bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2024–06–09
fifty-four papers selected by
Christian Frezza, Universität zu Köln
  1. De novo and salvage purine synthesis pathways across tissues and tumors.
  2. CPT1A loss disrupts BCAA metabolism to confer therapeutic vulnerability in TP53-mutated liver cancer.
  3. Neuronal activity-driven O-GlcNAcylation promotes mitochondrial plasticity.
  4. A developmental constraint model of cancer cell states and tumor heterogeneity.
  5. Nucleotide depletion promotes cell fate transitions by inducing DNA replication stress.
  6. The picky mTORC1 in metabolic enzyme degradation.
  7. Germline status and micronutrient availability regulate a somatic mitochondrial quality control pathway via short-chain fatty acid metabolism.
  8. Circadian-independent light regulation of mammalian metabolism.
  9. Nucleotide metabolism in cancer cells fuels a UDP-driven macrophage cross-talk, promoting immunosuppression and immunotherapy resistance.
  10. UnitedMet harnesses RNA-metabolite covariation to impute metabolite levels in clinical samples.
  11. The ribotoxic stress response drives UV-mediated cell death.
  12. Cysteine S -acetylation is a post-translational modification involved in metabolic regulation.
  13. A myzozoan-specific protein is an essential membrane-anchoring component of the succinate dehydrogenase complex in Toxoplasma parasites.
  14. ZBP1 causes inflammation by inducing RIPK3-mediated necroptosis and RIPK1 kinase activity-independent apoptosis.
  15. Imaging brain glucose metabolism in vivo reveals propionate as a major anaplerotic substrate in pyruvate dehydrogenase deficiency.
  16. TORSEL, a 4EBP1-based mTORC1 live-cell sensor, reveals nutrient-sensing targeting by histone deacetylase inhibitors.
  17. Lipid unsaturation promotes BAX and BAK pore activity during apoptosis.
  18. A mild increase in nutrient signaling to mTORC1 in mice leads to parenchymal damage, myeloid inflammation and shortened lifespan.
  19. Plasma membrane abundance dictates phagocytic capacity and functional cross-talk in myeloid cells.
  20. Nuclear receptor Nur77 and Yin-Yang 1 synergistically increase mitochondrial abundance and activity in macrophages.
  21. Dysfunctional circadian clock accelerates cancer metastasis by intestinal microbiota triggering accumulation of myeloid-derived suppressor cells.
  22. Hungry for fat: Metabolic crosstalk with lipid-rich CAFs fuels pancreatic cancer.
  23. Insights into endothelial metabolic heterogeneity.
  24. ZBTB11 Depletion Targets Metabolic Vulnerabilities in K-Ras Inhibitor Resistant PDAC.
  25. Father's diet influences son's metabolic health through sperm RNA.
  26. Tumor-associated macrophages restrict CD8+ T cell function through collagen deposition and metabolic reprogramming of the breast cancer microenvironment.
  27. A disease-associated gene desert directs macrophage inflammation through ETS2.
  28. Inside the microbial black box: a redox-centric framework for deciphering microbial metabolism.
  29. Fibrotic tumors tune metabolism for immune evasion.
  30. An unexpected role for the ketogenic diet in triggering tumor metastasis by modulating BACH1-mediated transcription.
  31. Intersection of Immunology and Metabolism in Myocardial Disease.
  32. FBP1 orchestrates keratinocyte proliferation/differentiation and suppresses psoriasis through metabolic control of histone acetylation.
  33. Chemoproteomic Identification of Spermidine-Binding Proteins and Antitumor-Immunity Activators.
  34. 2022 WUOF/SIU International Consultation on Urological Diseases: Genetics and Tumor Microenvironment of Renal Cell Carcinoma.
  35. Circadian checkpoint.
  36. Senescent glia link mitochondrial dysfunction and lipid accumulation.
  37. A YAP-centered mechanotransduction loop drives collective breast cancer cell invasion.
  38. Lysosomal control of the cGAS-STING signaling.
  39. Structural basis for human mitochondrial tRNA maturation.
  40. Eating Around the Clock: Circadian Rhythms of Eating and Metabolism.
  41. Enhancing tumor-infiltrating T cells with an exclusive fuel source.
  42. A PRMT5-ZNF326 axis mediates innate immune activation upon replication stress.
  43. Developmental origin of oligodendrocytes determines their function in the adult brain.
  44. Blockage of L2HGDH-mediated S-2HG catabolism orchestrates macrophage polarization to elicit antitumor immunity.
  45. Histone acylation at a glance.
  46. Engineering focusing on cancer.
  47. Isthmus progenitor cells contribute to homeostatic cellular turnover and support regeneration following intestinal injury.
  48. Valine aminoacyl-tRNA synthetase promotes therapy resistance in melanoma.
  49. The manganese transporter SLC39A8 links alkaline ceramidase 1 to inflammatory bowel disease.
  50. Functional diversity among cardiolipin binding sites on the mitochondrial ADP/ATP carrier.
  51. The bioenergetics of nucleocytoplasmic transport.
  52. Cardiolipin clustering promotes mitochondrial membrane dynamics.
  53. Determining the ERK-regulated phosphoproteome driving KRAS-mutant cancer.
  54. Microbiota regulates the TET1-mediated DNA hydroxymethylation program in innate lymphoid cell differentiation.
  1. Cell. 2024 May 30. pii: S0092-8674(24)00520-8. [Epub ahead of print]
    De novo and salvage purine synthesis pathways across tissues and tumors.
    Diem H Tran, Dohun Kim, Rushendhiran Kesavan, Harrison Brown, Trishna Dey, Mona Hoseini Soflaee, Hieu S Vu, Alpaslan Tasdogan, Jason Guo, Divya Bezwada, Houssam Al Saad, Feng Cai, Ashley Solmonson, Halie Rion, Rawand Chabatya, Salma Merchant, Nathan J Manales, Vanina T Tcheuyap, Megan Mulkey, Thomas P Mathews, James Brugarolas, Sean J Morrison, Hao Zhu, Ralph J DeBerardinis, Gerta Hoxhaj.
      Purine nucleotides are vital for RNA and DNA synthesis, signaling, metabolism, and energy homeostasis. To synthesize purines, cells use two principal routes: the de novo and salvage pathways. Traditionally, it is believed that proliferating cells predominantly rely on de novo synthesis, whereas differentiated tissues favor the salvage pathway. Unexpectedly, we find that adenine and inosine are the most effective circulating precursors for supplying purine nucleotides to tissues and tumors, while hypoxanthine is rapidly catabolized and poorly salvaged in vivo. Quantitative metabolic analysis demonstrates comparative contribution from de novo synthesis and salvage pathways in maintaining purine nucleotide pools in tumors. Notably, feeding mice nucleotides accelerates tumor growth, while inhibiting purine salvage slows down tumor progression, revealing a crucial role of the salvage pathway in tumor metabolism. These findings provide fundamental insights into how normal tissues and tumors maintain purine nucleotides and highlight the significance of purine salvage in cancer.
    Keywords:  cancer metabolism; de novo purine synthesis; in vivo isotope tracing; nucleotide diet; nucleotide metabolism; purine bases; purine degradation; purine salvage; tissue; tumor growth
    DOI:  https://doi.org/10.1016/j.cell.2024.05.011
  2. Cancer Lett. 2024 May 31. pii: S0304-3835(24)00400-2. [Epub ahead of print]595 217006
    CPT1A loss disrupts BCAA metabolism to confer therapeutic vulnerability in TP53-mutated liver cancer.
    Yanfeng Liu, Fan Wang, Guoquan Yan, Yu Tong, Wenyun Guo, Songling Li, Yifei Qian, Qianyu Li, Yu Shu, Lei Zhang, Yonglong Zhang, Qiang Xia.
      Driver genomic mutations in tumors define specific molecular subtypes that display distinct malignancy competence, therapeutic resistance and clinical outcome. Although TP53 mutation has been identified as the most common mutation in hepatocellular carcinoma (HCC), current understanding on the biological traits and therapeutic strategies of this subtype has been largely unknown. Here, we reveal that fatty acid β oxidation (FAO) is remarkable repressed in TP53 mutant HCC and which links to poor prognosis in HCC patients. We further demonstrate that carnitine palmitoyltransferase 1 (CPT1A), the rate-limiting enzyme of FAO, is universally downregulated in liver tumor tissues, and which correlates with poor prognosis in HCC and promotes HCC progression in the de novo liver tumor and xenograft tumor models. Mechanically, hepatic Cpt1a loss disrupts lipid metabolism and acetyl-CoA production. Such reduction in acetyl-CoA reduced histone acetylation and epigenetically reprograms branched-chain amino acids (BCAA) catabolism, and leads to the accumulation of cellular BCAAs and hyperactivation of mTOR signaling. Importantly, we reveal that genetic ablation of CPT1A renders TP53 mutant liver cancer mTOR-addicted and sensitivity to mTOR inhibitor AZD-8055 treatment. Consistently, Cpt1a loss in HCC directs tumor cell therapeutic response to AZD-8055. CONCLUSION: Our results show genetic evidence for CPT1A as a metabolic tumor suppressor in HCC and provide a therapeutic approach for TP53 mutant HCC patients.
    Keywords:  BCAA metabolism; CPT1A; Fatty acid β oxidation; Hepatocellular carcinoma; TP53 mutant
    DOI:  https://doi.org/10.1016/j.canlet.2024.217006
  3. Dev Cell. 2024 Jun 04. pii: S1534-5807(24)00325-3. [Epub ahead of print]
    Neuronal activity-driven O-GlcNAcylation promotes mitochondrial plasticity.
    Seungyoon B Yu, Haoming Wang, Richard G Sanchez, Natasha M Carlson, Khanh Nguyen, Andrew Zhang, Zachary D Papich, Ahmed A Abushawish, Zachary Whiddon, Weronika Matysik, Jie Zhang, Thomas C Whisenant, Majid Ghassemian, John N Koberstein, Melissa L Stewart, Samuel A Myers, Gulcin Pekkurnaz.
      Neuronal activity is an energy-intensive process that is largely sustained by instantaneous fuel utilization and ATP synthesis. However, how neurons couple ATP synthesis rate to fuel availability is largely unknown. Here, we demonstrate that the metabolic sensor enzyme O-linked N-acetyl glucosamine (O-GlcNAc) transferase regulates neuronal activity-driven mitochondrial bioenergetics in hippocampal and cortical neurons. We show that neuronal activity upregulates O-GlcNAcylation in mitochondria. Mitochondrial O-GlcNAcylation is promoted by activity-driven glucose consumption, which allows neurons to compensate for high energy expenditure based on fuel availability. To determine the proteins that are responsible for these adjustments, we mapped the mitochondrial O-GlcNAcome of neurons. Finally, we determine that neurons fail to meet activity-driven metabolic demand when O-GlcNAcylation dynamics are prevented. Our findings suggest that O-GlcNAcylation provides a fuel-dependent feedforward control mechanism in neurons to optimize mitochondrial performance based on neuronal activity. This mechanism thereby couples neuronal metabolism to mitochondrial bioenergetics and plays a key role in sustaining energy homeostasis.
    Keywords:  ATP synthesis; O-GlcNAc transferase; O-GlcNAcylation; glycosylation; mitochondria; neuronal metabolism; synaptic activity
    DOI:  https://doi.org/10.1016/j.devcel.2024.05.008
  4. Cell. 2024 Jun 06. pii: S0092-8674(24)00458-6. [Epub ahead of print]187(12): 2907-2918
    A developmental constraint model of cancer cell states and tumor heterogeneity.
    Ayushi S Patel, Itai Yanai.
      Cancer is a disease that stems from a fundamental liability inherent to multicellular life forms in which an individual cell is capable of reneging on the interests of the collective organism. Although cancer is commonly described as an evolutionary process, a less appreciated aspect of tumorigenesis may be the constraints imposed by the organism's developmental programs. Recent work from single-cell transcriptomic analyses across a range of cancer types has revealed the recurrence, plasticity, and co-option of distinct cellular states among cancer cell populations. Here, we note that across diverse cancer types, the observed cell states are proximate within the developmental hierarchy of the cell of origin. We thus posit a model by which cancer cell states are directly constrained by the organism's "developmental map." According to this model, a population of cancer cells traverses the developmental map, thereby generating a heterogeneous set of states whose interactions underpin emergent tumor behavior.
    Keywords:  cancer cell states; cellular plasticity; developmental constraints; tumor heterogeneity; tumorigenesis
    DOI:  https://doi.org/10.1016/j.cell.2024.04.032
  5. Dev Cell. 2024 May 30. pii: S1534-5807(24)00327-7. [Epub ahead of print]
    Nucleotide depletion promotes cell fate transitions by inducing DNA replication stress.
    Brian T Do, Peggy P Hsu, Sidney Y Vermeulen, Zhishan Wang, Taghreed Hirz, Keene L Abbott, Najihah Aziz, Joseph M Replogle, Stefan Bjelosevic, Jonathan Paolino, Samantha A Nelson, Samuel Block, Alicia M Darnell, Raphael Ferreira, Hanyu Zhang, Jelena Milosevic, Daniel R Schmidt, Christopher Chidley, Isaac S Harris, Jonathan S Weissman, Yana Pikman, Kimberly Stegmaier, Sihem Cheloufi, Xiaofeng A Su, David B Sykes, Matthew G Vander Heiden.
      Control of cellular identity requires coordination of developmental programs with environmental factors such as nutrient availability, suggesting that perturbing metabolism can alter cell state. Here, we find that nucleotide depletion and DNA replication stress drive differentiation in human and murine normal and transformed hematopoietic systems, including patient-derived acute myeloid leukemia (AML) xenografts. These cell state transitions begin during S phase and are independent of ATR/ATM checkpoint signaling, double-stranded DNA break formation, and changes in cell cycle length. In systems where differentiation is blocked by oncogenic transcription factor expression, replication stress activates primed regulatory loci and induces lineage-appropriate maturation genes despite the persistence of progenitor programs. Altering the baseline cell state by manipulating transcription factor expression causes replication stress to induce genes specific for alternative lineages. The ability of replication stress to selectively activate primed maturation programs across different contexts suggests a general mechanism by which changes in metabolism can promote lineage-appropriate cell state transitions.
    Keywords:  cancer; cell fate; cell state; dependencies; differentiation; epigenetics; hematopoiesis; metabolism; nucleotides; replication; replication stress
    DOI:  https://doi.org/10.1016/j.devcel.2024.05.010
  6. Mol Cell. 2024 Jun 06. pii: S1097-2765(24)00436-2. [Epub ahead of print]84(11): 2011-2013
    The picky mTORC1 in metabolic enzyme degradation.
    Yujin Chun, David A Fruman, Gina Lee.
      In this issue of Molecular Cell, Yi et al.1 demonstrate that reduced mTORC1 activity induces the CTLH E3 ligase-dependent degradation of HMGCS1, an enzyme in the mevalonate pathway, thus revealing a unique connection between mTORC1 signaling and the degradation of a specific metabolic enzyme via the ubiquitin-proteasome system.
    DOI:  https://doi.org/10.1016/j.molcel.2024.05.013
  7. bioRxiv. 2024 May 21. pii: 2024.05.20.594820. [Epub ahead of print]
    Germline status and micronutrient availability regulate a somatic mitochondrial quality control pathway via short-chain fatty acid metabolism.
    James P Held, Nadir H Dbouk, Adrianna M Strozak, Lantana K Grub, Hayeon Ryou, Samantha H Schaffner, Maulik R Patel.
      Reproductive status, such as pregnancy and menopause in women, profoundly influences metabolism of the body. Mitochondria likely orchestrate many of these metabolic changes. However, the influence of reproductive status on somatic mitochondria and the underlying mechanisms remain largely unexplored. We demonstrate that reproductive signals modulate mitochondria in the Caenorhabditis elegans soma. We show that the germline acts via an RNA endonuclease, HOE-1, which despite its housekeeping role in tRNA maturation, selectively regulates the mitochondrial unfolded protein response (UPRmt). Mechanistically, we uncover a fatty acid metabolism pathway acting upstream of HOE-1 to convey germline status. Furthermore, we link vitamin B12's dietary intake to the germline's regulatory impact on HOE-1-driven UPRmt. Combined, our study uncovers a germline-somatic mitochondrial connection, reveals the underlying mechanism, and highlights the importance of micronutrients in modulating this connection. Our findings provide insights into the interplay between reproductive biology and metabolic regulation.
    DOI:  https://doi.org/10.1101/2024.05.20.594820
  8. Nat Metab. 2024 Jun 03.
    Circadian-independent light regulation of mammalian metabolism.
    Feng Rao, Tian Xue.
      The daily light-dark cycle is a key zeitgeber (time cue) for entraining an organism's biological clock, whereby light sensing by retinal photoreceptors, particularly intrinsically photosensitive retinal ganglion cells, stimulates the suprachiasmatic nucleus of the hypothalamus, a central pacemaker that in turn orchestrates the rhythm of peripheral metabolic activities. Non-rhythmic effects of light on metabolism have also been long known, and their transduction mechanisms are only beginning to unfold. Here, we summarize emerging evidence that, in mammals, light exposure or deprivation profoundly affects glucose homeostasis, thermogenesis and other metabolic activities in a clock-independent manner. Such light regulation could involve melanopsin-based, intrinsically photosensitive retinal ganglion cell-initiated brain circuits via the suprachiasmatic nucleus of the hypothalamus and other nuclei, or direct stimulation of opsins expressed in the hypothalamus, adipose tissue, blood vessels and skin to regulate sympathetic tone, lipolysis, glucose uptake, mitochondrial activation, thermogenesis, food intake, blood pressure and melanogenesis. These photic signalling events may coordinate with circadian-based mechanisms to maintain metabolic homeostasis, with dysregulation of this system underlying metabolic diseases caused by aberrant light exposure, such as environmental night light and shift work.
    DOI:  https://doi.org/10.1038/s42255-024-01051-6
  9. Nat Cancer. 2024 Jun 06.
    Nucleotide metabolism in cancer cells fuels a UDP-driven macrophage cross-talk, promoting immunosuppression and immunotherapy resistance.
    Tommaso Scolaro, Marta Manco, Mathieu Pecqueux, Ricardo Amorim, Rosa Trotta, Heleen H Van Acker, Matthias Van Haele, Niranjan Shirgaonkar, Stefan Naulaerts, Jan Daniluk, Fran Prenen, Chiara Varamo, Donatella Ponti, Ginevra Doglioni, Ana Margarida Ferreira Campos, Juan Fernandez Garcia, Silvia Radenkovic, Pegah Rouhi, Aleksandar Beatovic, Liwei Wang, Yu Wang, Amalia Tzoumpa, Asier Antoranz, Ara Sargsian, Mario Di Matteo, Emanuele Berardi, Jermaine Goveia, Bart Ghesquière, Tania Roskams, Stefaan Soenen, Thomas Voets, Bella Manshian, Sarah-Maria Fendt, Peter Carmeliet, Abhishek D Garg, Ramanuj DasGupta, Baki Topal, Massimiliano Mazzone.
      Many individuals with cancer are resistant to immunotherapies. Here, we identify the gene encoding the pyrimidine salvage pathway enzyme cytidine deaminase (CDA) among the top upregulated metabolic genes in several immunotherapy-resistant tumors. We show that CDA in cancer cells contributes to the uridine diphosphate (UDP) pool. Extracellular UDP hijacks immunosuppressive tumor-associated macrophages (TAMs) through its receptor P2Y6. Pharmacologic or genetic inhibition of CDA in cancer cells (or P2Y6 in TAMs) disrupts TAM-mediated immunosuppression, promoting cytotoxic T cell entry and susceptibility to anti-programmed cell death protein 1 (anti-PD-1) treatment in resistant pancreatic ductal adenocarcinoma (PDAC) and melanoma models. Conversely, CDA overexpression in CDA-depleted PDACs or anti-PD-1-responsive colorectal tumors or systemic UDP administration (re)establishes resistance. In individuals with PDAC, high CDA levels in cancer cells correlate with increased TAMs, lower cytotoxic T cells and possibly anti-PD-1 resistance. In a pan-cancer single-cell atlas, CDAhigh cancer cells match with T cell cytotoxicity dysfunction and P2RY6high TAMs. Overall, we suggest CDA and P2Y6 as potential targets for cancer immunotherapy.
    DOI:  https://doi.org/10.1038/s43018-024-00771-8
  10. medRxiv. 2024 May 25. pii: 2024.05.24.24307903. [Epub ahead of print]
    UnitedMet harnesses RNA-metabolite covariation to impute metabolite levels in clinical samples.
    Amy X Xie, Wesley Tansey, Ed Reznik.
      Comprehensively studying metabolism requires the measurement of metabolite levels. However, in contrast to the broad availability of gene expression data, metabolites are rarely measured in large molecularly-defined cohorts of tissue samples. To address this basic barrier to metabolic discovery, we propose a Bayesian framework ("UnitedMet") which leverages the empirical strength of RNA-metabolite covariation to impute otherwise unmeasured metabolite levels from widely available transcriptomic data. We demonstrate that UnitedMet is equally capable of imputing whole pool sizes as well as the outcomes of isotope tracing experiments. We apply UnitedMet to investigate the metabolic impact of driver mutations in kidney cancer, identifying a novel association between BAP1 and a highly oxidative tumor phenotype. We similarly apply UnitedMet to determine that advanced kidney cancers upregulate oxidative phosphorylation relative to early-stage disease, that oxidative metabolism in kidney cancer is associated with inferior outcomes to combination therapy, and that kidney cancer metastases themselves demonstrate elevated oxidative phosphorylation relative to primary tumors. UnitedMet therefore enables the assessment of metabolic phenotypes in contexts where metabolite measurements were not taken or are otherwise infeasible, opening new avenues for the generation and evaluation of metabolite-centered hypotheses. UnitedMet is open source and publicly available ( https://github.com/reznik-lab/UnitedMet ).
    DOI:  https://doi.org/10.1101/2024.05.24.24307903
  11. Cell. 2024 May 31. pii: S0092-8674(24)00527-0. [Epub ahead of print]
    The ribotoxic stress response drives UV-mediated cell death.
    Niladri K Sinha, Connor McKenney, Zhong Y Yeow, Jeffrey J Li, Ki Hong Nam, Tomer M Yaron-Barir, Jared L Johnson, Emily M Huntsman, Lewis C Cantley, Alban Ordureau, Sergi Regot, Rachel Green.
      While ultraviolet (UV) radiation damages DNA, eliciting the DNA damage response (DDR), it also damages RNA, triggering transcriptome-wide ribosomal collisions and eliciting a ribotoxic stress response (RSR). However, the relative contributions, timing, and regulation of these pathways in determining cell fate is unclear. Here we use time-resolved phosphoproteomic, chemical-genetic, single-cell imaging, and biochemical approaches to create a chronological atlas of signaling events activated in cells responding to UV damage. We discover that UV-induced apoptosis is mediated by the RSR kinase ZAK and not through the DDR. We identify two negative-feedback modules that regulate ZAK-mediated apoptosis: (1) GCN2 activation limits ribosomal collisions and attenuates ZAK-mediated RSR and (2) ZAK activity leads to phosphodegron autophosphorylation and its subsequent degradation. These events tune ZAK's activity to collision levels to establish regimes of homeostasis, tolerance, and death, revealing its key role as the cellular sentinel for nucleic acid damage.
    Keywords:  DNA damage response; GCN2; UV radiation; ZAK; apoptosis; collisions; phosphoproteomics; ribosomes; ribotoxic stress; signaling
    DOI:  https://doi.org/10.1016/j.cell.2024.05.018
  12. bioRxiv. 2024 May 21. pii: 2024.05.21.595030. [Epub ahead of print]
    Cysteine S -acetylation is a post-translational modification involved in metabolic regulation.
    E Keith Keenan, Akshay Bareja, Yannie Lam, Paul A Grimsrud, Matthew D Hirschey.
      Cysteine is a reactive amino acid central to the catalytic activities of many enzymes. It is also a common target of post-translational modifications (PTMs), such as palmitoylation. This long-chain acyl PTM can modify cysteine residues and induce changes in protein subcellular localization. We hypothesized that cysteine could also be modified by short-chain acyl groups, such as cysteine S -acetylation. To test this, we developed sample preparation and non-targeted mass spectrometry protocols to analyze the mouse liver proteome for cysteine acetylation. Our findings revealed hundreds of sites of cysteine acetylation across multiple tissue types, revealing a previously uncharacterized cysteine acetylome. Cysteine acetylation shows a marked cytoplasmic subcellular localization signature, with tissue-specific acetylome patterns and specific changes upon metabolic stress. This study uncovers a novel aspect of cysteine biochemistry, highlighting short-chain modifications alongside known long-chain acyl PTMs. These findings enrich our understanding of the landscape of acyl modifications and suggest new research directions in enzyme activity regulation and cellular signaling in metabolism.
    DOI:  https://doi.org/10.1101/2024.05.21.595030
  13. Open Biol. 2024 Jun;14(6): 230463
    A myzozoan-specific protein is an essential membrane-anchoring component of the succinate dehydrogenase complex in Toxoplasma parasites.
    Soraya M Zwahlen, Jenni A Hayward, Capella S Maguire, Alex R Qin, Giel G van Dooren.
      Succinate dehydrogenase (SDH) is a protein complex that functions in the tricarboxylic acid cycle and the electron transport chain of mitochondria. In most eukaryotes, SDH is highly conserved and comprises the following four subunits: SdhA and SdhB form the catalytic core of the complex, while SdhC and SdhD anchor the complex in the membrane. Toxoplasma gondii is an apicomplexan parasite that infects one-third of humans worldwide. The genome of T. gondii encodes homologues of the catalytic subunits SdhA and SdhB, although the physiological role of the SDH complex in the parasite and the identity of the membrane-anchoring subunits are poorly understood. Here, we show that the SDH complex contributes to optimal proliferation and O2 consumption in the disease-causing tachyzoite stage of the T. gondii life cycle. We characterize a small membrane-bound subunit of the SDH complex called mitochondrial protein ookinete developmental defect (MPODD), which is conserved among myzozoans, a phylogenetic grouping that incorporates apicomplexan parasites and their closest free-living relatives. We demonstrate that TgMPODD is essential for SDH activity and plays a key role in attaching the TgSdhA and TgSdhB proteins to the membrane anchor of the complex. Our findings highlight a unique and important feature of mitochondrial energy metabolism in apicomplexan parasites and their relatives.
    Keywords:  Toxoplasma; apicomplexa; electron transport chain; mitochondria; tricarboxylic acid cycle
    DOI:  https://doi.org/10.1098/rsob.230463
  14. Cell Death Differ. 2024 Jun 07.
    ZBP1 causes inflammation by inducing RIPK3-mediated necroptosis and RIPK1 kinase activity-independent apoptosis.
    Lioba Koerner, Laurens Wachsmuth, Snehlata Kumari, Robin Schwarzer, Theresa Wagner, Huipeng Jiao, Manolis Pasparakis.
      Z-DNA binding protein 1 (ZBP1) has important functions in anti-viral immunity and in the regulation of inflammatory responses. ZBP1 induces necroptosis by directly engaging and activating RIPK3, however, the mechanisms by which ZBP1 induces inflammation and in particular the role of RIPK1 and the contribution of cell death-independent signaling remain elusive. Here we show that ZBP1 causes skin inflammation by inducing RIPK3-mediated necroptosis and RIPK1-caspase-8-mediated apoptosis in keratinocytes. ZBP1 induced TNFR1-independent skin inflammation in mice with epidermis-specific ablation of FADD by triggering keratinocyte necroptosis. Moreover, transgenic expression of C-terminally truncated constitutively active ZBP1 (ZBP1ca) in mouse epidermis caused skin inflammation that was only partially inhibited by abrogation of RIPK3-MLKL-dependent necroptosis and fully prevented by combined deficiency in MLKL and caspase-8. Importantly, ZBP1ca induced caspase-8-mediated skin inflammation by RHIM-dependent but kinase activity-independent RIPK1 signaling. Furthermore, ZBP1ca-induced inflammatory cytokine production in the skin was completely prevented by combined inhibition of apoptosis and necroptosis arguing against a cell death-independent pro-inflammatory function of ZBP1. Collectively, these results showed that ZBP1 induces inflammation by activating necroptosis and RIPK1 kinase activity-independent apoptosis.
    DOI:  https://doi.org/10.1038/s41418-024-01321-6
  15. Cell Metab. 2024 Jun 04. pii: S1550-4131(24)00178-5. [Epub ahead of print]36(6): 1394-1410.e12
    Imaging brain glucose metabolism in vivo reveals propionate as a major anaplerotic substrate in pyruvate dehydrogenase deficiency.
    Isaac Marin-Valencia, Arif Kocabas, Carlos Rodriguez-Navas, Vesselin Z Miloushev, Manuel González-Rodríguez, Hannah Lees, Kelly E Henry, Jake Vaynshteyn, Valerie Longo, Kofi Deh, Roozbeh Eskandari, Arsen Mamakhanyan, Marjan Berishaj, Kayvan R Keshari.
      A vexing problem in mitochondrial medicine is our limited capacity to evaluate the extent of brain disease in vivo. This limitation has hindered our understanding of the mechanisms that underlie the imaging phenotype in the brain of patients with mitochondrial diseases and our capacity to identify new biomarkers and therapeutic targets. Using comprehensive imaging, we analyzed the metabolic network that drives the brain structural and metabolic features of a mouse model of pyruvate dehydrogenase deficiency (PDHD). As the disease progressed in this animal, in vivo brain glucose uptake and glycolysis increased. Propionate served as a major anaplerotic substrate, predominantly metabolized by glial cells. A combination of propionate and a ketogenic diet extended lifespan, improved neuropathology, and ameliorated motor deficits in these animals. Together, intermediary metabolism is quite distinct in the PDHD brain-it plays a key role in the imaging phenotype, and it may uncover new treatments for this condition.
    Keywords:  brain; glucose; imaging; ketogenic diet; metabolism; propionate; pyruvate; pyruvate dehydrogenase deficiency
    DOI:  https://doi.org/10.1016/j.cmet.2024.05.002
  16. Cell Biosci. 2024 Jun 01. 14(1): 68
    TORSEL, a 4EBP1-based mTORC1 live-cell sensor, reveals nutrient-sensing targeting by histone deacetylase inhibitors.
    Canrong Li, Yuguo Yi, Yingyi Ouyang, Fengzhi Chen, Chuxin Lu, Shujun Peng, Yifan Wang, Xinyu Chen, Xiao Yan, Haolun Xu, Shuiming Li, Lin Feng, Xiaoduo Xie.
       BACKGROUND: Mammalian or mechanistic target of rapamycin complex 1 (mTORC1) is an effective therapeutic target for diseases such as cancer, diabetes, aging, and neurodegeneration. However, an efficient tool for monitoring mTORC1 inhibition in living cells or tissues is lacking.
    RESULTS: We developed a genetically encoded mTORC1 sensor called TORSEL. This sensor changes its fluorescence pattern from diffuse to punctate when 4EBP1 dephosphorylation occurs and interacts with eIF4E. TORSEL can specifically sense the physiological, pharmacological, and genetic inhibition of mTORC1 signaling in living cells and tissues. Importantly, TORSEL is a valuable tool for imaging-based visual screening of mTORC1 inhibitors. Using TORSEL, we identified histone deacetylase inhibitors that selectively block nutrient-sensing signaling to inhibit mTORC1.
    CONCLUSIONS: TORSEL is a unique living cell sensor that efficiently detects the inhibition of mTORC1 activity, and histone deacetylase inhibitors such as panobinostat target mTORC1 signaling through amino acid sensing.
    Keywords:  Amino acid sensing; HDAC inhibitor; Live-cell sensor; Panobinostat; mTORC1
    DOI:  https://doi.org/10.1186/s13578-024-01250-4
  17. Nat Commun. 2024 Jun 03. 15(1): 4700
    Lipid unsaturation promotes BAX and BAK pore activity during apoptosis.
    Shashank Dadsena, Rodrigo Cuevas Arenas, Gonçalo Vieira, Susanne Brodesser, Manuel N Melo, Ana J García-Sáez.
      BAX and BAK are proapoptotic members of the BCL2 family that directly mediate mitochondrial outer membrane permeabilition (MOMP), a central step in apoptosis execution. However, the molecular architecture of the mitochondrial apoptotic pore remains a key open question and especially little is known about the contribution of lipids to MOMP. By performing a comparative lipidomics analysis of the proximal membrane environment of BAK isolated in lipid nanodiscs, we find a significant enrichment of unsaturated species nearby BAK and BAX in apoptotic conditions. We then demonstrate that unsaturated lipids promote BAX pore activity in model membranes, isolated mitochondria and cellular systems, which is further supported by molecular dynamics simulations. Accordingly, the fatty acid desaturase FADS2 not only enhances apoptosis sensitivity, but also the activation of the cGAS/STING pathway downstream mtDNA release. The correlation of FADS2 levels with the sensitization to apoptosis of different lung and kidney cancer cell lines by co-treatment with unsaturated fatty acids supports the relevance of our findings. Altogether, our work provides an insight on how local lipid environment affects BAX and BAK function during apoptosis.
    DOI:  https://doi.org/10.1038/s41467-024-49067-6
  18. Nat Aging. 2024 Jun 07.
    A mild increase in nutrient signaling to mTORC1 in mice leads to parenchymal damage, myeloid inflammation and shortened lifespan.
    Ana Ortega-Molina, Cristina Lebrero-Fernández, Alba Sanz, Miguel Calvo-Rubio, Nerea Deleyto-Seldas, Lucía de Prado-Rivas, Ana Belén Plata-Gómez, Elena Fernández-Florido, Patricia González-García, Yurena Vivas-García, Elena Sánchez García, Osvaldo Graña-Castro, Nathan L Price, Alejandra Aroca-Crevillén, Eduardo Caleiras, Daniel Monleón, Consuelo Borrás, María Casanova-Acebes, Rafael de Cabo, Alejo Efeyan.
      The mechanistic target of rapamycin complex 1 controls cellular anabolism in response to growth factor signaling and to nutrient sufficiency signaled through the Rag GTPases. Inhibition of mTOR reproducibly extends longevity across eukaryotes. Here we report that mice that endogenously express active mutant variants of RagC exhibit multiple features of parenchymal damage that include senescence, expression of inflammatory molecules, increased myeloid inflammation with extensive features of inflammaging and a ~30% reduction in lifespan. Through bone marrow transplantation experiments, we show that myeloid cells are abnormally activated by signals emanating from dysfunctional RagC-mutant parenchyma, causing neutrophil extravasation that inflicts additional inflammatory damage. Therapeutic suppression of myeloid inflammation in aged RagC-mutant mice attenuates parenchymal damage and extends survival. Together, our findings link mildly increased nutrient signaling to limited lifespan in mammals, and support a two-component process of parenchymal damage and myeloid inflammation that together precipitate a time-dependent organ deterioration that limits longevity.
    DOI:  https://doi.org/10.1038/s43587-024-00635-x
  19. Sci Immunol. 2024 Jun 07. 9(96): eadl2388
    Plasma membrane abundance dictates phagocytic capacity and functional cross-talk in myeloid cells.
    Benjamin Y Winer, Alexander H Settle, Alexandrina M Yakimov, Carlos Jeronimo, Tomi Lazarov, Murray Tipping, Michelle Saoi, Anjelique Sawh, Anna-Liisa L Sepp, Michael Galiano, Justin S A Perry, Yung Yu Wong, Frederic Geissmann, Justin Cross, Ting Zhou, Lance C Kam, H Amalia Pasolli, Tobias Hohl, Jason G Cyster, Orion D Weiner, Morgan Huse.
      Professional phagocytes like neutrophils and macrophages tightly control what they consume, how much they consume, and when they move after cargo uptake. We show that plasma membrane abundance is a key arbiter of these cellular behaviors. Neutrophils and macrophages lacking the G protein subunit Gβ4 exhibited profound plasma membrane expansion, accompanied by marked reduction in plasma membrane tension. These biophysical changes promoted the phagocytosis of bacteria, fungus, apoptotic corpses, and cancer cells. We also found that Gβ4-deficient neutrophils are defective in the normal inhibition of migration following cargo uptake. Sphingolipid synthesis played a central role in these phenotypes by driving plasma membrane accumulation in cells lacking Gβ4. In Gβ4 knockout mice, neutrophils not only exhibited enhanced phagocytosis of inhaled fungal conidia in the lung but also increased trafficking of engulfed pathogens to other organs. Together, these results reveal an unexpected, biophysical control mechanism central to myeloid functional decision-making.
    DOI:  https://doi.org/10.1126/sciimmunol.adl2388
  20. FEBS Lett. 2024 Jun 02.
    Nuclear receptor Nur77 and Yin-Yang 1 synergistically increase mitochondrial abundance and activity in macrophages.
    Duco S Koenis, Inkie J A Evers-van Gogh, Pieter B van Loenen, Wilbert Zwart, Eric Kalkhoven, Carlie J M de Vries.
      Mitochondrial biogenesis requires precise regulation of both mitochondrial-encoded and nuclear-encoded genes. Nuclear receptor Nur77 is known to regulate mitochondrial metabolism in macrophages and skeletal muscle. Here, we compared genome-wide Nur77 binding site and target gene expression in these two cell types, which revealed conserved regulation of mitochondrial genes and enrichment of motifs for the transcription factor Yin-Yang 1 (YY1). We show that Nur77 and YY1 interact, that YY1 increases Nur77 activity, and that their binding sites are co-enriched at mitochondrial ribosomal protein gene loci in macrophages. Nur77 and YY1 co-expression synergistically increases Mrpl1 expression as well as mitochondrial abundance and activity in macrophages but not skeletal muscle. As such, we identify a macrophage-specific Nur77-YY1 interaction that enhances mitochondrial metabolism.
    Keywords:  macrophage; mitochondria; nuclear receptor; skeletal muscle; transcriptional regulation
    DOI:  https://doi.org/10.1002/1873-3468.14942
  21. Cell Metab. 2024 Jun 04. pii: S1550-4131(24)00172-4. [Epub ahead of print]36(6): 1320-1334.e9
    Dysfunctional circadian clock accelerates cancer metastasis by intestinal microbiota triggering accumulation of myeloid-derived suppressor cells.
    Jing-Lin Liu, Xu Xu, Youlutuziayi Rixiati, Chu-Yi Wang, Heng-Li Ni, Wen-Shu Chen, Hui-Min Gong, Zi-Long Zhang, Shi Li, Tong Shen, Jian-Ming Li.
      Circadian homeostasis in mammals is a key intrinsic mechanism for responding to the external environment. However, the interplay between circadian rhythms and the tumor microenvironment (TME) and its influence on metastasis are still unclear. Here, in patients with colorectal cancer (CRC), disturbances of circadian rhythm and the accumulation of monocytes and granulocytes were closely related to metastasis. Moreover, dysregulation of circadian rhythm promoted lung metastasis of CRC by inducing the accumulation of myeloid-derived suppressor cells (MDSCs) and dysfunctional CD8+ T cells in the lungs of mice. Also, gut microbiota and its derived metabolite taurocholic acid (TCA) contributed to lung metastasis of CRC by triggering the accumulation of MDSCs in mice. Mechanistically, TCA promoted glycolysis of MDSCs epigenetically by enhancing mono-methylation of H3K4 of target genes and inhibited CHIP-mediated ubiquitination of PDL1. Our study links the biological clock with MDSCs in the TME through gut microbiota/metabolites in controlling the metastatic spread of CRC, uncovering a systemic mechanism for cancer metastasis.
    Keywords:  circadian clock; intestinal microbiota; metabolites; metastasis; myeloid-derived suppressor cells
    DOI:  https://doi.org/10.1016/j.cmet.2024.04.019
  22. Cell Metab. 2024 Jun 04. pii: S1550-4131(24)00183-9. [Epub ahead of print]36(6): 1172-1174
    Hungry for fat: Metabolic crosstalk with lipid-rich CAFs fuels pancreatic cancer.
    Kostas A Papavassiliou, Athanasios G Papavassiliou.
      Some cancers prefer to metabolize lipids for their growth and metastasis. In a recent Cancer Cell study, Niu et al. revealed that SET domain containing 2, histone lysine methyltransferase (SETD2)-deficient pancreatic cancer cells induce the differentiation of lipid-laden cancer-associated fibroblasts (CAFs), which, in turn, transport lipids to promote tumor growth.
    DOI:  https://doi.org/10.1016/j.cmet.2024.05.007
  23. Nat Rev Cardiol. 2024 Jun 05.
    Insights into endothelial metabolic heterogeneity.
    Corey McAleese.
      
    DOI:  https://doi.org/10.1038/s41569-024-01049-3
  24. bioRxiv. 2024 May 21. pii: 2024.05.19.594824. [Epub ahead of print]
    ZBTB11 Depletion Targets Metabolic Vulnerabilities in K-Ras Inhibitor Resistant PDAC.
    Nathan L Tran, Jiewei Jiang, Min Ma, Gillian E Gadbois, Kevin C M Gulay, Alyssa Verano, Haowen Zhou, Chun-Teng Huang, David A Scott, Anne G Bang, Herve Tiriac, Andrew M Lowy, Eric S Wang, Fleur M Ferguson.
      Over 95% of pancreatic ductal adenocarcinomas (PDAC) harbor oncogenic mutations in K-Ras. Upon treatment with K-Ras inhibitors, PDAC cancer cells undergo metabolic reprogramming towards an oxidative phosphorylation-dependent, drug-resistant state. However, direct inhibition of complex I is poorly tolerated in patients due to on-target induction of peripheral neuropathy. In this work, we develop molecular glue degraders against ZBTB11, a C2H2 zinc finger transcription factor that regulates the nuclear transcription of components of the mitoribosome and electron transport chain. Our ZBTB11 degraders leverage the differences in demand for biogenesis of mitochondrial components between human neurons and rapidly-dividing pancreatic cancer cells, to selectively target the K-Ras inhibitor resistant state in PDAC. Combination treatment of both K-Ras inhibitor-resistant cell lines and multidrug resistant patient-derived organoids resulted in superior anti-cancer activity compared to single agent treatment, while sparing hiPSC-derived neurons. Proteomic and stable isotope tracing studies revealed mitoribosome depletion and impairment of the TCA cycle as key events that mediate this response. Together, this work validates ZBTB11 as a vulnerability in K-Ras inhibitor-resistant PDAC and provides a suite of molecular glue degrader tool compounds to investigate its function.
    DOI:  https://doi.org/10.1101/2024.05.19.594824
  25. Nature. 2024 Jun 05.
    Father's diet influences son's metabolic health through sperm RNA.
    Chen Cai, Qi Chen.
      
    Keywords:  Metabolism; Non-coding RNAs; Obesity
    DOI:  https://doi.org/10.1038/d41586-024-01502-w
  26. Nat Cancer. 2024 Jun 03.
    Tumor-associated macrophages restrict CD8+ T cell function through collagen deposition and metabolic reprogramming of the breast cancer microenvironment.
    Kevin M Tharp, Kelly Kersten, Ori Maller, Greg A Timblin, Connor Stashko, Fernando P Canale, Rosa E Menjivar, Mary-Kate Hayward, Ilona Berestjuk, Johanna Ten Hoeve, Bushra Samad, Alastrair J Ironside, Marina Pasca di Magliano, Alexander Muir, Roger Geiger, Alexis J Combes, Valerie M Weaver.
      Tumor progression is accompanied by fibrosis, a condition of excessive extracellular matrix accumulation, which is associated with diminished antitumor immune infiltration. Here we demonstrate that tumor-associated macrophages (TAMs) respond to the stiffened fibrotic tumor microenvironment (TME) by initiating a collagen biosynthesis program directed by transforming growth factor-β. A collateral effect of this programming is an untenable metabolic milieu for productive CD8+ T cell antitumor responses, as collagen-synthesizing macrophages consume environmental arginine, synthesize proline and secrete ornithine that compromises CD8+ T cell function in female breast cancer. Thus, a stiff and fibrotic TME may impede antitumor immunity not only by direct physical exclusion of CD8+ T cells but also through secondary effects of a mechano-metabolic programming of TAMs, which creates an inhospitable metabolic milieu for CD8+ T cells to respond to anticancer immunotherapies.
    DOI:  https://doi.org/10.1038/s43018-024-00775-4
  27. Nature. 2024 Jun 05.
    A disease-associated gene desert directs macrophage inflammation through ETS2.
    C T Stankey, C Bourges, L M Haag, T Turner-Stokes, A P Piedade, C Palmer-Jones, I Papa, M Silva Dos Santos, Q Zhang, A J Cameron, A Legrini, T Zhang, C S Wood, F N New, L O Randzavola, L Speidel, A C Brown, A Hall, F Saffioti, E C Parkes, W Edwards, H Direskeneli, P C Grayson, L Jiang, P A Merkel, G Saruhan-Direskeneli, A H Sawalha, E Tombetti, A Quaglia, D Thorburn, J C Knight, A P Rochford, C D Murray, P Divakar, M Green, E Nye, J I MacRae, N B Jamieson, P Skoglund, M Z Cader, C Wallace, D C Thomas, J C Lee.
      Increasing rates of autoimmune and inflammatory disease present a burgeoning threat to human health1. This is compounded by the limited efficacy of available treatments1 and high failure rates during drug development2, highlighting an urgent need to better understand disease mechanisms. Here we show how functional genomics could address this challenge. By investigating an intergenic haplotype on chr21q22-which has been independently linked to inflammatory bowel disease, ankylosing spondylitis, primary sclerosing cholangitis and Takayasu's arteritis3-6-we identify that the causal gene, ETS2, is a central regulator of human inflammatory macrophages and delineate the shared disease mechanism that amplifies ETS2 expression. Genes regulated by ETS2 were prominently expressed in diseased tissues and more enriched for inflammatory bowel disease GWAS hits than most previously described pathways. Overexpressing ETS2 in resting macrophages reproduced the inflammatory state observed in chr21q22-associated diseases, with upregulation of multiple drug targets, including TNF and IL-23. Using a database of cellular signatures7, we identified drugs that might modulate this pathway and validated the potent anti-inflammatory activity of one class of small molecules in vitro and ex vivo. Together, this illustrates the power of functional genomics, applied directly in primary human cells, to identify immune-mediated disease mechanisms and potential therapeutic opportunities.
    DOI:  https://doi.org/10.1038/s41586-024-07501-1
  28. Trends Microbiol. 2024 Jun 01. pii: S0966-842X(24)00134-3. [Epub ahead of print]
    Inside the microbial black box: a redox-centric framework for deciphering microbial metabolism.
    John A Bouranis, Malak M Tfaily.
      Microbial metabolism influences the global climate and human health and is governed by the balance between NADH and NAD+ through redox reactions. Historically, oxidative (i.e., catabolism) and reductive (i.e., fermentation) pathways have been studied in isolation, obscuring the complete metabolic picture. However, new omics technologies and biotechnological tools now allow an integrated system-level understanding of the drivers of microbial metabolism through observation and manipulation of redox reactions. Here we present perspectives on the importance of viewing microbial metabolism as the dynamic interplay between oxidative and reductive processes and apply this framework to diverse microbial systems. Additionally, we highlight novel biotechnologies to monitor and manipulate microbial redox status to control metabolism in unprecedented ways. This redox-focused systems biology framework enables a more mechanistic understanding of microbial metabolism.
    Keywords:  NADH; biogeochemical cycling; metabolism; microbiome; redox
    DOI:  https://doi.org/10.1016/j.tim.2024.05.003
  29. Nat Cancer. 2024 Jun 03.
    Fibrotic tumors tune metabolism for immune evasion.
    Matthew D Perricone, Costas A Lyssiotis.
      
    DOI:  https://doi.org/10.1038/s43018-024-00758-5
  30. Sci Adv. 2024 Jun 07. 10(23): eadm9481
    An unexpected role for the ketogenic diet in triggering tumor metastasis by modulating BACH1-mediated transcription.
    Zhenyi Su, Yanqing Liu, Zhangchuan Xia, Anil K Rustgi, Wei Gu.
      We have found that the ketogenic (Keto) diet is able to, unexpectedly, promote the metastatic potential of cancer cells in complementary mouse models. Notably, the Keto diet-induced tumor metastasis is dependent on BTB domain and CNC homolog 1 (BACH1) and its up-regulation of pro-metastatic targets, including cell migration-inducing hyaluronidase 1, in response to the Keto diet. By contrast, upon genetic knockout or pharmacological inhibition of endogenous BACH1, the Keto diet-mediated activation of those targets is largely diminished, and the effects on tumor metastasis are completely abolished. Mechanistically, upon administration of the Keto diet, the levels of activating transcription factor 4 (ATF4) are markedly induced. Through direct interaction with BACH1, ATF4 is recruited to those pro-metastatic target promoters and enhances BACH1-mediated transcriptional activation. Together, these data implicate a distinct transcription regulatory program of BACH1 for tumor metastasis induced by the Keto diet. Our study also raises a potential health risk of the Keto diet in human patients with cancer.
    DOI:  https://doi.org/10.1126/sciadv.adm9481
  31. Circ Res. 2024 Jun 07. 134(12): 1824-1840
    Intersection of Immunology and Metabolism in Myocardial Disease.
    Edward B Thorp, Anja Karlstaedt.
      Immunometabolism is an emerging field at the intersection of immunology and metabolism. Immune cell activation plays a critical role in the pathogenesis of cardiovascular diseases and is integral for regeneration during cardiac injury. We currently possess a limited understanding of the processes governing metabolic interactions between immune cells and cardiomyocytes. The impact of this intercellular crosstalk can manifest as alterations to the steady state flux of metabolites and impact cardiac contractile function. Although much of our knowledge is derived from acute inflammatory response, recent work emphasizes heterogeneity and flexibility in metabolism between cardiomyocytes and immune cells during pathological states, including ischemic, cardiometabolic, and cancer-associated disease. Metabolic adaptation is crucial because it influences immune cell activation, cytokine release, and potential therapeutic vulnerabilities. This review describes current concepts about immunometabolic regulation in the heart, focusing on intercellular crosstalk and intrinsic factors driving cellular regulation. We discuss experimental approaches to measure the cardio-immunologic crosstalk, which are necessary to uncover unknown mechanisms underlying the immune and cardiac interface. Deeper insight into these axes holds promise for therapeutic strategies that optimize cardioimmunology crosstalk for cardiac health.
    Keywords:  cardiovascular diseases; cytokines; immunity; insulin
    DOI:  https://doi.org/10.1161/CIRCRESAHA.124.323660
  32. Cell Death Dis. 2024 Jun 04. 15(6): 392
    FBP1 orchestrates keratinocyte proliferation/differentiation and suppresses psoriasis through metabolic control of histone acetylation.
    Pengfei Zhang, Ju Yang, Xiong Liu, Congshu Huang, Yuandong Tao, Pan Shen, Zhijie Bai, Chengrong Xiao, Lei Zhou, Gaofu Li, Li Zhang, Wei Zhou, Yue Gao.
      Keratinocyte proliferation and differentiation in epidermis are well-controlled and essential for reacting to stimuli such as ultraviolet light. Imbalance between proliferation and differentiation is a characteristic feature of major human skin diseases such as psoriasis and squamous cell carcinoma. However, the effect of keratinocyte metabolism on proliferation and differentiation remains largely elusive. We show here that the gluconeogenic enzyme fructose-1,6-bisphosphatase 1 (FBP1) promotes differentiation while inhibits proliferation of keratinocyte and suppresses psoriasis development. FBP1 is identified among the most upregulated genes induced by UVB using transcriptome sequencing and is elevated especially in upper epidermis. Fbp1 heterozygous mice exhibit aberrant epidermis phenotypes with local hyperplasia and dedifferentiation. Loss of FBP1 promotes proliferation and inhibits differentiation of keratinocytes in vitro. Mechanistically, FBP1 loss facilitates glycolysis-mediated acetyl-CoA production, which increases histone H3 acetylation at lysine 9, resulting in enhanced transcription of proliferation genes. We further find that the expression of FBP1 is dramatically reduced in human psoriatic lesions and in skin of mouse imiquimod psoriasis model. Fbp1 deficiency in mice facilitates psoriasis-like skin lesions development through glycolysis and acetyl-CoA production. Collectively, our findings reveal a previously unrecognized role of FBP1 in epidermal homeostasis and provide evidence for FBP1 as a metabolic psoriasis suppressor.
    DOI:  https://doi.org/10.1038/s41419-024-06706-6
  33. J Am Chem Soc. 2024 Jun 07.
    Chemoproteomic Identification of Spermidine-Binding Proteins and Antitumor-Immunity Activators.
    Vaibhav Pal Singh, Shuhei Hirose, Misao Takemoto, Asmaa M A S Farrag, Shin-Ichi Sato, Tasuku Honjo, Kenji Chamoto, Motonari Uesugi.
      Cancer immune therapies, particularly programmed cell death protein 1 (PD-1) blockade immunotherapy, falter in aged individuals due to compromised T-cell immunity. Spermidine, a biogenic polyamine that declines along with aging, shows promise in restoring antitumor immunity by enhancing mitochondrial fatty acid oxidation (FAO). Herein, we report a spermidine-based chemoproteomic probe (probe 2) that enables profiling of spermidine-binding proteins and screening for small-molecule enhancers of mitochondrial FAO. Chemoproteomic profiling by the probe revealed 140 proteins engaged in cellular interaction with spermidine, with a significant majority being mitochondrial proteins. Hydroxyl coenzyme A (CoA) dehydrogenase subunits α (HADHA) and other lipid metabolism-linked proteins are among the mitochondrial proteins that have attracted considerable interest. Screening spermidine analogs with the probe led to the discovery of compound 13, which interacts with these lipid metabolism-linked proteins and activates HADHA. This simple and biostable synthetic compound we named "spermimic" mirrors spermidine's ability to enhance mitochondrial bioenergetics and displays similar effectiveness in augmenting PD-1 blockade therapy in mice. This study lays the foundation for developing small-molecule activators of antitumor immunity, offering potential in combination cancer immunotherapy.
    DOI:  https://doi.org/10.1021/jacs.3c14615
  34. Soc Int Urol J. 2022 Nov;3(6): 386-396
    2022 WUOF/SIU International Consultation on Urological Diseases: Genetics and Tumor Microenvironment of Renal Cell Carcinoma.
    Sari Khaleel, Christopher Ricketts, W Marston Linehan, Mark Ball, Brandon Manley, Samra Turajilic, James Brugarolas, Ari Hakimi.
      Renal cell carcinoma is a diverse group of diseases that can be distinguished by distinct histopathologic and genomic features. In this comprehensive review, we highlight recent advancements in our understanding of the genetic and microenvironmental hallmarks of kidney cancer. We begin with clear cell renal cell carcinoma (ccRCC), the most common subtype of this disease. We review the chromosomal and genetic alterations that drive initiation and progression of ccRCC, which has recently been shown to follow multiple highly conserved evolutionary trajectories that in turn impact disease progression and prognosis. We also review the diverse genetic events that define the many recently recognized rare subtypes within non-clear cell RCC. Finally, we discuss our evolving understanding of the ccRCC microenvironment, which has been revolutionized by recent bulk and single-cell transcriptomic analyses, suggesting potential biomarkers for guiding systemic therapy in the management of advanced ccRCC.
    Keywords:  Renal cell carcinoma; clear cell carcinoma; genetics; non-clear cell renal cell carcinoma; tumor microenvironment
    DOI:  https://doi.org/10.48083/BLPV3411
  35. Nat Immunol. 2024 Jun;25(6): 931
    Circadian checkpoint.
    Nicholas J Bernard.
      
    DOI:  https://doi.org/10.1038/s41590-024-01876-z
  36. Nature. 2024 Jun 05.
    Senescent glia link mitochondrial dysfunction and lipid accumulation.
    China N Byrns, Alexandra E Perlegos, Karl N Miller, Zhecheng Jin, Faith R Carranza, Palak Manchandra, Connor H Beveridge, Caitlin E Randolph, V Sai Chaluvadi, Shirley L Zhang, Ananth R Srinivasan, F C Bennett, Amita Sehgal, Peter D Adams, Gaurav Chopra, Nancy M Bonini.
      Senescence is a cellular state linked to ageing and age-onset disease across many mammalian species1,2. Acutely, senescent cells promote wound healing3,4 and prevent tumour formation5; but they are also pro-inflammatory, thus chronically exacerbate tissue decline. Whereas senescent cells are active targets for anti-ageing therapy6-11, why these cells form in vivo, how they affect tissue ageing and the effect of their elimination remain unclear12,13. Here we identify naturally occurring senescent glia in ageing Drosophila brains and decipher their origin and influence. Using Activator protein 1 (AP1) activity to screen for senescence14,15, we determine that senescent glia can appear in response to neuronal mitochondrial dysfunction. In turn, senescent glia promote lipid accumulation in non-senescent glia; similar effects are seen in senescent human fibroblasts in culture. Targeting AP1 activity in senescent glia mitigates senescence biomarkers, extends fly lifespan and health span, and prevents lipid accumulation. However, these benefits come at the cost of increased oxidative damage in the brain, and neuronal mitochondrial function remains poor. Altogether, our results map the trajectory of naturally occurring senescent glia in vivo and indicate that these cells link key ageing phenomena: mitochondrial dysfunction and lipid accumulation.
    DOI:  https://doi.org/10.1038/s41586-024-07516-8
  37. Nat Commun. 2024 Jun 07. 15(1): 4866
    A YAP-centered mechanotransduction loop drives collective breast cancer cell invasion.
    Antoine A Khalil, Daan Smits, Peter D Haughton, Thijs Koorman, Karin A Jansen, Mathijs P Verhagen, Mirjam van der Net, Kitty van Zwieten, Lotte Enserink, Lisa Jansen, Abdelrahman G El-Gammal, Daan Visser, Milena Pasolli, Max Tak, Denise Westland, Paul J van Diest, Cathy B Moelans, M Guy Roukens, Sandra Tavares, Anne-Marie Fortier, Morag Park, Riccardo Fodde, Martijn Gloerich, Fried J T Zwartkruis, Patrick Wb Derksen, Johan de Rooij.
      Dense and aligned Collagen I fibers are associated with collective cancer invasion led by protrusive tumor cells, leader cells. In some breast tumors, a population of cancer cells (basal-like cells) maintain several epithelial characteristics and express the myoepithelial/basal cell marker Keratin 14 (K14). Emergence of leader cells and K14 expression are regarded as interconnected events triggered by Collagen I, however the underlying mechanisms remain unknown. Using breast carcinoma organoids, we show that Collagen I drives a force-dependent loop, specifically in basal-like cancer cells. The feed-forward loop is centered around the mechanotransducer Yap and independent of K14 expression. Yap promotes a transcriptional program that enhances Collagen I alignment and tension, which further activates Yap. Active Yap is detected in invading breast cancer cells in patients and required for collective invasion in 3D Collagen I and in the mammary fat pad of mice. Our work uncovers an essential function for Yap in leader cell selection during collective cancer invasion.
    DOI:  https://doi.org/10.1038/s41467-024-49230-z
  38. Trends Cell Biol. 2024 Jun 06. pii: S0962-8924(24)00111-9. [Epub ahead of print]
    Lysosomal control of the cGAS-STING signaling.
    Yinfeng Xu, Wei Wan.
      The cyclic GMP-AMP (cGAMP) synthase (cGAS)-stimulator of interferon genes (STING) pathway has a crucial role in combating pathogen infection. However, its aberrant activation is involved in several human disorders. Lysosomes are emerging as key negative regulators of cGAS-STING signaling. Here, we discuss the lysosomal control of cGAS-STING signaling and its implication in human disorders.
    Keywords:  STING; autophagy; cGAS; human disorders; innate immunity; lysosome
    DOI:  https://doi.org/10.1016/j.tcb.2024.05.004
  39. Nat Commun. 2024 Jun 01. 15(1): 4683
    Structural basis for human mitochondrial tRNA maturation.
    Vincent Meynier, Steven W Hardwick, Marjorie Catala, Johann J Roske, Stephanie Oerum, Dimitri Y Chirgadze, Pierre Barraud, Wyatt W Yue, Ben F Luisi, Carine Tisné.
      The human mitochondrial genome is transcribed into two RNAs, containing mRNAs, rRNAs and tRNAs, all dedicated to produce essential proteins of the respiratory chain. The precise excision of tRNAs by the mitochondrial endoribonucleases (mt-RNase), P and Z, releases all RNA species from the two RNA transcripts. The tRNAs then undergo 3'-CCA addition. In metazoan mitochondria, RNase P is a multi-enzyme assembly that comprises the endoribonuclease PRORP and a tRNA methyltransferase subcomplex. The requirement for this tRNA methyltransferase subcomplex for mt-RNase P cleavage activity, as well as the mechanisms of pre-tRNA 3'-cleavage and 3'-CCA addition, are still poorly understood. Here, we report cryo-EM structures that visualise four steps of mitochondrial tRNA maturation: 5' and 3' tRNA-end processing, methylation and 3'-CCA addition, and explain the defined sequential order of the tRNA processing steps. The methyltransferase subcomplex recognises the pre-tRNA in a distinct mode that can support tRNA-end processing and 3'-CCA addition, likely resulting from an evolutionary adaptation of mitochondrial tRNA maturation complexes to the structurally-fragile mitochondrial tRNAs. This subcomplex can also ensure a tRNA-folding quality-control checkpoint before the sequential docking of the maturation enzymes. Altogether, our study provides detailed molecular insight into RNA-transcript processing and tRNA maturation in human mitochondria.
    DOI:  https://doi.org/10.1038/s41467-024-49132-0
  40. Annu Rev Nutr. 2024 Jun 07.
    Eating Around the Clock: Circadian Rhythms of Eating and Metabolism.
    Andrew W McHill, Matthew P Butler.
      The time of day that we eat is increasingly recognized as contributing as importantly to overall health as the amount or quality of the food we eat. The endogenous circadian clock has evolved to promote intake at optimal times when an organism is intended to be awake and active; but electric lights and abundant food allow eating around the clock with deleterious health outcomes. In this review, we highlight literature pertaining to the effects of food timing on health, beginning with animal models and then translation into human experiments. We emphasize the pitfalls and opportunities that technological advances bring in bettering understanding of eating behaviors and their association with health and disease. There is great promise for restricting the timing of food intake both in clinical interventions and in public health campaigns for improving health via nonpharmacological therapies.
    DOI:  https://doi.org/10.1146/annurev-nutr-062122-014528
  41. bioRxiv. 2024 May 21. pii: 2024.05.20.595053. [Epub ahead of print]
    Enhancing tumor-infiltrating T cells with an exclusive fuel source.
    Matthew L Miller, Rina Nagarajan, Timothy J Thauland, Manish J Butte.
      Solid tumors harbor immunosuppressive microenvironments that inhibit tumor infiltrating lymphocytes (TILs) through the voracious consumption of glucose. We sought to restore TIL function by providing them with an exclusive fuel source. The glucose disaccharide cellobiose, which is a building block of cellulose, contains a β-1,4-glycosidic bond that cannot be hydrolyzed by animals (or their tumors), but fungal and bacterial organisms have evolved enzymes to catabolize cellobiose and use the resulting glucose. By equipping T cells with two proteins that enable import and hydrolysis of cellobiose, we demonstrate that supplementation of cellobiose during glucose withdrawal restores T cell cytokine production and cellular proliferation. Murine tumor growth is suppressed and survival is prolonged. Offering exclusive access to a natural disaccharide is a new tool that augments cancer immunotherapies. Beyond cancer, this approach could be used to answer questions about the regulation of glucose metabolism across many cell types, biological processes, and diseases.
    DOI:  https://doi.org/10.1101/2024.05.20.595053
  42. Sci Adv. 2024 Jun 07. 10(23): eadm9589
    A PRMT5-ZNF326 axis mediates innate immune activation upon replication stress.
    Phuong Mai Hoang, Denis Torre, Patrick Jaynes, Jessica Ho, Kevin Mohammed, Erik Alvstad, Wan Yee Lam, Vartika Khanchandani, Jie Min Lee, Chin Min Clarissa Toh, Rui Xue Lee, Akshaya Anbuselvan, Sukchan Lee, Robert P Sebra, Martin J Walsh, Ivan Marazzi, Dennis Kappei, Ernesto Guccione, Anand D Jeyasekharan.
      DNA replication stress (RS) is a widespread phenomenon in carcinogenesis, causing genomic instability and extensive chromatin alterations. DNA damage leads to activation of innate immune signaling, but little is known about transcriptional regulators mediating such signaling upon RS. Using a chemical screen, we identified protein arginine methyltransferase 5 (PRMT5) as a key mediator of RS-dependent induction of interferon-stimulated genes (ISGs). This response is also associated with reactivation of endogenous retroviruses (ERVs). Using quantitative mass spectrometry, we identify proteins with PRMT5-dependent symmetric dimethylarginine (SDMA) modification induced upon RS. Among these, we show that PRMT5 targets and modulates the activity of ZNF326, a zinc finger protein essential for ISG response. Our data demonstrate a role for PRMT5-mediated SDMA in the context of RS-induced transcriptional induction, affecting physiological homeostasis and cancer therapy.
    DOI:  https://doi.org/10.1126/sciadv.adm9589
  43. Nat Neurosci. 2024 Jun 07.
    Developmental origin of oligodendrocytes determines their function in the adult brain.
    Sarah Foerster, Elisa M Floriddia, David van Bruggen, Petra Kukanja, Bastien Hervé, Shangli Cheng, Eosu Kim, Benjamin U Phillips, Christopher J Heath, Richa B Tripathi, Cody Call, Theresa Bartels, Katherine Ridley, Björn Neumann, Laura López-Cruz, Abbe H Crawford, Cian J Lynch, Manuel Serrano, Lisa Saksida, David H Rowitch, Wiebke Möbius, Klaus-Armin Nave, Matthew N Rasband, Dwight E Bergles, Nicoletta Kessaris, William D Richardson, Timothy J Bussey, Chao Zhao, Gonçalo Castelo-Branco, Robin J M Franklin.
      In the mouse embryonic forebrain, developmentally distinct oligodendrocyte progenitor cell populations and their progeny, oligodendrocytes, emerge from three distinct regions in a spatiotemporal gradient from ventral to dorsal. However, the functional importance of this oligodendrocyte developmental heterogeneity is unknown. Using a genetic strategy to ablate dorsally derived oligodendrocyte lineage cells (OLCs), we show here that the areas in which dorsally derived OLCs normally reside in the adult central nervous system become populated and myelinated by OLCs of ventral origin. These ectopic oligodendrocytes (eOLs) have a distinctive gene expression profile as well as subtle myelination abnormalities. The failure of eOLs to fully assume the role of the original dorsally derived cells results in locomotor and cognitive deficits in the adult animal. This study reveals the importance of developmental heterogeneity within the oligodendrocyte lineage and its importance for homeostatic brain function.
    DOI:  https://doi.org/10.1038/s41593-024-01666-8
  44. Cell Rep. 2024 Jun 02. pii: S2211-1247(24)00628-4. [Epub ahead of print]43(6): 114300
    Blockage of L2HGDH-mediated S-2HG catabolism orchestrates macrophage polarization to elicit antitumor immunity.
    Shuang Feng, Duowei Wang, Yanyan Jin, Shi Huang, Tong Liang, Wei Sun, Xiuli Du, Luoyi Zhuo, Chun Shan, Wenbo Zhang, Tian Jing, Sen Zhao, Ruisi Hong, Linjun You, Guilai Liu, Leilei Chen, Dan Ye, Xianjing Li, Yong Yang.
      The high infiltration of tumor-associated macrophages (TAMs) in the immunosuppressive tumor microenvironment prominently attenuates the efficacy of immune checkpoint blockade (ICB) therapies, yet the underlying mechanisms are not fully understood. Here, we investigate the metabolic profile of TAMs and identify S-2-hydroxyglutarate (S-2HG) as a potential immunometabolite that shapes macrophages into an antitumoral phenotype. Blockage of L-2-hydroxyglutarate dehydrogenase (L2HGDH)-mediated S-2HG catabolism in macrophages promotes tumor regression. Mechanistically, based on its structural similarity to α-ketoglutarate (α-KG), S-2HG has the potential to block the enzymatic activity of 2-oxoglutarate-dependent dioxygenases (2-OGDDs), consequently reshaping chromatin accessibility. Moreover, S-2HG-treated macrophages enhance CD8+ T cell-mediated antitumor activity and sensitivity to anti-PD-1 therapy. Overall, our study uncovers the role of blockage of L2HGDH-mediated S-2HG catabolism in orchestrating macrophage antitumoral polarization and, further, provides the potential of repolarizing macrophages by S-2HG to overcome resistance to anti-PD-1 therapy.
    Keywords:  CP: Immunology; CP: Metabolism; L2HGDH; S-2HG; T cell; antigen presentation; cancer immunotherapy; macrophage; metabolism; α-KG
    DOI:  https://doi.org/10.1016/j.celrep.2024.114300
  45. J Cell Sci. 2024 Jun 01. pii: jcs261250. [Epub ahead of print]137(11):
    Histone acylation at a glance.
    Saikat Bhattacharya, Benjamin P Tu.
      An important mechanism of gene expression regulation is the epigenetic modification of histones. The cofactors and substrates for these modifications are often intermediary metabolites, and it is becoming increasingly clear that the metabolic and nutritional state of cells can influence these marks. These connections between the balance of metabolites, histone modifications and downstream transcriptional changes comprise a metabolic signaling program that can enable cells to adapt to changes in nutrient availability. Beyond acetylation, there is evidence now that histones can be modified by other acyl groups. In this Cell Science at a Glance article and the accompanying poster, we focus on these histone acylation modifications and provide an overview of the players that govern these acylations and their connections with metabolism.
    Keywords:  Acetylation; Acylation; Chromatin; Epigenetics; Histone modification; Metabolism
    DOI:  https://doi.org/10.1242/jcs.261250
  46. Cancer Cell. 2024 May 24. pii: S1535-6108(24)00160-0. [Epub ahead of print]
    Engineering focusing on cancer.
    Kayvan R Keshari, Daniel A Heller, Rostislav Boltyanskiy, Hedvig Hricak, Thomas Magaldi, Michael Overholtzer.
      While cancer research and care have benefited from revolutionary advances in the ability to manipulate and study living systems, the field is limited by a lack of synergy to leverage the power of engineering approaches. Cancer engineering is an emerging subfield of biomedical engineering that unifies engineering and cancer biology to better understand, diagnose, and treat cancer. We highlight cancer engineering's unique challenges, the importance of creating dedicated centers and departments that enable translational collaboration, and educational approaches to arm a new generation of scientists with engineering expertise and a fundamental understanding of cancer biology to transform clinical cancer care.
    DOI:  https://doi.org/10.1016/j.ccell.2024.04.013
  47. Cell. 2024 Jun 06. pii: S0092-8674(24)00490-2. [Epub ahead of print]187(12): 3056-3071.e17
    Isthmus progenitor cells contribute to homeostatic cellular turnover and support regeneration following intestinal injury.
    Ermanno Malagola, Alessandro Vasciaveo, Yosuke Ochiai, Woosook Kim, Biyun Zheng, Luca Zanella, Alexander L E Wang, Moritz Middelhoff, Henrik Nienhüser, Lu Deng, Feijing Wu, Quin T Waterbury, Bryana Belin, Jonathan LaBella, Leah B Zamechek, Melissa H Wong, Linheng Li, Chandan Guha, Chia-Wei Cheng, Kelley S Yan, Andrea Califano, Timothy C Wang.
      The currently accepted intestinal epithelial cell organization model proposes that Lgr5+ crypt-base columnar (CBC) cells represent the sole intestinal stem cell (ISC) compartment. However, previous studies have indicated that Lgr5+ cells are dispensable for intestinal regeneration, leading to two major hypotheses: one favoring the presence of a quiescent reserve ISC and the other calling for differentiated cell plasticity. To investigate these possibilities, we studied crypt epithelial cells in an unbiased fashion via high-resolution single-cell profiling. These studies, combined with in vivo lineage tracing, show that Lgr5 is not a specific ISC marker and that stemness potential exists beyond the crypt base and resides in the isthmus region, where undifferentiated cells participate in intestinal homeostasis and regeneration following irradiation (IR) injury. Our results provide an alternative model of intestinal epithelial cell organization, suggesting that stemness potential is not restricted to CBC cells, and neither de-differentiation nor reserve ISC are drivers of intestinal regeneration.
    Keywords:  adult stem cells; cell potency; epithelial stem cells; intestinal stem cells; intestine; plasticity; regeneration; regulatory network analysis; single cell; stemness signature
    DOI:  https://doi.org/10.1016/j.cell.2024.05.004
  48. Nat Cell Biol. 2024 Jun 07.
    Valine aminoacyl-tRNA synthetase promotes therapy resistance in melanoma.
    Najla El-Hachem, Marine Leclercq, Miguel Susaeta Ruiz, Raphael Vanleyssem, Kateryna Shostak, Pierre-René Körner, Coralie Capron, Lorena Martin-Morales, Patrick Roncarati, Arnaud Lavergne, Arnaud Blomme, Silvia Turchetto, Eric Goffin, Palaniraja Thandapani, Ivan Tarassov, Laurent Nguyen, Bernard Pirotte, Alain Chariot, Jean-Christophe Marine, Michael Herfs, Francesca Rapino, Reuven Agami, Pierre Close.
      Transfer RNA dynamics contribute to cancer development through regulation of codon-specific messenger RNA translation. Specific aminoacyl-tRNA synthetases can either promote or suppress tumourigenesis. Here we show that valine aminoacyl-tRNA synthetase (VARS) is a key player in the codon-biased translation reprogramming induced by resistance to targeted (MAPK) therapy in melanoma. The proteome rewiring in patient-derived MAPK therapy-resistant melanoma is biased towards the usage of valine and coincides with the upregulation of valine cognate tRNAs and of VARS expression and activity. Strikingly, VARS knockdown re-sensitizes MAPK-therapy-resistant patient-derived melanoma in vitro and in vivo. Mechanistically, VARS regulates the messenger RNA translation of valine-enriched transcripts, among which hydroxyacyl-CoA dehydrogenase mRNA encodes for a key enzyme in fatty acid oxidation. Resistant melanoma cultures rely on fatty acid oxidation and hydroxyacyl-CoA dehydrogenase for their survival upon MAPK treatment. Together, our data demonstrate that VARS may represent an attractive therapeutic target for the treatment of therapy-resistant melanoma.
    DOI:  https://doi.org/10.1038/s41556-024-01439-2
  49. Nat Commun. 2024 Jun 05. 15(1): 4775
    The manganese transporter SLC39A8 links alkaline ceramidase 1 to inflammatory bowel disease.
    Eun-Kyung Choi, Thekkelnaycke M Rajendiran, Tanu Soni, Jin-Ho Park, Luisa Aring, Chithra K Muraleedharan, Vicky Garcia-Hernandez, Nobuhiko Kamada, Linda C Samuelson, Asma Nusrat, Shigeki Iwase, Young Ah Seo.
      The metal ion transporter SLC39A8 is associated with physiological traits and diseases, including blood manganese (Mn) levels and inflammatory bowel diseases (IBD). The mechanisms by which SLC39A8 controls Mn homeostasis and epithelial integrity remain elusive. Here, we generate Slc39a8 intestinal epithelial cell-specific-knockout (Slc39a8-IEC KO) mice, which display markedly decreased Mn levels in blood and most organs. Radiotracer studies reveal impaired intestinal absorption of dietary Mn in Slc39a8-IEC KO mice. SLC39A8 is localized to the apical membrane and mediates 54Mn uptake in intestinal organoid monolayer cultures. Unbiased transcriptomic analysis identifies alkaline ceramidase 1 (ACER1), a key enzyme in sphingolipid metabolism, as a potential therapeutic target for SLC39A8-associated IBDs. Importantly, treatment with an ACER1 inhibitor attenuates colitis in Slc39a8-IEC KO mice by remedying barrier dysfunction. Our results highlight the essential roles of SLC39A8 in intestinal Mn absorption and epithelial integrity and offer a therapeutic target for IBD associated with impaired Mn homeostasis.
    DOI:  https://doi.org/10.1038/s41467-024-49049-8
  50. EMBO J. 2024 Jun 05.
    Functional diversity among cardiolipin binding sites on the mitochondrial ADP/ATP carrier.
    Nanami Senoo, Dinesh K Chinthapalli, Matthew G Baile, Vinaya K Golla, Bodhisattwa Saha, Abraham O Oluwole, Oluwaseun B Ogunbona, James A Saba, Teona Munteanu, Yllka Valdez, Kevin Whited, Macie S Sheridan, Dror Chorev, Nathan N Alder, Eric R May, Carol V Robinson, Steven M Claypool.
      Lipid-protein interactions play a multitude of essential roles in membrane homeostasis. Mitochondrial membranes have a unique lipid-protein environment that ensures bioenergetic efficiency. Cardiolipin (CL), the signature mitochondrial lipid, plays multiple roles in promoting oxidative phosphorylation (OXPHOS). In the inner mitochondrial membrane, the ADP/ATP carrier (AAC in yeast; adenine nucleotide translocator, ANT in mammals) exchanges ADP and ATP, enabling OXPHOS. AAC/ANT contains three tightly bound CLs, and these interactions are evolutionarily conserved. Here, we investigated the role of these buried CLs in AAC/ANT using a combination of biochemical approaches, native mass spectrometry, and molecular dynamics simulations. We introduced negatively charged mutations into each CL-binding site of yeast Aac2 and established experimentally that the mutations disrupted the CL interactions. While all mutations destabilized Aac2 tertiary structure, transport activity was impaired in a binding site-specific manner. Additionally, we determined that a disease-associated missense mutation in one CL-binding site in human ANT1 compromised its structure and transport activity, resulting in OXPHOS defects. Our findings highlight the conserved significance of CL in AAC/ANT structure and function, directly tied to specific lipid-protein interactions.
    Keywords:  Cardiolipin; Lipid–Protein Interaction; Membrane Transport; Mitochondria; Oxidative Phosphorylation
    DOI:  https://doi.org/10.1038/s44318-024-00132-2
  51. J Cell Biol. 2024 Jul 01. pii: e202405121. [Epub ahead of print]223(7):
    The bioenergetics of nucleocytoplasmic transport.
    G W Gant Luxton.
      How nucleocytoplasmic transport (NCT) rates change due to cellular physiology-mediated fluctuations in GTP availability remains unclear. In this issue, Scott et al. (https://doi.org/10.1083/jcb.202308152) demonstrate that cell migration, spreading, and nucleocytoskeletal coupling impact GTP levels, thereby regulating NCT, RNA export, and protein synthesis.
    DOI:  https://doi.org/10.1083/jcb.202405121
  52. bioRxiv. 2024 May 23. pii: 2024.05.21.595226. [Epub ahead of print]
    Cardiolipin clustering promotes mitochondrial membrane dynamics.
    Kelly E Zuccaro, Luciano A Abriata, Fernando Teixeira Pinto Meireles, Frank R Moss, Adam Frost, Matteo Dal Peraro, Halil Aydin.
      Cardiolipin (CL) is a mitochondria-specific phospholipid that forms heterotypic interactions with membrane-shaping proteins and regulates the dynamic remodeling and function of mitochondria. However, the precise mechanisms through which CL influences mitochondrial morphology are not well understood. In this study, employing molecular dynamics (MD) simulations, we observed CL localize near the membrane-binding sites of the mitochondrial fusion protein Optic Atrophy 1 (OPA1). To validate these findings experimentally, we developed a bromine-labeled CL probe to enhance cryoEM contrast and characterize the structure of OPA1 assemblies bound to the CL-brominated lipid bilayers. Our images provide direct evidence of interactions between CL and two conserved motifs within the paddle domain (PD) of OPA1, which control membrane-shaping mechanisms. We further observed a decrease in membrane remodeling activity for OPA1 in lipid compositions with increasing concentrations of monolyso-cardiolipin (MLCL). Suggesting that the partial replacement of CL by MLCL accumulation, as observed in Barth syndrome-associated mutations of the tafazzin phospholipid transacylase, compromises the stability of protein-membrane interactions. Our analyses provide insights into how biological membranes regulate the mechanisms governing mitochondrial homeostasis.
    Teaser: This study reveals how CL modulates the activity of OPA1 and how MLCL impacts its ability to govern mitochondrial function.
    DOI:  https://doi.org/10.1101/2024.05.21.595226
  53. Science. 2024 Jun 07. 384(6700): eadk0850
    Determining the ERK-regulated phosphoproteome driving KRAS-mutant cancer.
    Jennifer E Klomp, J Nathaniel Diehl, Jeffrey A Klomp, A Cole Edwards, Runying Yang, Alexis J Morales, Khalilah E Taylor, Kristina Drizyte-Miller, Kirsten L Bryant, Antje Schaefer, Jared L Johnson, Emily M Huntsman, Tomer M Yaron, Mariaelena Pierobon, Elisa Baldelli, Alex W Prevatte, Natalie K Barker, Laura E Herring, Emanuel F Petricoin, Lee M Graves, Lewis C Cantley, Adrienne D Cox, Channing J Der, Clint A Stalnecker.
      To delineate the mechanisms by which the ERK1 and ERK2 mitogen-activated protein kinases support mutant KRAS-driven cancer growth, we determined the ERK-dependent phosphoproteome in KRAS-mutant pancreatic cancer. We determined that ERK1 and ERK2 share near-identical signaling and transforming outputs and that the KRAS-regulated phosphoproteome is driven nearly completely by ERK. We identified 4666 ERK-dependent phosphosites on 2123 proteins, of which 79 and 66%, respectively, were not previously associated with ERK, substantially expanding the depth and breadth of ERK-dependent phosphorylation events and revealing a considerably more complex function for ERK in cancer. We established that ERK controls a highly dynamic and complex phosphoproteome that converges on cyclin-dependent kinase regulation and RAS homolog guanosine triphosphatase function (RHO GTPase). Our findings establish the most comprehensive molecular portrait and mechanisms by which ERK drives KRAS-dependent pancreatic cancer growth.
    DOI:  https://doi.org/10.1126/science.adk0850
  54. Nat Commun. 2024 Jun 05. 15(1): 4792
    Microbiota regulates the TET1-mediated DNA hydroxymethylation program in innate lymphoid cell differentiation.
    Xusheng Zhang, Xintong Gao, Zhen Liu, Fei Shao, Dou Yu, Min Zhao, Xiwen Qin, Shuo Wang.
      Innate lymphoid cell precursors (ILCPs) develop into distinct subsets of innate lymphoid cells (ILCs) with specific functions. The epigenetic program underlying the differentiation of ILCPs into ILC subsets remains poorly understood. Here, we reveal the genome-wide distribution and dynamics of the DNA methylation and hydroxymethylation in ILC subsets and their respective precursors. Additionally, we find that the DNA hydroxymethyltransferase TET1 suppresses ILC1 but not ILC2 or ILC3 differentiation. TET1 deficiency promotes ILC1 differentiation by inhibiting TGF-β signaling. Throughout ILCP differentiation at postnatal stage, gut microbiota contributes to the downregulation of TET1 level. Microbiota decreases the level of cholic acid in the gut, impairs TET1 expression and suppresses DNA hydroxymethylation, ultimately resulting in an expansion of ILC1s. In adult mice, TET1 suppresses the hyperactivation of ILC1s to maintain intestinal homeostasis. Our findings provide insights into the microbiota-mediated epigenetic programming of ILCs, which links microbiota-DNA methylation crosstalk to ILC differentiation.
    DOI:  https://doi.org/10.1038/s41467-024-48794-0
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