalhor, A Toomu, J M Duran, E Adler, J Hu, K Zhang, K L Christman, Z Fu, B Bintu, K R King.
      Sterile inflammation after myocardial infarction is classically credited to myeloid cells interacting with dead cell debris in the infarct zone1,2. Here we show that cardiomyocytes are the dominant initiators of a previously undescribed type I interferon response in the infarct borderzone. Using spatial transcriptomics analysis in mice and humans, we find that myocardial infarction induces colonies of interferon-induced cells (IFNICs) expressing interferon-stimulated genes decorating the borderzone, where cardiomyocytes experience mechanical stress, nuclear rupture and escape of chromosomal DNA. Cardiomyocyte-selective deletion of Irf3 abrogated IFNIC colonies, whereas mice lacking Irf3 in fibroblasts, macrophages, neutrophils or endothelial cells, Ccr2-deficient mice or plasmacytoid-dendritic-cell-depleted mice did not. Interferons blunted the protective matricellular programs and contractile function of borderzone fibroblasts, and increased vulnerability to pathological remodelling. In mice that died after myocardial infarction, IFNIC colonies were immediately adjacent to sites of ventricular rupture, while mice lacking IFNICs were protected from rupture and exhibited improved survival3. Together, these results reveal a pathological borderzone niche characterized by a cardiomyocyte-initiated innate immune response. We suggest that selective inhibition of IRF3 activation in non-immune cells could limit ischaemic cardiomyopathy while avoiding broad immunosuppression.
    DOI:  https://doi.org/10.1038/s41586-024-07806-1
  42. Nat Cardiovasc Res. 2023 Jun;2(6): 504-516
    Metabolite signaling in the heart.
    Emily Flam, Zolt Arany.
      The heart is the most metabolically active organ in the body, sustaining a continuous and high flux of nutrient catabolism via oxidative phosphorylation. The nature and relative contribution of these fuels have been studied extensively for decades. By contrast, less attention has been placed on how intermediate metabolites generated from this catabolism affect intracellular signaling. Numerous metabolites, including intermediates of glycolysis and the tricarboxylic acid (TCA) cycle, nucleotides, amino acids, fatty acids and ketones, are increasingly appreciated to affect signaling in the heart, via various mechanisms ranging from protein-metabolite interactions to modifying epigenetic marks. We review here the current state of knowledge of intermediate metabolite signaling in the heart.
    DOI:  https://doi.org/10.1038/s44161-023-00270-6
  43. Cell Stem Cell. 2024 Aug 16. pii: S1934-5909(24)00287-X. [Epub ahead of print]
    Context-dependent roles of mitochondrial LONP1 in orchestrating the balance between airway progenitor versus progeny cells.
    Le Xu, Chunting Tan, Justinn Barr, Nicole Talaba, Jamie Verheyden, Ji Sun Chin, Samvel Gaboyan, Nikita Kasaraneni, Ruth M Elgamal, Kyle J Gaulton, Grace Lin, Kamyar Afshar, Eugene Golts, Angela Meier, Laura E Crotty Alexander, Zea Borok, Yufeng Shen, Wendy K Chung, David J McCulley, Xin Sun.
      While all eukaryotic cells are dependent on mitochondria for function, in a complex tissue, which cell type and which cell behavior are more sensitive to mitochondrial deficiency remain unpredictable. Here, we show that in the mouse airway, compromising mitochondrial function by inactivating mitochondrial protease gene Lonp1 led to reduced progenitor proliferation and differentiation during development, apoptosis of terminally differentiated ciliated cells and their replacement by basal progenitors and goblet cells during homeostasis, and failed airway progenitor migration into damaged alveoli following influenza infection. ATF4 and the integrated stress response (ISR) pathway are elevated and responsible for the airway phenotypes. Such context-dependent sensitivities are predicted by the selective expression of Bok, which is required for ISR activation. Reduced LONP1 expression is found in chronic obstructive pulmonary disease (COPD) airways with squamous metaplasia. These findings illustrate a cellular energy landscape whereby compromised mitochondrial function could favor the emergence of pathological cell types.
    Keywords:  ATF4; BOK; COPD; airway homeostasis; differentiated progeny cells; influenza infection; integrated stress response; lung epithelial cells; mitochondria; progenitor basal cells
    DOI:  https://doi.org/10.1016/j.stem.2024.08.001
  44. Leukemia. 2024 Aug 26.
    Stearoyl-CoA desaturase inhibition is toxic to acute myeloid leukemia displaying high levels of the de novo fatty acid biosynthesis and desaturation.
    Vilma Dembitz, Hannah Lawson, Richard Burt, Sirisha Natani, Céline Philippe, Sophie C James, Samantha Atkinson, Jozef Durko, Lydia M Wang, Joana Campos, Aoife M S Magee, Keith Woodley, Michael J Austin, Ana Rio-Machin, Pedro Casado, Findlay Bewicke-Copley, Giovanny Rodriguez Blanco, Diego Pereira-Martins, Lieve Oudejans, Emeline Boet, Alex von Kriegsheim, Juerg Schwaller, Andrew J Finch, Bela Patel, Jean-Emmanuel Sarry, Jerome Tamburini, Jan Jacob Schuringa, Lori Hazlehurst, John A Copland Iii, Mariia Yuneva, Barrie Peck, Pedro Cutillas, Jude Fitzgibbon, Kevin Rouault-Pierre, Kamil Kranc, Paolo Gallipoli.
      Identification of specific and therapeutically actionable vulnerabilities, ideally present across multiple mutational backgrounds, is needed to improve acute myeloid leukemia (AML) patients' outcomes. We identify stearoyl-CoA desaturase (SCD), the key enzyme in fatty acid (FA) desaturation, as prognostic of patients' outcomes and, using the clinical-grade inhibitor SSI-4, show that SCD inhibition (SCDi) is a therapeutic vulnerability across multiple AML models in vitro and in vivo. Multiomic analysis demonstrates that SCDi causes lipotoxicity, which induces AML cell death via pleiotropic effects. Sensitivity to SCDi correlates with AML dependency on FA desaturation regardless of mutational profile and is modulated by FA biosynthesis activity. Finally, we show that lipotoxicity increases chemotherapy-induced DNA damage and standard chemotherapy further sensitizes AML cells to SCDi. Our work supports developing FA desaturase inhibitors in AML while stressing the importance of identifying predictive biomarkers of response and biologically validated combination therapies to realize their full therapeutic potential.
    DOI:  https://doi.org/10.1038/s41375-024-02390-9
  45. Cell. 2024 Aug 20. pii: S0092-8674(24)00892-4. [Epub ahead of print]
    The Fanconi anemia pathway induces chromothripsis and ecDNA-driven cancer drug resistance.
    Justin L Engel, Xiao Zhang, Mingming Wu, Yan Wang, Jose Espejo Valle-Inclán, Qing Hu, Kidist S Woldehawariat, Mathijs A Sanders, Agata Smogorzewska, Jin Chen, Isidro Cortés-Ciriano, Roger S Lo, Peter Ly.
      Chromothripsis describes the catastrophic shattering of mis-segregated chromosomes trapped within micronuclei. Although micronuclei accumulate DNA double-strand breaks and replication defects throughout interphase, how chromosomes undergo shattering remains unresolved. Using CRISPR-Cas9 screens, we identify a non-canonical role of the Fanconi anemia (FA) pathway as a driver of chromothripsis. Inactivation of the FA pathway suppresses chromosome shattering during mitosis without impacting interphase-associated defects within micronuclei. Mono-ubiquitination of FANCI-FANCD2 by the FA core complex promotes its mitotic engagement with under-replicated micronuclear chromosomes. The structure-selective SLX4-XPF-ERCC1 endonuclease subsequently induces large-scale nucleolytic cleavage of persistent DNA replication intermediates, which stimulates POLD3-dependent mitotic DNA synthesis to prime shattered fragments for reassembly in the ensuing cell cycle. Notably, FA-pathway-induced chromothripsis generates complex genomic rearrangements and extrachromosomal DNA that confer acquired resistance to anti-cancer therapies. Our findings demonstrate how pathological activation of a central DNA repair mechanism paradoxically triggers cancer genome evolution through chromothripsis.
    Keywords:  DNA repair; DNA replication; Fanconi anemia; chromothripsis; ecDNA; fragile sites; genome rearrangements; genomic instability; micronuclei; mitosis
    DOI:  https://doi.org/10.1016/j.cell.2024.08.001
  46. Nat Commun. 2024 Aug 25. 15(1): 7323
    Structural basis for allosteric regulation of human phosphofructokinase-1.
    Eric M Lynch, Heather Hansen, Lauren Salay, Madison Cooper, Stepan Timr, Justin M Kollman, Bradley A Webb.
      Phosphofructokinase-1 (PFK1) catalyzes the rate-limiting step of glycolysis, committing glucose to conversion into cellular energy. PFK1 is highly regulated to respond to the changing energy needs of the cell. In bacteria, the structural basis of PFK1 regulation is a textbook example of allostery; molecular signals of low and high cellular energy promote transition between an active R-state and inactive T-state conformation, respectively. Little is known, however, about the structural basis for regulation of eukaryotic PFK1. Here, we determine structures of the human liver isoform of PFK1 (PFKL) in the R- and T-state by cryoEM, providing insight into eukaryotic PFK1 allosteric regulatory mechanisms. The T-state structure reveals conformational differences between the bacterial and eukaryotic enzyme, the mechanisms of allosteric inhibition by ATP binding at multiple sites, and an autoinhibitory role of the C-terminus in stabilizing the T-state. We also determine structures of PFKL filaments that define the mechanism of higher-order assembly and demonstrate that these structures are necessary for higher-order assembly of PFKL in cells.
    DOI:  https://doi.org/10.1038/s41467-024-51808-6
  47. Nat Cardiovasc Res. 2023 Sep;2(9): 805-818
    Loss-of-function mutations in Dnmt3a and Tet2 lead to accelerated atherosclerosis and concordant macrophage phenotypes.
    Philipp J Rauch, Jayakrishnan Gopakumar, Alexander J Silver, Daniel Nachun, Herra Ahmad, Marie McConkey, Tetsushi Nakao, Marc Bosse, Thiago Rentz, Nora Vivanco Gonzalez, Noah F Greenwald, Erin F McCaffrey, Zumana Khair, Manu Gopakumar, Kameron B Rodrigues, Amy E Lin, Eti Sinha, Maia Fefer, Drew N Cohen, Amélie Vromman, Eugenia Shvartz, Galina Sukhova, Sean Bendall, Michael Angelo, Peter Libby, Benjamin L Ebert, Siddhartha Jaiswal.
      Clonal hematopoiesis of indeterminate potential (CHIP) is defined by the presence of a cancer-associated somatic mutation in white blood cells in the absence of overt hematological malignancy. It arises most commonly from loss-of-function mutations in the epigenetic regulators DNMT3A and TET2. CHIP predisposes to both hematological malignancies and atherosclerotic cardiovascular disease in humans. Here we demonstrate that loss of Dnmt3a in myeloid cells increased murine atherosclerosis to a similar degree as previously seen with loss of Tet2. Loss of Dnmt3a enhanced inflammation in macrophages in vitro and generated a distinct adventitial macrophage population in vivo which merges a resident macrophage profile with an inflammatory cytokine signature. These changes surprisingly phenocopy the effect of loss of Tet2. Our results identify a common pathway promoting heightened innate immune cell activation with loss of either gene, providing a biological basis for the excess atherosclerotic disease burden in carriers of these two most prevalent CHIP mutations.
    DOI:  https://doi.org/10.1038/s44161-023-00326-7
  48. Trends Biochem Sci. 2024 Aug 23. pii: S0968-0004(24)00188-9. [Epub ahead of print]
    Cytosine methylation flags mitochondrial RNA for degradation.
    Emeline Recazens, Alexis A Jourdain.
      Mitochondrial double-stranded RNA (dsRNA) can form spontaneously in mitochondria, blocking mitochondrial gene expression and triggering an immune response. A recent study by Kim, Tan, et al. identified a safeguard mechanism in which NOP2/Sun RNA methyltransferase 4 (NSUN4)-mediated RNA methylation (m5C) recruits the RNA degradation machinery to prevent dsRNA formation.
    Keywords:  5-methylcytosine; RNA degradation; dsRNA; immunity; mitochondrial RNA; nucleic acid sensing
    DOI:  https://doi.org/10.1016/j.tibs.2024.08.001
  49. Aging Cell. 2024 Aug 26. e14296
    Mitochondrial heterogeneity and crosstalk in aging: Time for a paradigm shift?
    Antentor O Hinton, Zer Vue, Estevão Scudese, Kit Neikirk, Annet Kirabo, Monty Montano.
      The hallmarks of aging have been influential in guiding the biology of aging research, with more recent and growing recognition of the interdependence of these hallmarks on age-related health outcomes. However, a current challenge is personalizing aging trajectories to promote healthy aging, given the diversity of genotypes and lived experience. We suggest that incorporating heterogeneity-including intrinsic (e.g., genetic and structural) and extrinsic (e.g., environmental and exposome) factors and their interdependence of hallmarks-may move the dial. This editorial perspective will focus on one hallmark, namely mitochondrial dysfunction, to exemplify how consideration of heterogeneity and interdependence or crosstalk may reveal new perspectives and opportunities for personalizing aging research. To this end, we highlight heterogeneity within mitochondria as a model.
    Keywords:  aging; mitochondria; organelle contacts; protein targeting; structure
    DOI:  https://doi.org/10.1111/acel.14296
  50. Nat Commun. 2024 Aug 23. 15(1): 7284
    From resonance to chaos by modulating spatiotemporal patterns through a synthetic optogenetic oscillator.
    Jung Hun Park, Gábor Holló, Yolanda Schaerli.
      Oscillations are a recurrent phenomenon in biological systems across scales, but deciphering their fundamental principles is very challenging. Here, we tackle this challenge by redesigning the wellcharacterised synthetic oscillator known as "repressilator" in Escherichia coli and controlling it using optogenetics, creating the "optoscillator". Bacterial colonies manifest oscillations as spatial ring patterns. When we apply periodic light pulses, the optoscillator behaves as a forced oscillator and we systematically investigate the properties of the rings under various light conditions. Combining experiments with mathematical modeling, we demonstrate that this simple oscillatory circuit can generate complex dynamics that are transformed into distinct spatial patterns. We report the observation of synchronisation, resonance, subharmonic resonance and period doubling. Furthermore, we present evidence of a chaotic regime. This work highlights the intricate spatiotemporal patterns accessible by synthetic oscillators and underscores the potential of our approach in revealing fundamental principles of biological oscillations.
    DOI:  https://doi.org/10.1038/s41467-024-51626-w
  51. J Cell Physiol. 2024 Aug 26. e31421
    Impact of oxytosis on the cross-talk of mTORC with mitochondrial proteins in drug-resistant cancer stem cells.
    Santhi L Pandrangi, Prasanthi Chittineedi, Ram K Manthari, Balaji Suhruth.
      By delivering the environmental inputs to transport nutrients and growth factors, Mechanistic Target of Rapamycin (mTOR) plays a significant role in the growth and metabolism of eukaryotic cells through the regulation of numerous elementary cellular processes such as autophagy, protein synthesis, via translation of mitochondrial protein transcription factor A mitochondrial, mitochondrial ribosomal proteins, and mitochondrial respiratory complexes I &V that are encoded in the nucleus with the help of translation initiation factor 4E-BP. These mitochondrial proteins are involved in cell signaling to regulate proper cell growth, proliferation, and death which are essential for tumor growth and proliferation. This suggests that tumor cells are dependent on mTORC1 for various metabolic pathways. However, this crucial regulator is activated and regulated by calcium homeostasis. Mounting evidence suggests the role of calcium ions in regulating mitochondrial enzymes and proteins. Hence, disrupting calcium homeostasis leads to calcium-dependent cell death called "Oxytosis" through hampering the expression of various mitochondrial proteins. "Oxytosis" is a novel non-apoptotic cell death characterized by glutamate cytotoxicity and ferritin degradation. The present review focuses on the crosstalk between mTORC1 and mitochondrial proteins in the cancer pathophysiology and the impact of calcium ions on disrupting mTORC1 leading to the induction of "Oxytosis."
    Keywords:  calcium; mTOR; mitochondria; oxytosis
    DOI:  https://doi.org/10.1002/jcp.31421
  52. Nat Immunol. 2024 Aug 28.
    NaCl enhances CD8+ T cell effector functions in cancer immunotherapy.
    Caterina Scirgolea, Rosa Sottile, Marco De Luca, Alberto Susana, Silvia Carnevale, Simone Puccio, Valentina Ferrari, Veronica Lise, Giorgia Contarini, Alice Scarpa, Eloise Scamardella, Simona Feno, Chiara Camisaschi, Gabriele De Simone, Gianluca Basso, Desiree Giuliano, Emilia Maria Cristina Mazza, Luca Gattinoni, Rahul Roychoudhuri, Emanuele Voulaz, Diletta Di Mitri, Matteo Simonelli, Agnese Losurdo, Davide Pozzi, Carlson Tsui, Axel Kallies, Sara Timo, Giuseppe Martano, Elettra Barberis, Marcello Manfredi, Maria Rescigno, Sebastien Jaillon, Enrico Lugli.
      CD8+ T cells control tumors but inevitably become dysfunctional in the tumor microenvironment. Here, we show that sodium chloride (NaCl) counteracts T cell dysfunction to promote cancer regression. NaCl supplementation during CD8+ T cell culture induced effector differentiation, IFN-γ production and cytotoxicity while maintaining the gene networks responsible for stem-like plasticity. Accordingly, adoptive transfer of tumor-specific T cells resulted in superior anti-tumor immunity in a humanized mouse model. In mice, a high-salt diet reduced the growth of experimental tumors in a CD8+ T cell-dependent manner by inhibiting terminal differentiation and enhancing the effector potency of CD8+ T cells. Mechanistically, NaCl enhanced glutamine consumption, which was critical for transcriptional, epigenetic and functional reprogramming. In humans, CD8+ T cells undergoing antigen recognition in tumors and predicting favorable responses to checkpoint blockade immunotherapy resembled those induced by NaCl. Thus, NaCl metabolism is a regulator of CD8+ T cell effector function, with potential implications for cancer immunotherapy.
    DOI:  https://doi.org/10.1038/s41590-024-01923-9
  53. Nat Cardiovasc Res. 2023 Aug;2(8): 711
    ZBP1 links mtDNA instability to sustained IFN-I responses and cardiomyopathy.
    Maria Papatriantafyllou.
      
    DOI:  https://doi.org/10.1038/s44161-023-00315-w
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