bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2024‒09‒15
37 papers selected by
Christian Frezza, Universität zu Köln
  1. Spatial single-cell isotope tracing reveals heterogeneity of de novo fatty acid synthesis in cancer.
  2. Menopause age shaped by genes that influence mutation risk.
  3. Systematic mapping of mitochondrial calcium uniporter channel (MCUC)-mediated calcium signaling networks.
  4. Organization of a functional glycolytic metabolon on mitochondria for metabolic efficiency.
  5. O-GlcNAc transferase regulates glycolytic metabolon formation on mitochondria to enhance ATP production.
  6. Visualizing mitochondrial dynamics at the nanoscale.
  7. Endothelial metabolic control of insulin sensitivity through resident macrophages.
  8. Efferocytosis drives a tryptophan metabolism pathway in macrophages to promote tissue resolution.
  9. A pinch of salt boosts T cell function.
  10. Rewired glutamate metabolism diminishes cytostatic action of L-asparaginase.
  11. Ammonia-induced lysosomal and mitochondrial damage causes cell death of effector CD8+ T cells.
  12. Targeting PRMT3 impairs methylation and oligomerization of HSP60 to boost anti-tumor immunity by activating cGAS/STING signaling.
  13. Creating a dietary vulnerability.
  14. Disruption of nucleotide biosynthesis reprograms mitochondrial metabolism to inhibit adipogenesis.
  15. Glutaminolysis provides nucleotides and amino acids to regulate osteoclast differentiation in mice.
  16. The inflammaging clock strikes IL-11!
  17. Mitochondrial reprogramming by activating OXPHOS via glutamine metabolism in African American patients with bladder cancer.
  18. Small-molecule GSDMD agonism in tumors stimulates antitumor immunity without toxicity.
  19. Structural and systems characterization of phosphorylation on metabolic enzymes identifies sex-specific metabolic reprogramming in obesity.
  20. Intercellular extrachromosomal DNA copy-number heterogeneity drives neuroblastoma cell state diversity.
  21. Organelle Communication with the Nucleus.
  22. cGAS activation in classical dendritic cells causes autoimmunity in TREX1-deficient mice.
  23. Inherent metabolic preferences differentially regulate the sensitivity of Th1 and Th2 cells to ribosome-inhibiting antibiotics.
  24. A genetically encoded fluorescent reporter for polyamines.
  25. The NRF2-CARM1 axis links glucose sensing to transcriptional and epigenetic regulation of the pentose phosphate pathway in gastric cancer.
  26. The bacterial quorum sensing signal 2'-aminoacetophenone rewires immune cell bioenergetics through the Ppargc1a/Esrra axis to mediate tolerance to infection.
  27. Starvation-induced phosphorylation activates gasdermin A to initiate pyroptosis.
  28. The emerging view on the origin and early evolution of eukaryotic cells.
  29. CPT2-mediated Fatty Acid Oxidation Is Dispensable for Humoral Immunity.
  30. Deep intravital brain tumor imaging enabled by tailored three-photon microscopy and analysis.
  31. Gasdermin D-mediated metabolic crosstalk promotes tissue repair.
  32. Mitochondrial RNA cytosolic leakage drives the SASP.
  33. TGF-β and RAS jointly unmask primed enhancers to drive metastasis.
  34. Cancer knocks you out by fasting: Cachexia as a consequence of metabolic alterations in cancer.
  35. Hypothalamic SLC7A14 accounts for aging-reduced lipolysis in white adipose tissue of male mice.
  36. X chromosome dosage shapes renal cell carcinoma risk.
  37. Biomolecular condensates regulate cellular electrochemical equilibria.
  1. Nat Metab. 2024 Sep 09.
    Spatial single-cell isotope tracing reveals heterogeneity of de novo fatty acid synthesis in cancer.
    Elena Buglakova, Måns Ekelöf, Michaela Schwaiger-Haber, Lisa Schlicker, Martijn R Molenaar, Mohammed Shahraz, Lachlan Stuart, Andreas Eisenbarth, Volker Hilsenstein, Gary J Patti, Almut Schulze, Marteinn T Snaebjornsson, Theodore Alexandrov.
      While heterogeneity is a key feature of cancer, understanding metabolic heterogeneity at the single-cell level remains a challenge. Here we present 13C-SpaceM, a method for spatial single-cell isotope tracing that extends the previously published SpaceM method with detection of 13C6-glucose-derived carbons in esterified fatty acids. We validated 13C-SpaceM on spatially heterogeneous models using liver cancer cells subjected to either normoxia-hypoxia or ATP citrate lyase depletion. This revealed substantial single-cell heterogeneity in labelling of the lipogenic acetyl-CoA pool and in relative fatty acid uptake versus synthesis hidden in bulk analyses. Analysing tumour-bearing brain tissue from mice fed a 13C6-glucose-containing diet, we found higher glucose-dependent synthesis of saturated fatty acids and increased elongation of essential fatty acids in tumours compared with healthy brains. Furthermore, our analysis uncovered spatial heterogeneity in lipogenic acetyl-CoA pool labelling in tumours. Our method enhances spatial probing of metabolic activities in single cells and tissues, providing insights into fatty acid metabolism in homoeostasis and disease.
    DOI:  https://doi.org/10.1038/s42255-024-01118-4
  2. Nature. 2024 Sep 11.
    Menopause age shaped by genes that influence mutation risk.
    Anne Goriely.
      
    Keywords:  Ageing; Cancer; Genetics
    DOI:  https://doi.org/10.1038/d41586-024-02665-2
  3. EMBO J. 2024 Sep 11.
    Systematic mapping of mitochondrial calcium uniporter channel (MCUC)-mediated calcium signaling networks.
    Hilda Delgado de la Herran, Denis Vecellio Reane, Yiming Cheng, Máté Katona, Fabian Hosp, Elisa Greotti, Jennifer Wettmarshausen, Maria Patron, Hermine Mohr, Natalia Prudente de Mello, Margarita Chudenkova, Matteo Gorza, Safal Walia, Michael Sheng-Fu Feng, Anja Leimpek, Dirk Mielenz, Natalia S Pellegata, Thomas Langer, György Hajnóczky, Matthias Mann, Marta Murgia, Fabiana Perocchi.
      The mitochondrial calcium uniporter channel (MCUC) mediates mitochondrial calcium entry, regulating energy metabolism and cell death. Although several MCUC components have been identified, the molecular basis of mitochondrial calcium signaling networks and their remodeling upon changes in uniporter activity have not been assessed. Here, we map the MCUC interactome under resting conditions and upon chronic loss or gain of mitochondrial calcium uptake. We identify 89 high-confidence interactors that link MCUC to several mitochondrial complexes and pathways, half of which are associated with human disease. As a proof-of-concept, we validate the mitochondrial intermembrane space protein EFHD1 as a binding partner of the MCUC subunits MCU, EMRE, and MCUB. We further show a MICU1-dependent inhibitory effect of EFHD1 on calcium uptake. Next, we systematically survey compensatory mechanisms and functional consequences of mitochondrial calcium dyshomeostasis by analyzing the MCU interactome upon EMRE, MCUB, MICU1, or MICU2 knockdown. While silencing EMRE reduces MCU interconnectivity, MCUB loss-of-function leads to a wider interaction network. Our study provides a comprehensive and high-confidence resource to gain insights into players and mechanisms regulating mitochondrial calcium signaling and their relevance in human diseases.
    Keywords:  Calcium Signaling; Mitochondria; Mitochondrial Calcium Uniporter; Organelle; Proteomics
    DOI:  https://doi.org/10.1038/s44318-024-00219-w
  4. Nat Metab. 2024 Sep 11.
    Organization of a functional glycolytic metabolon on mitochondria for metabolic efficiency.
    Haoming Wang, John W Vant, Andrew Zhang, Richard G Sanchez, Youjun Wu, Mary L Micou, Vincent Luczak, Zachary Whiddon, Natasha M Carlson, Seungyoon B Yu, Mirna Jabbo, Seokjun Yoon, Ahmed A Abushawish, Majid Ghassemian, Takeya Masubuchi, Quan Gan, Shigeki Watanabe, Eric R Griffis, Marc Hammarlund, Abhishek Singharoy, Gulcin Pekkurnaz.
      Glucose, the primary cellular energy source, is metabolized through glycolysis initiated by the rate-limiting enzyme hexokinase (HK). In energy-demanding tissues like the brain, HK1 is the dominant isoform, primarily localized on mitochondria, and is crucial for efficient glycolysis-oxidative phosphorylation coupling and optimal energy generation. This study unveils a unique mechanism regulating HK1 activity, glycolysis and the dynamics of mitochondrial coupling, mediated by the metabolic sensor enzyme O-GlcNAc transferase (OGT). OGT catalyses reversible O-GlcNAcylation, a post-translational modification influenced by glucose flux. Elevated OGT activity induces dynamic O-GlcNAcylation of the regulatory domain of HK1, subsequently promoting the assembly of the glycolytic metabolon on the outer mitochondrial membrane. This modification enhances the mitochondrial association with HK1, orchestrating glycolytic and mitochondrial ATP production. Mutation in HK1's O-GlcNAcylation site reduces ATP generation in multiple cell types, specifically affecting metabolic efficiency in neurons. This study reveals a previously unappreciated pathway that links neuronal metabolism and mitochondrial function through OGT and the formation of the glycolytic metabolon, providing potential strategies for tackling metabolic and neurological disorders.
    DOI:  https://doi.org/10.1038/s42255-024-01121-9
  5. Nat Metab. 2024 Sep 11.
    O-GlcNAc transferase regulates glycolytic metabolon formation on mitochondria to enhance ATP production.
      
    DOI:  https://doi.org/10.1038/s42255-024-01120-w
  6. Light Sci Appl. 2024 Sep 09. 13(1): 244
    Visualizing mitochondrial dynamics at the nanoscale.
    Till Stephan, Peter Ilgen, Stefan Jakobs.
      The study of mitochondria is a formidable challenge for super-resolution microscopy due to their dynamic nature and complex membrane architecture. In this issue, Ren et al. introduce HBmito Crimson, a fluorogenic and photostable mitochondrial probe for STED microscopy and investigate how mitochondrial dynamics influence the spatial organization of mitochondrial DNA.
    DOI:  https://doi.org/10.1038/s41377-024-01582-3
  7. Cell Metab. 2024 Sep 08. pii: S1550-4131(24)00335-8. [Epub ahead of print]
    Endothelial metabolic control of insulin sensitivity through resident macrophages.
    Jing Zhang, Kim Anker Sjøberg, Songlin Gong, Tongtong Wang, Fengqi Li, Andrew Kuo, Stephan Durot, Adam Majcher, Raphaela Ardicoglu, Thibaut Desgeorges, Charlotte Greta Mann, Ines Soro Arnáiz, Gillian Fitzgerald, Paola Gilardoni, E Dale Abel, Shigeyuki Kon, Danyvid Olivares-Villagómez, Nicola Zamboni, Christian Wolfrum, Thorsten Hornemann, Raphael Morscher, Nathalie Tisch, Bart Ghesquière, Manfred Kopf, Erik A Richter, Katrien De Bock.
      Endothelial cells (ECs) not only form passive blood conduits but actively contribute to nutrient transport and organ homeostasis. The role of ECs in glucose homeostasis is, however, poorly understood. Here, we show that, in skeletal muscle, endothelial glucose transporter 1 (Glut1/Slc2a1) controls glucose uptake via vascular metabolic control of muscle-resident macrophages without affecting transendothelial glucose transport. Lowering endothelial Glut1 via genetic depletion (Glut1ΔEC) or upon a short-term high-fat diet increased angiocrine osteopontin (OPN/Spp1) secretion. This promoted resident muscle macrophage activation and proliferation, which impaired muscle insulin sensitivity. Consequently, co-deleting Spp1 from ECs prevented macrophage accumulation and improved insulin sensitivity in Glut1ΔEC mice. Mechanistically, Glut1-dependent endothelial glucose metabolic rewiring increased OPN in a serine metabolism-dependent fashion. Our data illustrate how the glycolytic endothelium creates a microenvironment that controls resident muscle macrophage phenotype and function and directly links resident muscle macrophages to the maintenance of muscle glucose homeostasis.
    Keywords:  GLUT1; endothelial cells; endothelial metabolism; inflammation; insulin sensitivity; osteopontin; resident macrophages; serine; skeletal muscle; vasculature
    DOI:  https://doi.org/10.1016/j.cmet.2024.08.008
  8. Nat Metab. 2024 Sep 06.
    Efferocytosis drives a tryptophan metabolism pathway in macrophages to promote tissue resolution.
    Santosh R Sukka, Patrick B Ampomah, Lancia N F Darville, David Ngai, Xiaobo Wang, George Kuriakose, Yuling Xiao, Jinjun Shi, John M Koomen, Robert H McCusker, Ira Tabas.
      Macrophage efferocytosis prevents apoptotic cell (AC) accumulation and triggers inflammation-resolution pathways. The mechanisms linking efferocytosis to resolution often involve changes in macrophage metabolism, but many gaps remain in our understanding of these processes. We now report that efferocytosis triggers an indoleamine 2,3-dioxygenase-1 (IDO1)-dependent tryptophan (Trp) metabolism pathway that promotes several key resolution processes, including the induction of pro-resolving proteins, such interleukin-10, and further enhancement of efferocytosis. The process begins with upregulation of Trp transport and metabolism, and it involves subsequent activation of the aryl hydrocarbon receptor (AhR) by the Trp metabolite kynurenine (Kyn). Through these mechanisms, macrophage IDO1 and AhR contribute to a proper resolution response in several different mouse models of efferocytosis-dependent tissue repair, notably during atherosclerosis regression induced by plasma low-density lipoprotein (LDL) lowering. These findings reveal an integrated metabolism programme in macrophages that links efferocytosis to resolution, with possible therapeutic implications for non-resolving chronic inflammatory diseases, notably atherosclerosis.
    DOI:  https://doi.org/10.1038/s42255-024-01115-7
  9. Nat Immunol. 2024 Sep 09.
    A pinch of salt boosts T cell function.
    Karina L Hajdu, Lorène Rousseau, Ping-Chih Ho.
      
    DOI:  https://doi.org/10.1038/s41590-024-01946-2
  10. Cancer Lett. 2024 Sep 11. pii: S0304-3835(24)00637-2. [Epub ahead of print] 217242
    Rewired glutamate metabolism diminishes cytostatic action of L-asparaginase.
    Katerina Hlozkova, Maryna Vasylkivska, Adam Boufersaoui, Bryan Marzullo, Matus Kolarik, Natividad Alquezar-Artieda, Mehak Shaikh, Fatemeh Alaei Faradonbeh, Marketa Zaliova, Martina Zwyrtkova, Violeta Bakardijeva-Mihaylova, Meritxell Alberich-Jorda, Jan Trka, Daniel A Tennant, Julia Starkova.
      Tumor cells often adapt to amino acid deprivation through metabolic rewiring, compensating for the loss with alternative amino acids/substrates. We have described such a scenario in leukemic cells treated with L-asparaginase (ASNase). Clinical effect of ASNase is based on nutrient stress achieved by its dual enzymatic action which leads to depletion of asparagine and glutamine and is accompanied with elevated aspartate and glutamate concentrations in serum of acute lymphoblastic leukemia patients. We showed that in these limited conditions glutamate uptake compensates for the loss of glutamine availability. Extracellular glutamate flux detection confirms its integration into the TCA cycle and its participation in nucleotide and glutathione synthesis. Importantly, it is glutamate-driven de novo synthesis of glutathione which is the essential metabolic pathway necessary for glutamate's pro-survival effect. In vivo findings support this effect by showing that inhibition of glutamate transporters enhances the therapeutic effect of ASNase. In summary, ASNase induces elevated extracellular glutamate levels under nutrient stress, which leads to a rewiring of intracellular glutamate metabolism and has a negative impact on ASNase treatment.
    DOI:  https://doi.org/10.1016/j.canlet.2024.217242
  11. Nat Cell Biol. 2024 Sep 11.
    Ammonia-induced lysosomal and mitochondrial damage causes cell death of effector CD8+ T cells.
    Huafeng Zhang, Jincheng Liu, Wu Yuan, Qian Zhang, Xiao Luo, Yonggang Li, Yue'e Peng, Jingyu Feng, Xiaoyu Liu, Jie Chen, Yabo Zhou, Jiadi Lv, Nannan Zhou, Jingwei Ma, Ke Tang, Bo Huang.
      Ammonia is thought to be a cytotoxin and its increase in the blood impairs cell function. However, whether and how this toxin triggers cell death under pathophysiological conditions remains unclear. Here we show that ammonia induces a distinct form of cell death in effector T cells. We found that rapidly proliferating T cells use glutaminolysis to release ammonia in the mitochondria, which is then translocated to and stored in the lysosomes. Excessive ammonia accumulation increases lysosomal pH and results in the termination of lysosomal ammonia storage and ammonia reflux into mitochondria, leading to mitochondrial damage and cell death, which is characterized by lysosomal alkalization, mitochondrial swelling and impaired autophagic flux. Inhibition of glutaminolysis or blocking lysosomal alkalization prevents ammonia-induced T cell death and improves T cell-based antitumour immunotherapy. These findings identify a distinct form of cell death that differs from previously known mechanisms.
    DOI:  https://doi.org/10.1038/s41556-024-01503-x
  12. Nat Commun. 2024 Sep 10. 15(1): 7930
    Targeting PRMT3 impairs methylation and oligomerization of HSP60 to boost anti-tumor immunity by activating cGAS/STING signaling.
    Yunxing Shi, Zongfeng Wu, Shaoru Liu, Dinglan Zuo, Yi Niu, Yuxiong Qiu, Liang Qiao, Wei He, Jiliang Qiu, Yunfei Yuan, Guocan Wang, Binkui Li.
      Immune checkpoint blockade (ICB) has emerged as a promising therapeutic option for hepatocellular carcinoma (HCC), but resistance to ICB occurs and patient responses vary. Here, we uncover protein arginine methyltransferase 3 (PRMT3) as a driver for immunotherapy resistance in HCC. We show that PRMT3 expression is induced by ICB-activated T cells via an interferon-gamma (IFNγ)-STAT1 signaling pathway, and higher PRMT3 expression levels correlate with reduced numbers of tumor-infiltrating CD8+ T cells and poorer response to ICB. Genetic depletion or pharmacological inhibition of PRMT3 elicits an influx of T cells into tumors and reduces tumor size in HCC mouse models. Mechanistically, PRMT3 methylates HSP60 at R446 to induce HSP60 oligomerization and maintain mitochondrial homeostasis. Targeting PRMT3-dependent HSP60 methylation disrupts mitochondrial integrity and increases mitochondrial DNA (mtDNA) leakage, which results in cGAS/STING-mediated anti-tumor immunity. Lastly, blocking PRMT3 functions synergize with PD-1 blockade in HCC mouse models. Our study thus identifies PRMT3 as a potential biomarker and therapeutic target to overcome immunotherapy resistance in HCC.
    DOI:  https://doi.org/10.1038/s41467-024-52170-3
  13. Nat Rev Cancer. 2024 Sep 10.
    Creating a dietary vulnerability.
    Daniela Senft.
      
    DOI:  https://doi.org/10.1038/s41568-024-00751-1
  14. J Lipid Res. 2024 Sep 06. pii: S0022-2275(24)00146-9. [Epub ahead of print] 100641
    Disruption of nucleotide biosynthesis reprograms mitochondrial metabolism to inhibit adipogenesis.
    Julia A Pinette, Jacob W Myers, Woo Yong Park, Heather G Bryant, Alex M Eddie, Genesis A Wilson, Claudia Montufar, Zayedali Shaikh, Zer Vue, Elizabeth R Nunn, Ryoichi Bessho, Matthew A Cottam, Volker H Haase, Antentor O Hinton, Jessica B Spinelli, Jean-Philippe Cartailler, Elma Zaganjor.
      A key organismal response to overnutrition involves the development of new adipocytes through the process of adipogenesis. Preadipocytes sense changes in the systemic nutrient status and metabolites can directly modulate adipogenesis. We previously identified a role of de novo nucleotide biosynthesis in adipogenesis induction, whereby inhibition of nucleotide biosynthesis suppresses the expression of the transcriptional regulators PPARγ and C/EBPα. Here, we set out to identify the global transcriptomic changes associated with the inhibition of nucleotide biosynthesis. Through RNA sequencing (RNAseq), we discovered that mitochondrial signatures were the most altered in response to inhibition of nucleotide biosynthesis. Blocking nucleotide biosynthesis induced rounded mitochondrial morphology, and altered mitochondrial function, and metabolism, reducing levels of tricarboxylic acid cycle intermediates, and increasing fatty acid oxidation (FAO). The loss of mitochondrial function induced by suppression of nucleotide biosynthesis was rescued by exogenous expression of PPARγ. Moreover, inhibition of FAO restored PPARγ expression, mitochondrial protein expression, and adipogenesis in the presence of nucleotide biosynthesis inhibition, suggesting a regulatory role of nutrient oxidation in differentiation. Collectively, our studies shed light on the link between substrate oxidation and transcription in cell fate determination.
    Keywords:  adipocytes; adipogenesis; fatty acid oxidation; lipid droplets; metabolism; nucleotides; purine; pyrimidine
    DOI:  https://doi.org/10.1016/j.jlr.2024.100641
  15. EMBO Rep. 2024 Sep 13.
    Glutaminolysis provides nucleotides and amino acids to regulate osteoclast differentiation in mice.
    Guoli Hu, Yilin Yu, Yinshi Ren, Robert J Tower, Guo-Fang Zhang, Courtney M Karner.
      Osteoclasts are bone resorbing cells that are essential to maintain skeletal integrity and function. While many of the growth factors and molecular signals that govern osteoclastogenesis are well studied, how the metabolome changes during osteoclastogenesis is unknown. Using a multifaceted approach, we identified a metabolomic signature of osteoclast differentiation consisting of increased amino acid and nucleotide metabolism. Maintenance of the osteoclast metabolic signature is governed by elevated glutaminolysis. Mechanistically, glutaminolysis provides amino acids and nucleotides which are essential for osteoclast differentiation and bone resorption in vitro. Genetic experiments in mice found that glutaminolysis is essential for osteoclastogenesis and bone resorption in vivo. Highlighting the therapeutic implications of these findings, inhibiting glutaminolysis using CB-839 prevented ovariectomy induced bone loss in mice. Collectively, our data provide strong genetic and pharmacological evidence that glutaminolysis is essential to regulate osteoclast metabolism, promote osteoclastogenesis and modulate bone resorption in mice.
    Keywords:  Amino Acids; Glutaminolysis; Nucleotides; Osteoclast; Osteoporosis
    DOI:  https://doi.org/10.1038/s44319-024-00255-x
  16. Immunity. 2024 Sep 10. pii: S1074-7613(24)00409-6. [Epub ahead of print]57(9): 2010-2012
    The inflammaging clock strikes IL-11!
    Saad Khan, Veronica Chang, Daniel A Winer.
      Chronic inflammation is considered a hallmark of aging. In a recent issue of Nature, Widjaja et al. examined genetic and pharmacologic inhibition of interleukin (IL)-11 on aging pathology and found that inhibiting IL-11 signaling increases lifespan and healthspan in mice.
    DOI:  https://doi.org/10.1016/j.immuni.2024.08.010
  17. JCI Insight. 2024 Sep 10. pii: e172336. [Epub ahead of print]9(17):
    Mitochondrial reprogramming by activating OXPHOS via glutamine metabolism in African American patients with bladder cancer.
    Karthik Reddy Kami Reddy, Danthasinghe Waduge Badrajee Piyarathna, Jun Hyoung Park, Vasanta Putluri, Chandra Sekhar Amara, Abu Hena Mostafa Kamal, Jun Xu, Daniel Kraushaar, Shixia Huang, Sung Yun Jung, Livia S Eberlin, Jabril R Johnson, Rick A Kittles, Leomar Y Ballester, Krishna Parsawar, M Minhaj Siddiqui, Jianjun Gao, Adriana Langer Gramer, Roni J Bollag, Martha K Terris, Yair Lotan, Chad J Creighton, Seth P Lerner, Arun Sreekumar, Benny Abraham Kaipparettu, Nagireddy Putluri.
      Bladder cancer (BLCA) mortality is higher in African American (AA) patients compared with European American (EA) patients, but the molecular mechanism underlying race-specific differences are unknown. To address this gap, we conducted comprehensive RNA-Seq, proteomics, and metabolomics analysis of BLCA tumors from AA and EA. Our findings reveal a distinct metabolic phenotype in AA BLCA characterized by elevated mitochondrial oxidative phosphorylation (OXPHOS), particularly through the activation of complex I. The results provide insight into the complex I activation-driven higher OXPHOS activity resulting in glutamine-mediated metabolic rewiring and increased disease progression, which was also confirmed by [U]13C-glutamine tracing. Mechanistic studies further demonstrate that knockdown of NDUFB8, one of the components of complex I in AA BLCA cells, resulted in reduced basal respiration, ATP production, GLS1 expression, and proliferation. Moreover, preclinical studies demonstrate the therapeutic potential of targeting complex I, as evidenced by decreased tumor growth in NDUFB8-depleted AA BLCA tumors. Additionally, genetic and pharmacological inhibition of GLS1 attenuated mitochondrial respiration rates and tumor growth potential in AA BLCA. Taken together, these findings provide insight into BLCA disparity for targeting GLS1-Complex I for future therapy.
    Keywords:  Cancer; Metabolism; Mitochondria; Oncology; Urology
    DOI:  https://doi.org/10.1172/jci.insight.172336
  18. Cell. 2024 Sep 02. pii: S0092-8674(24)00898-5. [Epub ahead of print]
    Small-molecule GSDMD agonism in tumors stimulates antitumor immunity without toxicity.
    Pietro Fontana, Gang Du, Ying Zhang, Haiwei Zhang, Setu M Vora, Jun Jacob Hu, Ming Shi, Ahmet B Tufan, Liam B Healy, Shiyu Xia, Dian-Jang Lee, Zhouyihan Li, Pilar Baldominos, Heng Ru, Hongbo R Luo, Judith Agudo, Judy Lieberman, Hao Wu.
      Gasdermin-mediated inflammatory cell death (pyroptosis) can activate protective immunity in immunologically cold tumors. Here, we performed a high-throughput screen for compounds that could activate gasdermin D (GSDMD), which is expressed widely in tumors. We identified 6,7-dichloro-2-methylsulfonyl-3-N-tert-butylaminoquinoxaline (DMB) as a direct and selective GSDMD agonist that activates GSDMD pore formation and pyroptosis without cleaving GSDMD. In mouse tumor models, pulsed and low-level pyroptosis induced by DMB suppresses tumor growth without harming GSDMD-expressing immune cells. Protection is immune-mediated and abrogated in mice lacking lymphocytes. Vaccination with DMB-treated cancer cells protects mice from secondary tumor challenge, indicating that immunogenic cell death is induced. DMB treatment synergizes with anti-PD-1. DMB treatment does not alter circulating proinflammatory cytokine or leukocyte numbers or cause weight loss. Thus, our studies reveal a strategy that relies on a low level of tumor cell pyroptosis to induce antitumor immunity and raise the possibility of exploiting pyroptosis without causing overt toxicity.
    Keywords:  GSDMD; GSDMD agonist; antitumor immunity; cancer; checkpoint blockade; gasdermin; immunogenic cell death; immunotherapy; pyroptosis; tumor
    DOI:  https://doi.org/10.1016/j.cell.2024.08.007
  19. bioRxiv. 2024 Aug 29. pii: 2024.08.28.609894. [Epub ahead of print]
    Structural and systems characterization of phosphorylation on metabolic enzymes identifies sex-specific metabolic reprogramming in obesity.
    Tigist Y Tamir, Shreya Chaudhary, Annie X Li, Sonia E Trojan, Cameron T Flower, Paula Vo, Yufei Cui, Jeffrey C Davis, Rachit S Mukkamala, Francesca N Venditti, Alissandra L Hillis, Alex Toker, Matthew G Vander Heiden, Jessica B Spinelli, Norman J Kennedy, Roger J Davis, Forest M White.
      Coordination of adaptive metabolism through cellular signaling networks and metabolic response is essential for balanced flow of energy and homeostasis. Post-translational modifications such as phosphorylation offer a rapid, efficient, and dynamic mechanism to regulate metabolic networks. Although numerous phosphorylation sites have been identified on metabolic enzymes, much remains unknown about their contribution to enzyme function and systemic metabolism. In this study, we stratify phosphorylation sites on metabolic enzymes based on their location with respect to functional and dimerization domains. Our analysis reveals that the majority of published phosphosites are on oxidoreductases, with particular enrichment of phosphotyrosine (pY) sites in proximity to binding domains for substrates, cofactors, active sites, or dimer interfaces. We identify phosphosites altered in obesity using a high fat diet (HFD) induced obesity model coupled to multiomics, and interrogate the functional impact of pY on hepatic metabolism. HFD induced dysregulation of redox homeostasis and reductive metabolism at the phosphoproteome and metabolome level in a sex-specific manner, which was reversed by supplementing with the antioxidant butylated hydroxyanisole (BHA). Partial least squares regression (PLSR) analysis identified pY sites that predict HFD or BHA induced changes of redox metabolites. We characterize predictive pY sites on glutathione S-transferase pi 1 (GSTP1), isocitrate dehydrogenase 1 (IDH1), and uridine monophosphate synthase (UMPS) using CRISPRi-rescue and stable isotope tracing. Our analysis revealed that sites on GSTP1 and UMPS inhibit enzyme activity while the pY site on IDH1 induces activity to promote reductive carboxylation. Overall, our approach provides insight into the convergence points where cellular signaling fine-tunes metabolism.Summary Statement: By employing a multi-disciplinary approach we stratify structural features of phosphorylation sites on metabolic enzymes, map the systems level changes induced by obesity, identify key pathways with sex specific phosphoproteomic responses, and validate the functional role of phosphorylation sites for select enzymes.
    DOI:  https://doi.org/10.1101/2024.08.28.609894
  20. Cell Rep. 2024 Sep 09. pii: S2211-1247(24)01062-3. [Epub ahead of print]43(9): 114711
    Intercellular extrachromosomal DNA copy-number heterogeneity drives neuroblastoma cell state diversity.
    Maja C Stöber, Rocío Chamorro González, Lotte Brückner, Thomas Conrad, Nadine Wittstruck, Annabell Szymansky, Angelika Eggert, Johannes H Schulte, Richard P Koche, Anton G Henssen, Roland F Schwarz, Kerstin Haase.
      Neuroblastoma exhibits significant inter- and intra-tumor genetic heterogeneity and varying clinical outcomes. Extrachromosomal DNAs (ecDNAs) may drive this heterogeneity by independently segregating during cell division, leading to rapid oncogene amplification. While ecDNA-mediated oncogene amplification is linked to poor prognosis in various cancers, the effects of ecDNA copy-number heterogeneity on intermediate phenotypes are poorly understood. Here, we leverage DNA and RNA sequencing from the same single cells in cell lines and neuroblastoma patients to investigate these effects. By analyzing ecDNA amplicon structures, we reveal extensive intercellular ecDNA copy-number heterogeneity. We also provide direct evidence of how this heterogeneity influences the expression of cargo genes, including MYCN and its downstream targets, and the overall transcriptional state of neuroblastoma cells. Our findings highlight the role of ecDNA copy number in promoting rapid adaptability of cellular states within tumors, underscoring the need for ecDNA-specific treatment strategies to address tumor formation and adaptation.
    Keywords:  CP: Cancer; Extrachromosomal DNA; cell state diversity; copy number; neuroblastoma; single-cell RNA sequencing; tumor heterogeneity
    DOI:  https://doi.org/10.1016/j.celrep.2024.114711
  21. Results Probl Cell Differ. 2024 ;73 3-23
    Organelle Communication with the Nucleus.
    Sourabh Sengupta, Daniel L Levy.
      Compartmentalization of cellular components is critical to the spatiotemporal and environmental regulation of biochemical activities inside a cell, ensures the proper division of cellular labor and resources, and increases the efficiency of metabolic processes. However, compartmentalization also poses a challenge as organelles often need to communicate across these compartments to complete reaction pathways. These communication signals are often critical aspects of the cellular response to changing environmental conditions. A central signaling hub in the cell, the nucleus communicates with mitochondria, lysosomes, the endoplasmic reticulum, and the Golgi body to ensure optimal organellar and cellular performance. Here we review different mechanisms by which these organelles communicate with the nucleus, focusing on anterograde and retrograde signaling of mitochondria, localization-based signaling of lysosomes, the unfolded protein response of the endoplasmic reticulum, and evidence for nucleus-Golgi signaling. We also include a brief overview of some less well-characterized mechanisms of communication between non-nuclear organelles.
    Keywords:  Endoplasmic reticulum; Golgi; Inter-organellar communication; Lysosomes; Mitochondria; Nucleus
    DOI:  https://doi.org/10.1007/978-3-031-62036-2_1
  22. Proc Natl Acad Sci U S A. 2024 Sep 17. 121(38): e2411747121
    cGAS activation in classical dendritic cells causes autoimmunity in TREX1-deficient mice.
    Tong Li, Seoyun Yum, Junjiao Wu, Minghao Li, Yafang Deng, Lijun Sun, Xiaoxia Zuo, Zhijian J Chen.
      Detection of cytosolic DNA by the cyclic GMP-AMP (cGAMP) synthase (cGAS)-stimulator of interferon genes (STING) pathway provides immune defense against pathogens and cancer but can also cause autoimmunity when overactivated. The exonuclease three prime repair exonuclease 1 (TREX1) degrades DNA in the cytosol and prevents cGAS activation by self-DNA. Loss-of-function mutations of the TREX1 gene are linked to autoimmune diseases such as Aicardi-Goutières syndrome, and mice deficient in TREX1 develop lethal inflammation in a cGAS-dependent manner. In order to determine the type of cells in which cGAS activation drives autoinflammation, we generated conditional cGAS knockout mice on the Trex1-/- background. Here, we show that genetic ablation of the cGAS gene in classical dendritic cells (cDCs), but not in macrophages, was sufficient to rescue Trex1-/- mice from all observed disease phenotypes including lethality, T cell activation, tissue inflammation, and production of antinuclear antibodies and interferon-stimulated genes. These results show that cGAS activation in cDC causes autoinflammation in response to self-DNA accumulated in the absence of TREX1.
    Keywords:  STING; TREX1; cGAS; dendritic cell; inflammation
    DOI:  https://doi.org/10.1073/pnas.2411747121
  23. Immunology. 2024 Sep 12.
    Inherent metabolic preferences differentially regulate the sensitivity of Th1 and Th2 cells to ribosome-inhibiting antibiotics.
    Neha Jawla, Raunak Kar, Veena S Patil, G Aneeshkumar Arimbasseri.
      Mitochondrial translation is essential to maintain mitochondrial function and energy production. Mutations in genes associated with mitochondrial translation cause several developmental disorders, and immune dysfunction is observed in many such patients. Besides genetic mutations, several antibiotics targeting bacterial ribosomes are well-established to inhibit mitochondrial translation. However, the effect of such antibiotics on different immune cells is not fully understood. Here, we addressed the differential effect of mitochondrial translation inhibition on different subsets of helper T cells (Th) of mice and humans. Inhibition of mitochondrial translation reduced the levels of mitochondrially encoded electron transport chain subunits without affecting their nuclear-encoded counterparts. As a result, mitochondrial oxygen consumption reduced dramatically, but mitochondrial mass was unaffected. Most importantly, we show that inhibition of mitochondrial translation induced apoptosis, specifically in Th2 cells. This increase in apoptosis was associated with higher expression of Bim and Puma, two activators of the intrinsic pathway of apoptosis. We propose that this difference in the sensitivity of Th1 and Th2 cells to mitochondrial translation inhibition reflects the intrinsic metabolic demands of these subtypes. Though Th1 and Th2 cells exhibit similar levels of oxidative phosphorylation, Th1 cells exhibit higher levels of aerobic glycolysis than Th2 cells. Moreover, Th1 cells are more sensitive to the inhibition of glycolysis, while higher concentrations of glycolysis inhibitor 2-deoxyglucose are required to induce cell death in the Th2 lineage. These observations reveal that selection of metabolic pathways for substrate utilization during differentiation of Th1 and Th2 lineages is a fundamental process conserved across species.
    Keywords:  CD4+T cell; antibiotics; apoptosis; energy metabolism; mitochondrial translation
    DOI:  https://doi.org/10.1111/imm.13860
  24. bioRxiv. 2024 Aug 26. pii: 2024.08.24.609500. [Epub ahead of print]
    A genetically encoded fluorescent reporter for polyamines.
    Pushkal Sharma, Colin Y Kim, Heather R Keys, Shinya Imada, Alexander B Joseph, Luke Ferro, Tenzin Kunchok, Rachel Anderson, Omer H Yilmaz, Jing-Ke Weng, Ankur Jain.
      Polyamines are abundant and evolutionarily conserved metabolites that are essential for life. Dietary polyamine supplementation extends life-span and health-span. Dysregulation of polyamine homeostasis is linked to Parkinson's disease and cancer, driving interest in therapeutically targeting this pathway. However, measuring cellular polyamine levels, which vary across cell types and states, remains challenging. We introduce a first-in-class genetically encoded polyamine reporter for real-time measurement of polyamine concentrations in single living cells. This reporter utilizes the polyamine-responsive ribosomal frameshift motif from the OAZ1 gene. We demonstrate broad applicability of this approach and reveal dynamic changes in polyamine levels in response to genetic and pharmacological perturbations. Using this reporter, we conducted a genome-wide CRISPR screen and uncovered an unexpected link between mitochondrial respiration and polyamine import, which are both risk factors for genetic Parkinson's disease. By offering a new lens to examine polyamine biology, this reporter may advance our understanding of these ubiquitous metabolites and accelerate therapy development.
    DOI:  https://doi.org/10.1101/2024.08.24.609500
  25. Cell Death Dis. 2024 Sep 12. 15(9): 670
    The NRF2-CARM1 axis links glucose sensing to transcriptional and epigenetic regulation of the pentose phosphate pathway in gastric cancer.
    Miaomiao Ping, Guangyao Li, Qijiao Li, Yang Fang, Taotao Fan, Jing Wu, Ruiyi Zhang, Lesha Zhang, Bing Shen, Jizheng Guo.
      Cancer cells autonomously alter metabolic pathways in response to dynamic nutrient conditions in the microenvironment to maintain cell survival and proliferation. A better understanding of these adaptive alterations may reveal the vulnerabilities of cancer cells. Here, we demonstrate that coactivator-associated arginine methyltransferase 1 (CARM1) is frequently overexpressed in gastric cancer and predicts poor prognosis of patients with this cancer. Gastric cancer cells sense a reduced extracellular glucose content, leading to activation of nuclear factor erythroid 2-related factor 2 (NRF2). Subsequently, NRF2 mediates the classic antioxidant pathway to eliminate the accumulation of reactive oxygen species induced by low glucose. We found that NRF2 binds to the CARM1 promoter, upregulating its expression and triggering CARM1-mediated hypermethylation of histone H3 methylated at R arginine 17 (H3R17me2) in the glucose-6-phosphate dehydrogenase gene body. The upregulation of this dehydrogenase, driven by the H3R17me2 modification, redirects glucose carbon flux toward the pentose phosphate pathway. This redirection contributes to nucleotide synthesis (yielding nucleotide precursors, such as ribose-5-phosphate) and redox homeostasis and ultimately facilitates cancer cell survival and growth. NRF2 or CARM1 knockdown results in decreased H3R17me2a accompanied by the reduction of glucose-6-phosphate dehydrogenase under low glucose conditions. Collectively, this study reveals a significant role of CARM1 in regulating the tumor metabolic switch and identifies CARM1 as a potential therapeutic target for gastric cancer treatment.
    DOI:  https://doi.org/10.1038/s41419-024-07052-3
  26. Elife. 2024 Sep 13. pii: RP97568. [Epub ahead of print]13
    The bacterial quorum sensing signal 2'-aminoacetophenone rewires immune cell bioenergetics through the Ppargc1a/Esrra axis to mediate tolerance to infection.
    Arijit Chakraborty, Arunava Bandyopadhaya, Vijay K Singh, Filip Kovacic, Sujin Cha, William M Oldham, A Aria Tzika, Laurence G Rahme.
      How bacterial pathogens exploit host metabolism to promote immune tolerance and persist in infected hosts remains elusive. To achieve this, we show that Pseudomonas aeruginosa (PA), a recalcitrant pathogen, utilizes the quorum sensing (QS) signal 2'-aminoacetophenone (2-AA). Here, we unveil how 2-AA-driven immune tolerization causes distinct metabolic perturbations in murine macrophages' mitochondrial respiration and bioenergetics. We present evidence indicating that these effects stem from decreased pyruvate transport into mitochondria. This reduction is attributed to decreased expression of the mitochondrial pyruvate carrier (Mpc1), which is mediated by diminished expression and nuclear presence of its transcriptional regulator, estrogen-related nuclear receptor alpha (Esrra). Consequently, Esrra exhibits weakened binding to the Mpc1 promoter. This outcome arises from the impaired interaction between Esrra and the peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Ppargc1a). Ultimately, this cascade results in diminished pyruvate influx into mitochondria and, consequently reduced ATP production in tolerized murine and human macrophages. Exogenously added ATP in infected macrophages restores the transcript levels of Mpc1 and Esrra and enhances cytokine production and intracellular bacterial clearance. Consistent with the in vitro findings, murine infection studies corroborate the 2-AA-mediated long-lasting decrease in ATP and acetyl-CoA and its association with PA persistence, further supporting this QS signaling molecule as the culprit of the host bioenergetic alterations and PA persistence. These findings unveil 2-AA as a modulator of cellular immunometabolism and reveal an unprecedented mechanism of host tolerance to infection involving the Ppargc1a/Esrra axis in its influence on Mpc1/OXPHOS-dependent energy production and PA clearance. These paradigmatic findings pave the way for developing treatments to bolster host resilience to pathogen-induced damage. Given that QS is a common characteristic of prokaryotes, it is likely that 2-AA-like molecules with similar functions may be present in other pathogens.
    Keywords:  2'-aminoacetophenone; Esrra; MvfR; PqsR; Pseudomonas aeruginosa; immunology; inflammation; mouse; pseudomonas; quorum sensing; tolerance to infection
    DOI:  https://doi.org/10.7554/eLife.97568
  27. Cell Rep. 2024 Sep 10. pii: S2211-1247(24)01079-9. [Epub ahead of print]43(9): 114728
    Starvation-induced phosphorylation activates gasdermin A to initiate pyroptosis.
    Xinran Li, Xiao Li, Cong Xiang, Jin Cao, Jiansheng Guo, Shilei Zhu, Jingyi Tan, Lijing Wang, Chun Gao, Shengduo Liu, Lifeng Zhao, Bo Yuan, Pinglong Xu, Bing Yang, Dali Li, Bin Zhao, Xin-Hua Feng.
      Pyroptosis, a pro-inflammatory form of programmed cell death, is crucial for host defense against pathogens and danger signals. Proteolytic cleavage of gasdermin proteins B-E (GSDMB-GSDME) is well established as a trigger for pyroptosis, but the intracellular activation mechanism of GSDMA remains elusive. Here, we demonstrate that severe starvation induces pyroptosis through phosphorylation-induced activation of GSDMA. Nutrient stresses stimulate GSDMA activation via phosphorylation mediated by Unc-51-like autophagy-activating kinase 1 (ULK1). Phosphorylation of Ser353 on human GSDMA by ULK1 or the phospho-mimetic Ser353Asp mutant of GSDMA liberates GSDMA from auto-inhibition, facilitating its membrane targeting and initiation of pyroptosis. To further validate the significance of GSDMA phosphorylation, we generated a constitutively active mutant Ser354Asp of mouse Gsdma, which induced skin inflammation and hyperplasia in mice, reminiscent of phenotypes with activated Gsdma. This study uncovers phosphorylation of GSDMA as a mechanism underlying pyroptosis initiation and cellular response to nutrient stress.
    Keywords:  CP: Immunology; CP: Metabolism; GSDMA; ULK1; gastric cancer; phosphorylation; pyroptotic cell death; skin inflammation; starvation
    DOI:  https://doi.org/10.1016/j.celrep.2024.114728
  28. Nature. 2024 Sep;633(8029): 295-305
    The emerging view on the origin and early evolution of eukaryotic cells.
    Julian Vosseberg, Jolien J E van Hooff, Stephan Köstlbacher, Kassiani Panagiotou, Daniel Tamarit, Thijs J G Ettema.
      The origin of the eukaryotic cell, with its compartmentalized nature and generally large size compared with bacterial and archaeal cells, represents a cornerstone event in the evolution of complex life on Earth. In a process referred to as eukaryogenesis, the eukaryotic cell is believed to have evolved between approximately 1.8 and 2.7 billion years ago from its archaeal ancestors, with a symbiosis with a bacterial (proto-mitochondrial) partner being a key event. In the tree of life, the branch separating the first from the last common ancestor of all eukaryotes is long and lacks evolutionary intermediates. As a result, the timing and driving forces of the emergence of complex eukaryotic features remain poorly understood. During the past decade, environmental and comparative genomic studies have revealed vital details about the identity and nature of the host cell and the proto-mitochondrial endosymbiont, enabling a critical reappraisal of hypotheses underlying the symbiotic origin of the eukaryotic cell. Here we outline our current understanding of the key players and events underlying the emergence of cellular complexity during the prokaryote-to-eukaryote transition and discuss potential avenues of future research that might provide new insights into the enigmatic origin of the eukaryotic cell.
    DOI:  https://doi.org/10.1038/s41586-024-07677-6
  29. J Immunol. 2024 Sep 11. pii: ji2400285. [Epub ahead of print]
    CPT2-mediated Fatty Acid Oxidation Is Dispensable for Humoral Immunity.
    Meilu Li, Xian Zhou, Yanfeng Li, Xingxing Zhu, Yuzhen Li, Taro Hitosugi, Hu Zeng.
      B cell activation is accompanied by dynamic metabolic reprogramming, supported by a multitude of nutrients that include glucose, amino acids, and fatty acids. Although several studies have indicated that fatty acid mitochondrial oxidation is critical for immune cell functions, contradictory findings have been reported. Carnitine palmitoyltransferase II (CPT2) is a critical enzyme for long-chain fatty acid oxidation in mitochondria. In this study, we test the requirement of CPT2 for humoral immunity using a mouse model with a lymphocyte-specific deletion of CPT2. Stable [13C] isotope tracing reveals highly reduced fatty acid-derived citrate production in CPT2-deficient B cells. Yet, CPT2 deficiency has no significant impact on B cell development, B cell activation, germinal center formation, and Ab production upon either thymus-dependent or -independent Ag challenges. Together, our findings indicate that CPT2-mediated fatty acid oxidation is dispensable for humoral immunity, highlighting the metabolic flexibility of lymphocytes.
    DOI:  https://doi.org/10.4049/jimmunol.2400285
  30. Nat Commun. 2024 Sep 10. 15(1): 7383
    Deep intravital brain tumor imaging enabled by tailored three-photon microscopy and analysis.
    Marc Cicero Schubert, Stella Judith Soyka, Amr Tamimi, Emanuel Maus, Julian Schroers, Niklas Wißmann, Ekin Reyhan, Svenja Kristin Tetzlaff, Yvonne Yang, Robert Denninger, Robin Peretzke, Carlo Beretta, Michael Drumm, Alina Heuer, Verena Buchert, Alicia Steffens, Jordain Walshon, Kathleen McCortney, Sabine Heiland, Martin Bendszus, Peter Neher, Anna Golebiewska, Wolfgang Wick, Frank Winkler, Michael O Breckwoldt, Anna Kreshuk, Thomas Kuner, Craig Horbinski, Felix Tobias Kurz, Robert Prevedel, Varun Venkataramani.
      Intravital 2P-microscopy enables the longitudinal study of brain tumor biology in superficial mouse cortex layers. Intravital microscopy of the white matter, an important route of glioblastoma invasion and recurrence, has not been feasible, due to low signal-to-noise ratios and insufficient spatiotemporal resolution. Here, we present an intravital microscopy and artificial intelligence-based analysis workflow (Deep3P) that enables longitudinal deep imaging of glioblastoma up to a depth of 1.2 mm. We find that perivascular invasion is the preferred invasion route into the corpus callosum and uncover two vascular mechanisms of glioblastoma migration in the white matter. Furthermore, we observe morphological changes after white matter infiltration, a potential basis of an imaging biomarker during early glioblastoma colonization. Taken together, Deep3P allows for a non-invasive intravital investigation of brain tumor biology and its tumor microenvironment at subcortical depths explored, opening up opportunities for studying the neuroscience of brain tumors and other model systems.
    DOI:  https://doi.org/10.1038/s41467-024-51432-4
  31. Nature. 2024 Sep 11.
    Gasdermin D-mediated metabolic crosstalk promotes tissue repair.
    Zhexu Chi, Sheng Chen, Dehang Yang, Wenyu Cui, Yang Lu, Zhen Wang, Mobai Li, Weiwei Yu, Jian Zhang, Yu Jiang, Ruya Sun, Qianzhou Yu, Tianyi Hu, Xiaoyang Lu, Qiqi Deng, Yidong Yang, Tianming Zhao, Mengfei Chang, Yuying Li, Xue Zhang, Min Shang, Qian Xiao, Kefeng Ding, Di Wang.
      The establishment of an early pro-regenerative niche is crucial for tissue regeneration1,2. Gasdermin D (GSDMD)-dependent pyroptosis accounts for the release of inflammatory cytokines upon various insults3-5. However, little is known about its role in tissue regeneration followed by homeostatic maintenance. Here, we show that macrophage GSDMD deficiency delayed tissue recovery, with little impact on the local inflammatory milieu or the lytic pyroptosis process. Metabolite secretome profiling of hyperactivated macrophages unveiled the non-canonical metabolite-secreting function of GSDMD. And we further identified 11,12-epoxyeicosatrienoic acid (11,12-EET) as a bioactive pro-healing oxylipin, secreted from hyperactive macrophages in a GSDMD-dependent manner. Indeed, accumulation of 11,12-EET by direct supplementation or deletion of its hydrolytic enzyme Ephx2 accelerated muscle regeneration. We further demonstrated that the Ephx2 level accumulated within aged muscle. And consecutive 11,12-EET treatment rejuvenated aged muscle. Mechanistically, 11,12-EET amplifies FGF-FGFR signaling by modulating FGF liquid-liquid phase separation, hence boosting the activation and proliferation of muscle stem cells (MuSCs). These data depict a GSDMD-guided metabolite crosstalk between macrophages and MuSCs that governs the repair process, which offers new therapeutic insights for the regeneration of injured or aged tissues.
    DOI:  https://doi.org/10.1038/s41586-024-08022-7
  32. Res Sq. 2024 Aug 27. pii: rs.3.rs-4876596. [Epub ahead of print]
    Mitochondrial RNA cytosolic leakage drives the SASP.
    Stella Victorelli, Madeline Eppard, Seung-Hwa Woo, Stacia Everts, Helene Martini, Nicholas Pirius, Ana Catarina Franco, Yeaeun Han, Dominik Saul, Patrick Splinter, Steven O'Hara, Lucia Valenzuela-Pérez, Hyun Se Kim Lee, Diana Jurk, Nicholas LaRusso, Petra Hirsova, Joao Passos.
      Senescent cells secrete proinflammatory factors known as the senescence-associated secretory phenotype (SASP), contributing to tissue dysfunction and aging. Mitochondrial dysfunction is a key feature of senescence, influencing SASP via mitochondrial DNA (mtDNA) release and cGAS/STING pathway activation. Here, we demonstrate that mitochondrial RNA (mtRNA) also accumulates in the cytosol of senescent cells, activating RNA sensors RIG-I and MDA5, leading to MAVS aggregation and SASP induction. Inhibition of these RNA sensors significantly reduces SASP factors. Furthermore, BAX and BAK plays a key role in mtRNA leakage during senescence, and their deletion diminishes SASP expression in vitro and in a mouse model of Metabolic Dysfunction Associated Steatohepatitis (MASH). These findings highlight mtRNA's role in SASP regulation and its potential as a therapeutic target for mitigating age-related inflammation.
    DOI:  https://doi.org/10.21203/rs.3.rs-4876596/v1
  33. Cell. 2024 Aug 29. pii: S0092-8674(24)00905-X. [Epub ahead of print]
    TGF-β and RAS jointly unmask primed enhancers to drive metastasis.
    Jun Ho Lee, Francisco J Sánchez-Rivera, Lan He, Harihar Basnet, Fei Xavier Chen, Elena Spina, Liangji Li, Carles Torner, Jason E Chan, Dig Vijay Kumar Yarlagadda, Jin Suk Park, Carleigh Sussman, Charles M Rudin, Scott W Lowe, Tuomas Tammela, Maria J Macias, Richard P Koche, Joan Massagué.
      Epithelial-to-mesenchymal transitions (EMTs) and extracellular matrix (ECM) remodeling are distinct yet important processes during carcinoma invasion and metastasis. Transforming growth factor β (TGF-β) and RAS, signaling through SMAD and RAS-responsive element-binding protein 1 (RREB1), jointly trigger expression of EMT and fibrogenic factors as two discrete arms of a common transcriptional response in carcinoma cells. Here, we demonstrate that both arms come together to form a program for lung adenocarcinoma metastasis and identify chromatin determinants tying the expression of the constituent genes to TGF-β and RAS inputs. RREB1 localizes to H4K16acK20ac marks in histone H2A.Z-loaded nucleosomes at enhancers in the fibrogenic genes interleukin-11 (IL11), platelet-derived growth factor-B (PDGFB), and hyaluronan synthase 2 (HAS2), as well as the EMT transcription factor SNAI1, priming these enhancers for activation by a SMAD4-INO80 nucleosome remodeling complex in response to TGF-β. These regulatory properties segregate the fibrogenic EMT program from RAS-independent TGF-β gene responses and illuminate the operation and vulnerabilities of a bifunctional program that promotes metastatic outgrowth.
    Keywords:  EMT; RAS; SMAD; TGF-β; chromatin; enhancer; fibrosis; lung adenocarcinoma; metastasis
    DOI:  https://doi.org/10.1016/j.cell.2024.08.014
  34. J Cell Physiol. 2024 Sep 08. e31417
    Cancer knocks you out by fasting: Cachexia as a consequence of metabolic alterations in cancer.
    Salvatore Cortellino, Margherita D'Angelo, Massimiliano Quintiliani, Antonio Giordano.
      Neoplastic transformation reprograms tumor and surrounding host cell metabolism, increasing nutrient consumption and depletion in the tumor microenvironment. Tumors uptake nutrients from neighboring normal tissues or the bloodstream to meet energy and anabolic demands. Tumor-induced chronic inflammation, a high-energy process, also consumes nutrients to sustain its dysfunctional activities. These tumor-related metabolic and physiological changes, including chronic inflammation, negatively impact systemic metabolism and physiology. Furthermore, the adverse effects of antitumor therapy and tumor obstruction impair the endocrine, neural, and gastrointestinal systems, thereby confounding the systemic status of patients. These alterations result in decreased appetite, impaired nutrient absorption, inflammation, and shift from anabolic to catabolic metabolism. Consequently, cancer patients often suffer from malnutrition, which worsens prognosis and increases susceptibility to secondary adverse events. This review explores how neoplastic transformation affects tumor and microenvironment metabolism and inflammation, leading to poor prognosis, and discusses potential strategies and clinical interventions to improve patient outcomes.
    Keywords:  cachexia; cancer metabolism; detary interventions; inflammation; malnutrition
    DOI:  https://doi.org/10.1002/jcp.31417
  35. Nat Commun. 2024 Sep 11. 15(1): 7948
    Hypothalamic SLC7A14 accounts for aging-reduced lipolysis in white adipose tissue of male mice.
    Xiaoxue Jiang, Kan Liu, Peixiang Luo, Zi Li, Fei Xiao, Haizhou Jiang, Shangming Wu, Min Tang, Feixiang Yuan, Xiaoying Li, Yousheng Shu, Bo Peng, Shanghai Chen, Shihong Ni, Feifan Guo.
      The central nervous system has been implicated in the age-induced reduction in adipose tissue lipolysis. However, the underlying mechanisms remain unclear. Here, we show the expression of SLC7A14 is reduced in proopiomelanocortin (POMC) neurons of aged mice. Overexpression of SLC7A14 in POMC neurons alleviates the aging-reduced lipolysis, whereas SLC7A14 deletion mimics the age-induced lipolysis impairment. Metabolomics analysis reveals that POMC SLC7A14 increased taurochenodeoxycholic acid (TCDCA) content, which mediates the SLC7A14 knockout- or age-induced WAT lipolysis impairment. Furthermore, SLC7A14-increased TCDCA content is dependent on intestinal apical sodium-dependent bile acid transporter (ASBT), which is regulated by intestinal sympathetic afferent nerves. Finally, SLC7A14 regulates the intestinal sympathetic afferent nerves by inhibiting mTORC1 signaling through inhibiting TSC1 phosphorylation. Collectively, our study suggests the function for central SLC7A14 and an upstream mechanism for the mTORC1 signaling pathway. Moreover, our data provides insights into the brain-gut-adipose tissue crosstalk in age-induced lipolysis impairment.
    DOI:  https://doi.org/10.1038/s41467-024-52059-1
  36. Nat Genet. 2024 Sep;56(9): 1765
    X chromosome dosage shapes renal cell carcinoma risk.
    Tiago Faial.
      
    DOI:  https://doi.org/10.1038/s41588-024-01924-2
  37. Cell. 2024 Sep 06. pii: S0092-8674(24)00909-7. [Epub ahead of print]
    Biomolecular condensates regulate cellular electrochemical equilibria.
    Yifan Dai, Zhengqing Zhou, Wen Yu, Yuefeng Ma, Kyeri Kim, Nelson Rivera, Javid Mohammed, Erica Lantelme, Heileen Hsu-Kim, Ashutosh Chilkoti, Lingchong You.
      Control of the electrochemical environment in living cells is typically attributed to ion channels. Here, we show that the formation of biomolecular condensates can modulate the electrochemical environment in bacterial cells, which affects cellular processes globally. Condensate formation generates an electric potential gradient, which directly affects the electrochemical properties of a cell, including cytoplasmic pH and membrane potential. Condensate formation also amplifies cell-cell variability of their electrochemical properties due to passive environmental effect. The modulation of the electrochemical equilibria further controls cell-environment interactions, thus directly influencing bacterial survival under antibiotic stress. The condensate-mediated shift in intracellular electrochemical equilibria drives a change of the global gene expression profile. Our work reveals the biochemical functions of condensates, which extend beyond the functions of biomolecules driving and participating in condensate formation, and uncovers a role of condensates in regulating global cellular physiology.
    Keywords:  antibiotics; biomolecular condensates; electrochemical features of condensates; global cellular physiology; intracellular electrochemistry; ion flux; membrane potential
    DOI:  https://doi.org/10.1016/j.cell.2024.08.018
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