bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2023–11–19
fifty papers selected by
Christian Frezza, Universität zu Köln
  1. NAD+ regulates nucleotide metabolism and genomic DNA replication.
  2. Inhibition of the proline metabolism rate-limiting enzyme P5CS allows proliferation of glutamine-restricted cancer cells.
  3. Cristae dynamics is modulated in bioenergetically compromised mitochondria.
  4. Refeeding-associated AMPKγ1 complex activity is a hallmark of health and longevity.
  5. Vitamin B12 is a limiting factor for induced cellular plasticity and tissue repair.
  6. Rewiring of cortical glucose metabolism fuels human brain cancer growth.
  7. Branched-Chain Amino Acid Accumulation Fuels the Senescence-Associated Secretory Phenotype.
  8. Mitochondrial entry gate as regulatory hub.
  9. Sensitization of cancer cells to ferroptosis coincident with cell cycle arrest.
  10. Vitamin B12 emerges as key player during cellular reprogramming.
  11. ATR promotes mTORC1 activation via de novo cholesterol synthesis in p16-low cancer cells.
  12. Dietary branched-chain amino acids get to the heart of H3K23Pr.
  13. One-carbon unit supplementation fuels tumor-infiltrating T cells and augments checkpoint blockade.
  14. MYC-driven increases in mitochondrial DNA copy number occur early and persist throughout prostatic cancer progression.
  15. MCUb is an inducible regulator of calcium-dependent mitochondrial metabolism and substrate utilization in muscle.
  16. Glutamine metabolism inhibition has dual immunomodulatory and antibacterial activities against Mycobacterium tuberculosis.
  17. Stress granules plug and stabilize damaged endolysosomal membranes.
  18. Glucose Challenge Uncovers Temporal Fungibility of Metabolic Homeostasis Throughout the Day.
  19. Multi-omic screening of invasive GBM cells reveals targetable transsulfuration pathway alterations.
  20. MAPL loss dysregulates bile and liver metabolism in mice.
  21. The Warburg Effect Explained: Integration of Enhanced Glycolysis with Heterogeneous Mitochondria to Promote Cancer Cell Proliferation.
  22. Lipin-1 restrains macrophage lipid synthesis to promote inflammation resolution.
  23. Bacterial cGAS senses a viral RNA to initiate immunity.
  24. Active growth signaling promotes senescence and cancer cell sensitivity to CDK7 inhibition.
  25. Reprogramming tumor-associated macrophages to outcompete endovascular endothelial progenitor cells and suppress tumor neoangiogenesis.
  26. Oncogenic signals prime cancer cells for toxic cell overgrowth during a G1 cell cycle arrest.
  27. Mitoribosomal synthetic lethality overcomes multidrug resistance in MYC-driven neuroblastoma.
  28. Targeted perturbation of signaling-driven condensates.
  29. Inflammatory macrophages reprogram to immunosuppression by reducing mitochondrial translation.
  30. Phenotypic noise and plasticity in cancer evolution.
  31. Mitochondria-associated membrane collapse impairs TBK1-mediated proteostatic stress response in ALS.
  32. Transcription factor NFYa controls cardiomyocyte metabolism and proliferation during mouse fetal heart development.
  33. Lipid Quality Control and Ferroptosis: From Concept to Mechanism.
  34. Identification of Acetylation Sites of Fatty Acid Synthase (FASN) by Mass Spectrometry and FASN Activity Assay.
  35. Small cell lung cancer plasticity enables NFIB-independent metastasis.
  36. Microglia promote anti-tumour immunity and suppress breast cancer brain metastasis.
  37. Integrated chemical and genetic screens unveil FSP1 mechanisms of ferroptosis regulation.
  38. MICROGLIA IN CENTRAL CONTROL OF METABOLISM.
  39. Metabolic predictors of response to immune checkpoint blockade therapy.
  40. Inorganic polyphosphate and the regulation of mitochondrial physiology.
  41. FSP1 inhibition: pick your pocket.
  42. Single-cell CRISPR screens in vivo map T cell fate regulomes in cancer.
  43. Carbon dioxide regulates cholesterol levels through SREBP2.
  44. Membrane potential mediates an ancient mechano-transduction mechanism for multi-cellular homeostasis.
  45. Persister cell plasticity in tumour drug resistance.
  46. Targeted suppression of mTORC2 reduces seizures across models of epilepsy.
  47. Disseminating cells in human oral tumours possess an EMT cancer stem cell marker profile that is predictive of metastasis in image-based machine learning.
  48. Rethinking cancer initiation: The role of large-scale mutational events.
  49. SMPDL3A links cholesterol metabolism to the cGAS-STING pathway.
  50. 3D reconstruction of murine mitochondria reveals changes in structure during aging linked to the MICOS complex.
  1. Nat Cell Biol. 2023 Nov 13.
    NAD+ regulates nucleotide metabolism and genomic DNA replication.
    Sebastian Howen Nesgaard Munk, Joanna Maria Merchut-Maya, Alba Adelantado Rubio, Arnaldur Hall, George Pappas, Giacomo Milletti, MyungHee Lee, Lea Giørtz Johnsen, Per Guldberg, Jiri Bartek, Apolinar Maya-Mendoza.
      The intricate orchestration of enzymatic activities involving nicotinamide adenine dinucleotide (NAD+) is essential for maintaining metabolic homeostasis and preserving genomic integrity. As a co-enzyme, NAD+ plays a key role in regulating metabolic pathways, such as glycolysis and Kreb's cycle. ADP-ribosyltransferases (PARPs) and sirtuins rely on NAD+ to mediate post-translational modifications of target proteins. The activation of PARP1 in response to DNA breaks leads to rapid depletion of cellular NAD+ compromising cell viability. Therefore, the levels of NAD+ must be tightly regulated. Here we show that exogenous NAD+, but not its precursors, has a direct effect on mitochondrial activity. Short-term incubation with NAD+ boosts Kreb's cycle and the electron transport chain and enhances pyrimidine biosynthesis. Extended incubation with NAD+ results in depletion of pyrimidines, accumulation of purines, activation of the replication stress response and cell cycle arrest. Moreover, a combination of NAD+ and 5-fluorouridine selectively kills cancer cells that rely on de novo pyrimidine synthesis. We propose an integrated model of how NAD+ regulates nucleotide metabolism, with relevance to healthspan, ageing and cancer therapy.
    DOI:  https://doi.org/10.1038/s41556-023-01280-z
  2. Nat Metab. 2023 Nov 13.
    Inhibition of the proline metabolism rate-limiting enzyme P5CS allows proliferation of glutamine-restricted cancer cells.
    Samantha J Linder, Tiziano Bernasocchi, Bárbara Martínez-Pastor, Kelly D Sullivan, Matthew D Galbraith, Caroline A Lewis, Christina M Ferrer, Ruben Boon, Giorgia G Silveira, Hyo Min Cho, Charles Vidoudez, Stuti Shroff, Joao P Oliveira-Costa, Kenneth N Ross, Rami Massri, Yusuke Matoba, Eugene Kim, Bo R Rueda, Shannon L Stott, Eyal Gottlieb, Joaquin M Espinosa, Raul Mostoslavsky.
      Glutamine is a critical metabolite for rapidly proliferating cells as it is used for the synthesis of key metabolites necessary for cell growth and proliferation. Glutamine metabolism has been proposed as a therapeutic target in cancer and several chemical inhibitors are in development or in clinical trials. How cells subsist when glutamine is limiting is poorly understood. Here, using an unbiased screen, we identify ALDH18A1, which encodes P5CS, the rate-limiting enzyme in the proline biosynthetic pathway, as a gene that cells can downregulate in response to glutamine starvation. Notably, P5CS downregulation promotes de novo glutamine synthesis, highlighting a previously unrecognized metabolic plasticity of cancer cells. The glutamate conserved from reducing proline synthesis allows cells to produce the key metabolites necessary for cell survival and proliferation under glutamine-restricted conditions. Our findings reveal an adaptive pathway that cancer cells acquire under nutrient stress, identifying proline biosynthesis as a previously unrecognized major consumer of glutamate, a pathway that could be exploited for developing effective metabolism-driven anticancer therapies.
    DOI:  https://doi.org/10.1038/s42255-023-00919-3
  3. Life Sci Alliance. 2024 Feb;pii: e202302386. [Epub ahead of print]7(2):
    Cristae dynamics is modulated in bioenergetically compromised mitochondria.
    Mathias Golombek, Thanos Tsigaras, Yulia Schaumkessel, Sebastian Hänsch, Stefanie Weidtkamp-Peters, Ruchika Anand, Andreas S Reichert, Arun Kumar Kondadi.
      Cristae membranes have been recently shown to undergo intramitochondrial merging and splitting events. Yet, the metabolic and bioenergetic factors regulating them are unclear. Here, we investigated whether and how cristae morphology and dynamics are dependent on oxidative phosphorylation (OXPHOS) complexes, the mitochondrial membrane potential (ΔΨm), and the ADP/ATP nucleotide translocator. Advanced live-cell STED nanoscopy combined with in-depth quantification were employed to analyse cristae morphology and dynamics after treatment of mammalian cells with rotenone, antimycin A, oligomycin A, and CCCP. This led to formation of enlarged mitochondria along with reduced cristae density but did not impair cristae dynamics. CCCP treatment leading to ΔΨm abrogation even enhanced cristae dynamics showing its ΔΨm-independent nature. Inhibition of OXPHOS complexes was accompanied by reduced ATP levels but did not affect cristae dynamics. However, inhibition of ADP/ATP exchange led to aberrant cristae morphology and impaired cristae dynamics in a mitochondrial subset. In sum, we provide quantitative data of cristae membrane remodelling under different conditions supporting an important interplay between OXPHOS, metabolite exchange, and cristae membrane dynamics.
    DOI:  https://doi.org/10.26508/lsa.202302386
  4. Nat Aging. 2023 Nov 13.
    Refeeding-associated AMPKγ1 complex activity is a hallmark of health and longevity.
    Roberto Ripa, Eugen Ballhysa, Joachim D Steiner, Raymond Laboy, Andrea Annibal, Nadine Hochhard, Christian Latza, Luca Dolfi, Chiara Calabrese, Anna M Meyer, Maria Cristina Polidori, Roman-Ulrich Müller, Adam Antebi.
      Late-life-initiated dietary interventions show limited efficacy in extending longevity or mitigating frailty, yet the underlying causes remain unclear. Here we studied the age-related fasting response of the short-lived killifish Nothobranchius furzeri. Transcriptomic analysis uncovered the existence of a fasting-like transcriptional program in the adipose tissue of old fish that overrides the feeding response, setting the tissue in persistent metabolic quiescence. The fasting-refeeding cycle triggers an inverse oscillatory expression of genes encoding the AMP-activated protein kinase (AMPK) regulatory subunits Prkag1 (γ1) and Prkag2 (γ2) in young individuals. Aging blunts such regulation, resulting in reduced Prkag1 expression. Transgenic fish with sustained AMPKγ1 countered the fasting-like transcriptional program, exhibiting a more youthful feeding and fasting response in older age, improved metabolic health and longevity. Accordingly, Prkag1 expression declines with age in human tissues and is associated with multimorbidity and multidimensional frailty risk. Thus, selective activation of AMPKγ1 prevents metabolic quiescence and preserves healthy aging in vertebrates, offering potential avenues for intervention.
    DOI:  https://doi.org/10.1038/s43587-023-00521-y
  5. Nat Metab. 2023 Nov 16.
    Vitamin B12 is a limiting factor for induced cellular plasticity and tissue repair.
    Marta Kovatcheva, Elena Melendez, Dafni Chondronasiou, Federico Pietrocola, Raquel Bernad, Adrià Caballe, Alexandra Junza, Jordi Capellades, Adrián Holguín-Horcajo, Neus Prats, Sylvere Durand, Meritxell Rovira, Oscar Yanes, Camille Stephan-Otto Attolini, Guido Kroemer, Manuel Serrano.
      Transient reprogramming by the expression of OCT4, SOX2, KLF4 and MYC (OSKM) is a therapeutic strategy for tissue regeneration and rejuvenation, but little is known about its metabolic requirements. Here we show that OSKM reprogramming in mice causes a global depletion of vitamin B12 and molecular hallmarks of methionine starvation. Supplementation with vitamin B12 increases the efficiency of reprogramming both in mice and in cultured cells, the latter indicating a cell-intrinsic effect. We show that the epigenetic mark H3K36me3, which prevents illegitimate initiation of transcription outside promoters (cryptic transcription), is sensitive to vitamin B12 levels, providing evidence for a link between B12 levels, H3K36 methylation, transcriptional fidelity and efficient reprogramming. Vitamin B12 supplementation also accelerates tissue repair in a model of ulcerative colitis. We conclude that vitamin B12, through its key role in one-carbon metabolism and epigenetic dynamics, improves the efficiency of in vivo reprogramming and tissue repair.
    DOI:  https://doi.org/10.1038/s42255-023-00916-6
  6. medRxiv. 2023 Oct 25. pii: 2023.10.24.23297489. [Epub ahead of print]
    Rewiring of cortical glucose metabolism fuels human brain cancer growth.
    Andrew J Scott, Anjali Mittal, Baharan Meghdadi, Sravya Palavalasa, Abhinav Achreja, Alexandra O'Brien, Ayesha U Kothari, Weihua Zhou, Jie Xu, Angelica Lin, Kari Wilder-Romans, Donna M Edwards, Zhe Wu, Jiane Feng, Anthony C Andren, Li Zhang, Vijay Tarnal, Kimberly A Redic, Nathan Qi, Joshua Fischer, Ethan Yang, Michael S Regan, Sylwia A Stopka, Gerard Baquer, Theodore S Lawrence, Sriram Venneti, Nathalie Y R Agar, Costas A Lyssiotis, Wajd N Al-Holou, Deepak Nagrath, Daniel R Wahl.
      The brain avidly consumes glucose to fuel neurophysiology. Cancers of the brain, such as glioblastoma (GBM), lose aspects of normal biology and gain the ability to proliferate and invade healthy tissue. How brain cancers rewire glucose utilization to fuel these processes is poorly understood. Here we perform infusions of 13 C-labeled glucose into patients and mice with brain cancer to define the metabolic fates of glucose-derived carbon in tumor and cortex. By combining these measurements with quantitative metabolic flux analysis, we find that human cortex funnels glucose-derived carbons towards physiologic processes including TCA cycle oxidation and neurotransmitter synthesis. In contrast, brain cancers downregulate these physiologic processes, scavenge alternative carbon sources from the environment, and instead use glucose-derived carbons to produce molecules needed for proliferation and invasion. Targeting this metabolic rewiring in mice through dietary modulation selectively alters GBM metabolism and slows tumor growth.
    Significance: This study is the first to directly measure biosynthetic flux in both glioma and cortical tissue in human brain cancer patients. Brain tumors rewire glucose carbon utilization away from oxidation and neurotransmitter production towards biosynthesis to fuel growth. Blocking these metabolic adaptations with dietary interventions slows brain cancer growth with minimal effects on cortical metabolism.
    DOI:  https://doi.org/10.1101/2023.10.24.23297489
  7. Adv Sci (Weinh). 2023 Nov 15. e2303489
    Branched-Chain Amino Acid Accumulation Fuels the Senescence-Associated Secretory Phenotype.
    Yaosi Liang, Christopher Pan, Tao Yin, Lu Wang, Xia Gao, Ergang Wang, Holly Quang, De Huang, Lianmei Tan, Kun Xiang, Yu Wang, Peter B Alexander, Qi-Jing Li, Tso-Pang Yao, Zhao Zhang, Xiao-Fan Wang.
      The essential branched-chain amino acids (BCAAs) leucine, isoleucine, and valine play critical roles in protein synthesis and energy metabolism. Despite their widespread use as nutritional supplements, BCAAs' full effects on mammalian physiology remain uncertain due to the complexities of BCAA metabolic regulation. Here a novel mechanism linking intrinsic alterations in BCAA metabolism is identified to cellular senescence and the senescence-associated secretory phenotype (SASP), both of which contribute to organismal aging and inflammation-related diseases. Altered BCAA metabolism driving the SASP is mediated by robust activation of the BCAA transporters Solute Carrier Family 6 Members 14 and 15 as well as downregulation of the catabolic enzyme BCAA transaminase 1 during onset of cellular senescence, leading to highly elevated intracellular BCAA levels in senescent cells. This, in turn, activates the mammalian target of rapamycin complex 1 (mTORC1) to establish the full SASP program. Transgenic Drosophila models further indicate that orthologous BCAA regulators are involved in the induction of cellular senescence and age-related phenotypes in flies, suggesting evolutionary conservation of this metabolic pathway during aging. Finally, experimentally blocking BCAA accumulation attenuates the inflammatory response in a mouse senescence model, highlighting the therapeutic potential of modulating BCAA metabolism for the treatment of age-related and inflammatory diseases.
    Keywords:  BCAA; SASP; age-related inflammation; mTORC1; senescence
    DOI:  https://doi.org/10.1002/advs.202303489
  8. Biochim Biophys Acta Mol Cell Res. 2023 Jul 04. pii: S0167-4889(23)00101-5. [Epub ahead of print] 119529
    Mitochondrial entry gate as regulatory hub.
    Fabian den Brave, Nikolaus Pfanner, Thomas Becker.
      Mitochondria import 1000-1300 different precursor proteins from the cytosol. The main mitochondrial entry gate is formed by the translocase of the outer membrane (TOM complex). Molecular coupling and modification of TOM subunits control and modulate protein import in response to cellular signaling. The TOM complex functions as regulatory hub to integrate mitochondrial protein biogenesis and quality control into the cellular proteostasis network.
    Keywords:  Mitochondria; Protein sorting; Proteostasis; Quality control; Stress response; TOM complex
    DOI:  https://doi.org/10.1016/j.bbamcr.2023.119529
  9. Cell Chem Biol. 2023 Nov 09. pii: S2451-9456(23)00372-0. [Epub ahead of print]
    Sensitization of cancer cells to ferroptosis coincident with cell cycle arrest.
    Jason Rodencal, Nathan Kim, Andrew He, Veronica L Li, Mike Lange, Jianping He, Amy Tarangelo, Zachary T Schafer, James A Olzmann, Jonathan Z Long, Julien Sage, Scott J Dixon.
      Ferroptosis is a non-apoptotic form of cell death that can be triggered by inhibiting the system xc- cystine/glutamate antiporter or the phospholipid hydroperoxidase glutathione peroxidase 4 (GPX4). We have investigated how cell cycle arrest caused by stabilization of p53 or inhibition of cyclin-dependent kinase 4/6 (CDK4/6) impacts ferroptosis sensitivity. Here, we show that cell cycle arrest can enhance sensitivity to ferroptosis induced by covalent GPX4 inhibitors (GPX4i) but not system xc- inhibitors. Greater sensitivity to GPX4i is associated with increased levels of oxidizable polyunsaturated fatty acid-containing phospholipids (PUFA-PLs). Higher PUFA-PL abundance upon cell cycle arrest involves reduced expression of membrane-bound O-acyltransferase domain-containing 1 (MBOAT1) and epithelial membrane protein 2 (EMP2). A candidate orally bioavailable GPX4 inhibitor increases lipid peroxidation and shrinks tumor volumes when combined with a CDK4/6 inhibitor. Thus, cell cycle arrest may make certain cancer cells more susceptible to ferroptosis in vivo.
    Keywords:  CDK4/6; EMP2; MBOAT1; MUFA; PUFA; ferroptosis; iron; lipid peroxidation; p53; palbociclib
    DOI:  https://doi.org/10.1016/j.chembiol.2023.10.011
  10. Nat Metab. 2023 Nov 16.
    Vitamin B12 emerges as key player during cellular reprogramming.
    Alba Vílchez-Acosta, Gabriela Desdín-Micó, Alejandro Ocampo.
      
    DOI:  https://doi.org/10.1038/s42255-023-00917-5
  11. bioRxiv. 2023 Oct 27. pii: 2023.10.27.564195. [Epub ahead of print]
    ATR promotes mTORC1 activation via de novo cholesterol synthesis in p16-low cancer cells.
    Naveen Kumar Tangudu, Zhentai Huang, Richard Fang, Raquel Buj, Apoorva Uboveja, Aidan R Cole, Cassandra Happe, Mai Sun, Stacy L Gelhaus, Matthew L MacDonald, Nadine Hempel, Nathaniel W Snyder, Katherine M Aird.
      DNA damage and cellular metabolism are intricately linked with bidirectional feedback. Two of the main effectors of the DNA damage response and control of cellular metabolism are ATR and mTORC1, respectively. Prior work has placed ATR upstream of mTORC1 during replication stress, yet the direct mechanism for how mTORC1 is activated in this context remain unclear. We previously published that p16-low cells have mTORC1 hyperactivation, which in part promotes their proliferation. Using this model, we found that ATR, but not ATM, is upstream of mTORC1 activation via de novo cholesterol synthesis and is associated with increased lanosterol synthase (LSS). Indeed, p16-low cells showed increased cholesterol abundance. Additionally, knockdown of either ATR or LSS decreased mTORC1 activity. Decreased mTORC1 activity due to ATR knockdown was rescued by cholesterol supplementation. Finally, using both LSS inhibitors and multiple FDA-approved de novo cholesterol synthesis inhibitors, we found that the de novo cholesterol biosynthesis pathway is a metabolic vulnerability of p16-low cells. Together, our data provide new evidence coupling the DNA damage response and cholesterol metabolism and demonstrate the feasibility of using FDA-approved cholesterol-lowering drugs in tumors with loss of p16.
    DOI:  https://doi.org/10.1101/2023.10.27.564195
  12. J Clin Invest. 2023 Nov 15. pii: e174953. [Epub ahead of print]133(22):
    Dietary branched-chain amino acids get to the heart of H3K23Pr.
    Christina Demetriadou, Daniel S Kantner, Nathaniel W Snyder.
      Cardiac metabolism provides effects that extend beyond the transformation of energy for the heart to operate effectively. Some metabolites also function as signaling molecules and exert transcriptional changes. Heart failure is a progressive pathology in which these metabolite functions falter. In this issue of the JCI, Yang et al. describe a protective effect from a low-branched chain amino acid (BCAA) diet in a mouse model of heart failure. The findings implicate a propionylation mark on histone H3 lysine 23 (H3K23Pr), previously shown to be dependent on the BCAA isoleucine, in transcriptional control of the cardiac stress response. The result underscores the interplay between metabolism and histone acylation, highlighting targeted dietary and pharmacological intervention as a means to decelerate cardiac hypertrophy.
    DOI:  https://doi.org/10.1172/JCI174953
  13. bioRxiv. 2023 Nov 03. pii: 2023.11.01.565193. [Epub ahead of print]
    One-carbon unit supplementation fuels tumor-infiltrating T cells and augments checkpoint blockade.
    Xincheng Xu, Zihong Chen, Caroline R Bartman, Xi Xing, Kellen Olszewski, Joshua D Rabinowitz.
      Nucleotides perform important metabolic functions, carrying energy and feeding nucleic acid synthesis. Here, we use isotope tracing-mass spectrometry to quantitate the contributions to purine nucleotides of salvage versus de novo synthesis. We further explore the impact of augmenting a key precursor for purine synthesis, one-carbon (1C) units. We show that tumors and tumor-infiltrating T cells (relative to splenic T cells) synthesize purines de novo . Purine synthesis requires two 1C units, which come from serine catabolism and circulating formate. Shortage of 1C units is a potential bottleneck for anti-tumor immunity. Elevating circulating formate drives its usage by tumor-infiltrating T cells. Orally administered methanol functions as a formate pro-drug, with deuteration enabling control of formate-production kinetics. In MC38 tumors, safe doses of methanol raise formate levels and augment anti-PD-1 checkpoint blockade, tripling durable regressions. Thus, 1C deficiency can gate antitumor immunity and this metabolic checkpoint can be overcome with pharmacological 1C supplementation.
    Statement of significance: Checkpoint blockade has revolutionized cancer therapy. Durable tumor control, however, is achieved in only a minority of patients. We show that the efficacy of anti-PD-1 blockade can be enhanced by metabolic supplementation with one-carbon donors. Such donors support nucleotide synthesis in tumor-infiltrating T cells and merit future clinical evaluation.
    DOI:  https://doi.org/10.1101/2023.11.01.565193
  14. JCI Insight. 2023 Nov 16. pii: e169868. [Epub ahead of print]
    MYC-driven increases in mitochondrial DNA copy number occur early and persist throughout prostatic cancer progression.
    Jiayu Chen, Qizhi Zheng, Jessica L Hicks, Levent Trabzonlu, Busra Ozbek, Tracy Jones, Ajay M Vaghasia, Tatianna C Larman, Rulin Wang, Mark C Markowski, Samuel R Denmeade, Kenneth J Pienta, Ralph H Hruban, Emmanuel S Antonarakis, Anuj Gupta, Chi V Dang, Srinivasan Yegnasubramanian, Angelo M De Marzo.
      Increased mitochondrial function may render some cancers vulnerable to mitochondrial inhibitors. Since mitochondrial function is regulated partly by mitochondrial DNA copy number (mtDNAcn), accurate measurements of mtDNAcn could help reveal which cancers are driven by increased mitochondrial function and may be candidates for mitochondrial inhibition. However, prior studies have employed bulk macrodissections that fail to account for cell type-specific or tumor cell heterogeneity in mtDNAcn. These studies have often produced unclear results, particularly in prostate cancer. Herein, we developed a multiplex in situ method to spatially quantify cell type specific mtDNAcn. We show that mtDNAcn is increased in luminal cells of high-grade prostatic intraepithelial neoplasia (HGPIN), is increased in prostatic adenocarcinomas (PCa), and is further elevated in metastatic castration-resistant prostate cancer. Increased PCa mtDNAcn was validated by two orthogonal methods and is accompanied by increases in mtRNAs and enzymatic activity. Mechanistically, MYC inhibition in prostate cancer cells decreases mtDNA replication and expression of several mtDNA replication genes, and MYC activation in the mouse prostate leads to increased mtDNA levels in the neoplastic prostate cells. Our in situ approach also revealed elevated mtDNAcn in precancerous lesions of the pancreas and colon/rectum, demonstrating generalization across cancer types using clinical tissue samples.
    Keywords:  Cancer; Metabolism; Mitochondria; Oncology
    DOI:  https://doi.org/10.1172/jci.insight.169868
  15. Cell Rep. 2023 Nov 16. pii: S2211-1247(23)01477-8. [Epub ahead of print]42(11): 113465
    MCUb is an inducible regulator of calcium-dependent mitochondrial metabolism and substrate utilization in muscle.
    Jiuzhou Huo, Vikram Prasad, Kelly M Grimes, Davy Vanhoutte, N Scott Blair, Suh-Chin Lin, Michael J Bround, Donald M Bers, Jeffery D Molkentin.
      Mitochondria use the electron transport chain to generate high-energy phosphate from oxidative phosphorylation, a process also regulated by the mitochondrial Ca2+ uniporter (MCU) and Ca2+ levels. Here, we show that MCUb, an inhibitor of MCU-mediated Ca2+ influx, is induced by caloric restriction, where it increases mitochondrial fatty acid utilization. To mimic the fasted state with reduced mitochondrial Ca2+ influx, we generated genetically altered mice with skeletal muscle-specific MCUb expression that showed greater fatty acid usage, less fat accumulation, and lower body weight. In contrast, mice lacking Mcub in skeletal muscle showed increased pyruvate dehydrogenase activity, increased muscle malonyl coenzyme A (CoA), reduced fatty acid utilization, glucose intolerance, and increased adiposity. Mechanistically, pyruvate dehydrogenase kinase 4 (PDK4) overexpression in muscle of Mcub-deleted mice abolished altered substrate preference. Thus, MCUb is an inducible control point in regulating skeletal muscle mitochondrial Ca2+ levels and substrate utilization that impacts total metabolic balance.
    Keywords:  CP: Metabolism; metabolism; mitochondria; obesity; skeletal muscle; substrate utilization
    DOI:  https://doi.org/10.1016/j.celrep.2023.113465
  16. Nat Commun. 2023 Nov 16. 14(1): 7427
    Glutamine metabolism inhibition has dual immunomodulatory and antibacterial activities against Mycobacterium tuberculosis.
    Sadiya Parveen, Jessica Shen, Shichun Lun, Liang Zhao, Jesse Alt, Benjamin Koleske, Robert D Leone, Rana Rais, Jonathan D Powell, John R Murphy, Barbara S Slusher, William R Bishai.
      As one of the most successful human pathogens, Mycobacterium tuberculosis (Mtb) has evolved a diverse array of determinants to subvert host immunity and alter host metabolic patterns. However, the mechanisms of pathogen interference with host metabolism remain poorly understood. Here we show that a glutamine metabolism antagonist, JHU083, inhibits Mtb proliferation in vitro and in vivo. JHU083-treated mice exhibit weight gain, improved survival, a 2.5 log lower lung bacillary burden at 35 days post-infection, and reduced lung pathology. JHU083 treatment also initiates earlier T-cell recruitment, increased proinflammatory myeloid cell infiltration, and a reduced frequency of immunosuppressive myeloid cells when compared to uninfected and rifampin-treated controls. Metabolomic analysis of lungs from JHU083-treated Mtb-infected mice reveals citrulline accumulation, suggesting elevated nitric oxide (NO) synthesis, and lowered levels of quinolinic acid which is derived from the immunosuppressive metabolite kynurenine. JHU083-treated macrophages also produce more NO potentiating their antibacterial activity. When tested in an immunocompromised mouse model of Mtb infection, JHU083 loses its therapeutic efficacy suggesting the drug's host-directed effects are likely to be predominant. Collectively, these data reveal that JHU083-mediated glutamine metabolism inhibition results in dual antibacterial and host-directed activity against tuberculosis.
    DOI:  https://doi.org/10.1038/s41467-023-43304-0
  17. Nature. 2023 Nov 15.
    Stress granules plug and stabilize damaged endolysosomal membranes.
    Claudio Bussi, Agustín Mangiarotti, Christian Vanhille-Campos, Beren Aylan, Enrica Pellegrino, Natalia Athanasiadi, Antony Fearns, Angela Rodgers, Titus M Franzmann, Anđela Šarić, Rumiana Dimova, Maximiliano G Gutierrez.
      Endomembrane damage represents a form of stress that is detrimental for eukaryotic cells1,2. To cope with this threat, cells possess mechanisms that repair the damage and restore cellular homeostasis3-7. Endomembrane damage also results in organelle instability and the mechanisms by which cells stabilize damaged endomembranes to enable membrane repair remains unknown. Here, by combining in vitro and in cellulo studies with computational modelling we uncover a biological function for stress granules whereby these biomolecular condensates form rapidly at endomembrane damage sites and act as a plug that stabilizes the ruptured membrane. Functionally, we demonstrate that stress granule formation and membrane stabilization enable efficient repair of damaged endolysosomes, through both ESCRT (endosomal sorting complex required for transport)-dependent and independent mechanisms. We also show that blocking stress granule formation in human macrophages creates a permissive environment for Mycobacterium tuberculosis, a human pathogen that exploits endomembrane damage to survive within the host.
    DOI:  https://doi.org/10.1038/s41586-023-06726-w
  18. bioRxiv. 2023 Nov 02. pii: 2023.10.30.564837. [Epub ahead of print]
    Glucose Challenge Uncovers Temporal Fungibility of Metabolic Homeostasis Throughout the Day.
    Dania M Malik, Seth D Rhoades, Shirley L Zhang, Arjun Sengupta, Annika Barber, Paula Haynes, Erna Sif Arnadottir, Allan Pack, Richard G Kibbey, Amita Sehgal, Aalim M Weljie.
      Rhythmicity is a central feature of behavioral and biological processes including metabolism, however, the mechanisms of metabolite cycling are poorly understood. A robust oscillation in a network of key metabolite pathways downstream of glucose is described in humans, then these pathways mechanistically probed through purpose-built 13 C 6 -glucose isotope tracing in Drosophila every 4h. A temporal peak in biosynthesis was noted by broad labelling of pathways downstream of glucose in wild-type flies shortly following lights on. Krebs cycle labelling was generally increased in a hyperactive mutant ( fumin ) along with glycolysis labelling primarily observed at dawn. Surprisingly, neither underlying feeding rhythms nor the presence of food explains the rhythmicity of glucose processing across genotypes. These results are consistent with clinical data demonstrating detrimental effects of mis-timed energy intake. This approach provides a window into the dynamic range of metabolic processing ability through the day and mechanistic basis for exploring circadian metabolic homeostasis in disease states.
    DOI:  https://doi.org/10.1101/2023.10.30.564837
  19. J Clin Invest. 2023 Nov 16. pii: e170397. [Epub ahead of print]
    Multi-omic screening of invasive GBM cells reveals targetable transsulfuration pathway alterations.
    Joseph H Garcia, Erin A Akins, Saket Jain, Kayla J Wolf, Jason Zhang, Nikita Choudhary, Meeki Lad, Poojan Shukla, Jennifer Rios, Kyounghee Seo, Sabraj A Gill, William H Carson, Luis R Carrete, Allison C Zheng, David R Raleigh, Sanjay Kumar, Manish K Aghi.
      While the poor prognosis of glioblastoma arises from the invasion of a subset of tumor cells, little is known of the metabolic alterations within these cells that fuel invasion. We integrated spatially addressable hydrogel biomaterial platforms, patient site-directed biopsies, and multi-omics analyses to define metabolic drivers of invasive glioblastoma cells. Metabolomics and lipidomics revealed elevations in the redox buffers cystathionine, hexosylceramides, and glucosyl ceramides in the invasive front of both hydrogel-cultured tumors and patient site-directed biopsies, with immunofluorescence indicating elevated reactive oxygen species (ROS) markers in invasive cells. Transcriptomics confirmed upregulation of ROS-producing and response genes at the invasive front in both hydrogel models and patient tumors. Amongst oncologic ROS, H2O2 specifically promoted glioblastoma invasion in 3D hydrogel spheroid cultures. A CRISPR metabolic gene screen revealed cystathionine gamma-lyase (CTH), which converts cystathionine to the non-essential amino acid cysteine in the transsulfuration pathway, to be essential for glioblastoma invasion. Correspondingly, supplementing CTH knockdown cells with exogenous cysteine rescued invasion. Pharmacologic CTH inhibition suppressed glioblastoma invasion, while CTH knockdown slowed glioblastoma invasion in vivo. Our studies highlight the importance of ROS metabolism in invasive glioblastoma cells and support further exploration of the transsulfuration pathway as a mechanistic and therapeutic target.
    Keywords:  Amino acid metabolism; Bioenergetics; Brain cancer; Metabolism; Oncology
    DOI:  https://doi.org/10.1172/JCI170397
  20. EMBO Rep. 2023 Nov 14. e57972
    MAPL loss dysregulates bile and liver metabolism in mice.
    Vanessa Goyon, Aurèle Besse-Patin, Rodolfo Zunino, Olesia Ignatenko, Mai Nguyen, Étienne Coyaud, Jonathan M Lee, Bich N Nguyen, Brian Raught, Heidi M McBride.
      Mitochondrial and peroxisomal anchored protein ligase (MAPL) is a dual ubiquitin and small ubiquitin-like modifier (SUMO) ligase with roles in mitochondrial quality control, cell death and inflammation in cultured cells. Here, we show that MAPL function in the organismal context converges on metabolic control, as knockout mice are viable, insulin-sensitive, and protected from diet-induced obesity. MAPL loss leads to liver-specific activation of the integrated stress response, inducing secretion of stress hormone FGF21. MAPL knockout mice develop fully penetrant spontaneous hepatocellular carcinoma. Mechanistically, the peroxisomal bile acid transporter ABCD3 is a primary MAPL interacting partner and SUMOylated in a MAPL-dependent manner. MAPL knockout leads to increased bile acid production coupled with defective regulatory feedback in liver in vivo and in isolated primary hepatocytes, suggesting cell-autonomous function. Together, our findings establish MAPL function as a regulator of bile acid synthesis whose loss leads to the disruption of bile acid feedback mechanisms. The consequences of MAPL loss in liver, along with evidence of tumor suppression through regulation of cell survival pathways, ultimately lead to hepatocellular carcinogenesis.
    Keywords:  MUL1; PMP70; SUMO; hepatocellular carcinoma; peroxisome
    DOI:  https://doi.org/10.15252/embr.202357972
  21. Int J Mol Sci. 2023 Oct 31. pii: 15787. [Epub ahead of print]24(21):
    The Warburg Effect Explained: Integration of Enhanced Glycolysis with Heterogeneous Mitochondria to Promote Cancer Cell Proliferation.
    Lilia Alberghina.
      The Warburg effect is the long-standing riddle of cancer biology. How does aerobic glycolysis, inefficient in producing ATP, confer a growth advantage to cancer cells? A new evaluation of a large set of literature findings covering the Warburg effect and its yeast counterpart, the Crabtree effect, led to an innovative working hypothesis presented here. It holds that enhanced glycolysis partially inactivates oxidative phosphorylation to induce functional rewiring of a set of TCA cycle enzymes to generate new non-canonical metabolic pathways that sustain faster growth rates. The hypothesis has been structured by constructing two metabolic maps, one for cancer metabolism and the other for the yeast Crabtree effect. New lines of investigation, suggested by these maps, are discussed as instrumental in leading toward a better understanding of cancer biology in order to allow the development of more efficient metabolism-targeted anticancer drugs.
    Keywords:  ATP synthase; OXPHOS; ROS; cancer; cellular biochemistry; mitochondria
    DOI:  https://doi.org/10.3390/ijms242115787
  22. bioRxiv. 2023 Oct 25. pii: 2023.10.23.563587. [Epub ahead of print]
    Lipin-1 restrains macrophage lipid synthesis to promote inflammation resolution.
    Temitayo T Bamgbose, Robert M Schilke, Oluwakemi O Igiehon, Ebubechukwu H Nkadi, David Custis, Sushma Bharrhan, Benjamin Schwarz, Eric Bohrnsen, Catharine M Bosio, Rona S Scott, Arif Yurdagul, Brian N Finck, Matthew D Woolard.
      Macrophages are critical to maintaining and restoring tissue homeostasis during inflammation. The lipid metabolic state of macrophages influences their function, but a deeper understanding of how lipid metabolism is regulated in pro-resolving macrophage responses is needed. Lipin-1 is a phosphatidic acid phosphatase with a transcriptional coregulatory activity (TC) that regulates lipid metabolism. We previously demonstrated that lipin-1 supports pro-resolving macrophage responses, and here, myeloid-associated lipin-1 is required for inflammation resolution, yet how lipin-1-regulated cellular mechanisms promote macrophage pro-resolution responses is unknown. We demonstrated that the loss of lipin-1 in macrophages led to increased free fatty acid, neutral lipid, and ceramide content and increased phosphorylation of acetyl-CoA carboxylase. The inhibition of the first step of lipid synthesis and transport of citrate from the mitochondria in macrophages reduced lipid content and restored efferocytosis and inflammation resolution in lipin-1 m KO macrophages and mice. Our findings suggest macrophage-associated lipin-1 restrains lipid synthesis, promoting pro-resolving macrophage function in response to pro-resolving stimuli.
    Teaser: Lipin 1 blockade of lipid biosynthesis inducing mitochondrial citrate export promotes efferocytosis and inflammation resolution.
    DOI:  https://doi.org/10.1101/2023.10.23.563587
  23. Nature. 2023 Nov 15.
    Bacterial cGAS senses a viral RNA to initiate immunity.
    Dalton V Banh, Cameron G Roberts, Adrian Morales-Amador, Brandon A Berryhill, Waqas Chaudhry, Bruce R Levin, Sean F Brady, Luciano A Marraffini.
      Cyclic oligonucleotide-based antiphage signalling systems (CBASS) protect prokaryotes from viral (phage) attack through the production of cyclic oligonucleotides, which activate effector proteins that trigger the death of the infected host1,2. How bacterial cyclases recognize phage infection is not known. Here we show that staphylococcal phages produce a structured RNA transcribed from the terminase subunit genes, termed CBASS-activating bacteriophage RNA (cabRNA), which binds to a positively charged surface of the CdnE03 cyclase and promotes the synthesis of the cyclic dinucleotide cGAMP to activate the CBASS immune response. Phages that escape the CBASS defence harbour mutations that lead to the generation of a longer form of the cabRNA that cannot activate CdnE03. As the mammalian cyclase OAS1 also binds viral double-stranded RNA during the interferon response, our results reveal a conserved mechanism for the activation of innate antiviral defence pathways.
    DOI:  https://doi.org/10.1038/s41586-023-06743-9
  24. Mol Cell. 2023 Nov 16. pii: S1097-2765(23)00854-7. [Epub ahead of print]83(22): 4078-4092.e6
    Active growth signaling promotes senescence and cancer cell sensitivity to CDK7 inhibition.
    Gemma A Wilson, Karla Vuina, Georgina Sava, Caroline Huard, Leticia Meneguello, Jasmin Coulombe-Huntington, Thierry Bertomeu, Rory J Maizels, Josh Lauring, Janos Kriston-Vizi, Mike Tyers, Simak Ali, Cosetta Bertoli, Robertus A M de Bruin.
      Tumor growth is driven by continued cellular growth and proliferation. Cyclin-dependent kinase 7's (CDK7) role in activating mitotic CDKs and global gene expression makes it therefore an attractive target for cancer therapies. However, what makes cancer cells particularly sensitive to CDK7 inhibition (CDK7i) remains unclear. Here, we address this question. We show that CDK7i, by samuraciclib, induces a permanent cell-cycle exit, known as senescence, without promoting DNA damage signaling or cell death. A chemogenetic genome-wide CRISPR knockout screen identified that active mTOR (mammalian target of rapamycin) signaling promotes samuraciclib-induced senescence. mTOR inhibition decreases samuraciclib sensitivity, and increased mTOR-dependent growth signaling correlates with sensitivity in cancer cell lines. Reverting a growth-promoting mutation in PIK3CA to wild type decreases sensitivity to CDK7i. Our work establishes that enhanced growth alone promotes CDK7i sensitivity, providing an explanation for why some cancers are more sensitive to CDK inhibition than normally growing cells.
    Keywords:  CDK inhibition; CDK7 inhibitor; cancer treatment; cell cycle; cell size; cell-cycle arrest; cellular growth; mTOR singaling; proliferation; samuraciclib; senescence
    DOI:  https://doi.org/10.1016/j.molcel.2023.10.017
  25. Immunity. 2023 Nov 14. pii: S1074-7613(23)00451-X. [Epub ahead of print]56(11): 2555-2569.e5
    Reprogramming tumor-associated macrophages to outcompete endovascular endothelial progenitor cells and suppress tumor neoangiogenesis.
    Mytrang H Do, Wei Shi, Liangliang Ji, Erik Ladewig, Xian Zhang, Raghvendra M Srivastava, Kristelle J Capistrano, Chaucie Edwards, Isha Malik, Briana G Nixon, Efstathios G Stamatiades, Ming Liu, Shun Li, Peng Li, Chun Chou, Ke Xu, Ting-Wei Hsu, Xinxin Wang, Timothy A Chan, Christina S Leslie, Ming O Li.
      Tumors develop by invoking a supportive environment characterized by aberrant angiogenesis and infiltration of tumor-associated macrophages (TAMs). In a transgenic model of breast cancer, we found that TAMs localized to the tumor parenchyma and were smaller than mammary tissue macrophages. TAMs had low activity of the metabolic regulator mammalian/mechanistic target of rapamycin complex 1 (mTORC1), and depletion of negative regulator of mTORC1 signaling, tuberous sclerosis complex 1 (TSC1), in TAMs inhibited tumor growth in a manner independent of adaptive lymphocytes. Whereas wild-type TAMs exhibited inflammatory and angiogenic gene expression profiles, TSC1-deficient TAMs had a pro-resolving phenotype. TSC1-deficient TAMs relocated to a perivascular niche, depleted protein C receptor (PROCR)-expressing endovascular endothelial progenitor cells, and rectified the hyperpermeable blood vasculature, causing tumor tissue hypoxia and cancer cell death. TSC1-deficient TAMs were metabolically active and effectively eliminated PROCR-expressing endothelial cells in cell competition experiments. Thus, TAMs exhibit a TSC1-dependent mTORC1-low state, and increasing mTORC1 signaling promotes a pro-resolving state that suppresses tumor growth, defining an innate immune tumor suppression pathway that may be exploited for cancer immunotherapy.
    Keywords:  TSC; cell competition; endothelial progenitor cell; mTORC1; tumor-associated macrophage
    DOI:  https://doi.org/10.1016/j.immuni.2023.10.010
  26. Mol Cell. 2023 Nov 16. pii: S1097-2765(23)00857-2. [Epub ahead of print]83(22): 4047-4061.e6
    Oncogenic signals prime cancer cells for toxic cell overgrowth during a G1 cell cycle arrest.
    Reece Foy, Lisa Crozier, Aanchal U Pareri, Juan Manuel Valverde, Ben Ho Park, Tony Ly, Adrian T Saurin.
      CDK4/6 inhibitors are remarkable anti-cancer drugs that can arrest tumor cells in G1 and induce their senescence while causing only relatively mild toxicities in healthy tissues. How they achieve this mechanistically is unclear. We show here that tumor cells are specifically vulnerable to CDK4/6 inhibition because during the G1 arrest, oncogenic signals drive toxic cell overgrowth. This overgrowth causes permanent cell cycle withdrawal by either preventing progression from G1 or inducing genotoxic damage during the subsequent S-phase and mitosis. Inhibiting or reverting oncogenic signals that converge onto mTOR can rescue this excessive growth, DNA damage, and cell cycle exit in cancer cells. Conversely, inducing oncogenic signals in non-transformed cells can drive these toxic phenotypes and sensitize the cells to CDK4/6 inhibition. Together, this demonstrates that cell cycle arrest and oncogenic cell growth is a synthetic lethal combination that is exploited by CDK4/6 inhibitors to induce tumor-specific toxicity.
    Keywords:  CDK4/6; breast cancer; cell cycle; cell growth; chemotherapy; growth factors; oncogenes; p21; p53; replication stress
    DOI:  https://doi.org/10.1016/j.molcel.2023.10.020
  27. Cell Death Dis. 2023 Nov 16. 14(11): 747
    Mitoribosomal synthetic lethality overcomes multidrug resistance in MYC-driven neuroblastoma.
    Karolina Borankova, Maria Krchniakova, Lionel Y W Leck, Adela Kubistova, Jakub Neradil, Patric J Jansson, Michael D Hogarty, Jan Skoda.
      Mitochondria are central for cancer responses to therapy-induced stress signals. Refractory tumors often show attenuated sensitivity to apoptotic signaling, yet clinically relevant molecular actors to target mitochondria-mediated resistance remain elusive. Here, we show that MYC-driven neuroblastoma cells rely on intact mitochondrial ribosome (mitoribosome) processivity and undergo cell death following pharmacological inhibition of mitochondrial translation, regardless of their multidrug/mitochondrial resistance and stem-like phenotypes. Mechanistically, inhibiting mitoribosomes induced the mitochondrial stress-activated integrated stress response (ISR), leading to downregulation of c-MYC/N-MYC proteins prior to neuroblastoma cell death, which could be both rescued by the ISR inhibitor ISRIB. The ISR blocks global protein synthesis and shifted the c-MYC/N-MYC turnover toward proteasomal degradation. Comparing models of various neuroectodermal tumors and normal fibroblasts revealed overexpression of MYC proteins phosphorylated at the degradation-promoting site T58 as a factor that predetermines vulnerability of MYC-driven neuroblastoma to mitoribosome inhibition. Reducing N-MYC levels in a neuroblastoma model with tunable MYCN expression mitigated cell death induction upon inhibition of mitochondrial translation and functionally validated the propensity of neuroblastoma cells for MYC-dependent cell death in response to the mitochondrial ISR. Notably, neuroblastoma cells failed to develop significant resistance to the mitoribosomal inhibitor doxycycline over a long-term repeated (pulsed) selection. Collectively, we identify mitochondrial translation machinery as a novel synthetic lethality target for multidrug-resistant MYC-driven tumors.
    DOI:  https://doi.org/10.1038/s41419-023-06278-x
  28. Mol Cell. 2023 Nov 16. pii: S1097-2765(23)00860-2. [Epub ahead of print]83(22): 4141-4157.e11
    Targeted perturbation of signaling-driven condensates.
    Tianshu Gui, Cassio Fleming, Caterina Manzato, Benjamin Bourgeois, Nafiseh Sirati, Jasper Heuer, Ioanna Papadionysiou, Daniel I van Montfort, Merel van Gijzen, Lydia M M Smits, Boudewijn M T Burgering, Tobias Madl, Jurian Schuijers.
      Biomolecular condensates have emerged as a major organizational principle in the cell. However, the formation, maintenance, and dissolution of condensates are still poorly understood. Transcriptional machinery partitions into biomolecular condensates at key cell identity genes to activate these. Here, we report a specific perturbation of WNT-activated β-catenin condensates that disrupts oncogenic signaling. We use a live-cell condensate imaging method in human cancer cells to discover FOXO and TCF-derived peptides that specifically inhibit β-catenin condensate formation on DNA, perturb nuclear β-catenin condensates in cells, and inhibit β-catenin-driven transcriptional activation and colorectal cancer cell growth. We show that these peptides compete with homotypic intermolecular interactions that normally drive condensate formation. Using this framework, we derive short peptides that specifically perturb condensates and transcriptional activation of YAP and TAZ in the Hippo pathway. We propose a "monomer saturation" model in which short interacting peptides can be used to specifically inhibit condensate-associated transcription in disease.
    Keywords:  NMR; WNT-signaling; biomolecular condensates; signaling inhibition; transcriptional regulation
    DOI:  https://doi.org/10.1016/j.molcel.2023.10.023
  29. Nat Commun. 2023 Nov 17. 14(1): 7471
    Inflammatory macrophages reprogram to immunosuppression by reducing mitochondrial translation.
    Marlies Cortés, Agnese Brischetto, M C Martinez-Campanario, Chiara Ninfali, Verónica Domínguez, Sara Fernández, Raquel Celis, Anna Esteve-Codina, Juan J Lozano, Julia Sidorova, Gloria Garrabou, Anna-Maria Siegert, Carlos Enrich, Belén Pintado, Manuel Morales-Ruiz, Pedro Castro, Juan D Cañete, Antonio Postigo.
      Acute inflammation can either resolve through immunosuppression or persist, leading to chronic inflammation. These transitions are driven by distinct molecular and metabolic reprogramming of immune cells. The anti-diabetic drug Metformin inhibits acute and chronic inflammation through mechanisms still not fully understood. Here, we report that the anti-inflammatory and reactive-oxygen-species-inhibiting effects of Metformin depend on the expression of the plasticity factor ZEB1 in macrophages. Using mice lacking Zeb1 in their myeloid cells and human patient samples, we show that ZEB1 plays a dual role, being essential in both initiating and resolving inflammation by inducing macrophages to transition into an immunosuppressed state. ZEB1 mediates these diverging effects in inflammation and immunosuppression by modulating mitochondrial content through activation of autophagy and inhibition of mitochondrial protein translation. During the transition from inflammation to immunosuppression, Metformin mimics the metabolic reprogramming of myeloid cells induced by ZEB1. Mechanistically, in immunosuppression, ZEB1 inhibits amino acid uptake, leading to downregulation of mTORC1 signalling and a decrease in mitochondrial translation in macrophages. These results identify ZEB1 as a driver of myeloid cell metabolic plasticity, suggesting that targeting its expression and function could serve as a strategy to modulate dysregulated inflammation and immunosuppression.
    DOI:  https://doi.org/10.1038/s41467-023-42277-4
  30. Trends Cell Biol. 2023 Nov 13. pii: S0962-8924(23)00206-4. [Epub ahead of print]
    Phenotypic noise and plasticity in cancer evolution.
    Frederick J H Whiting, Jacob Househam, Ann-Marie Baker, Andrea Sottoriva, Trevor A Graham.
      Non-genetic alterations can produce changes in a cell's phenotype. In cancer, these phenomena can influence a cell's fitness by conferring access to heritable, beneficial phenotypes. Herein, we argue that current discussions of 'phenotypic plasticity' in cancer evolution ignore a salient feature of the original definition: namely, that it occurs in response to an environmental change. We suggest 'phenotypic noise' be used to distinguish non-genetic changes in phenotype that occur independently from the environment. We discuss the conceptual and methodological techniques used to identify these phenomena during cancer evolution. We propose that the distinction will guide efforts to define mechanisms of phenotype change, accelerate translational work to manipulate phenotypes through treatment, and, ultimately, improve patient outcomes.
    Keywords:  cancer; evolution; noise; phenotype; plasticity
    DOI:  https://doi.org/10.1016/j.tcb.2023.10.002
  31. Proc Natl Acad Sci U S A. 2023 Nov 21. 120(47): e2315347120
    Mitochondria-associated membrane collapse impairs TBK1-mediated proteostatic stress response in ALS.
    Seiji Watanabe, Yuri Murata, Yasuyoshi Oka, Kotaro Oiwa, Mai Horiuchi, Yohei Iguchi, Okiru Komine, Akira Sobue, Masahisa Katsuno, Tomoo Ogi, Koji Yamanaka.
      The organelle contact site of the endoplasmic reticulum and mitochondria, known as the mitochondria-associated membrane (MAM), is a multifunctional microdomain in cellular homeostasis. We previously reported that MAM disruption is a common pathological feature in amyotrophic lateral sclerosis (ALS); however, the precise role of MAM in ALS was uncovered. Here, we show that the MAM is essential for TANK-binding kinase 1 (TBK1) activation under proteostatic stress conditions. A MAM-specific E3 ubiquitin ligase, autocrine motility factor receptor, ubiquitinated nascent proteins to activate TBK1 at the MAM, which results in ribosomal protein degradation. MAM or TBK1 deficiency under proteostatic stress conditions resulted in increased cellular vulnerability in vitro and motor impairment in vivo. Thus, MAM disruption exacerbates proteostatic stress via TBK1 inactivation in ALS. Our study has revealed a proteostatic mechanism mediated by the MAM-TBK1 axis, highlighting the physiological importance of the organelle contact sites.
    Keywords:  TANK-binding kinase 1; amyotrophic lateral sclerosis; mitochondria-associated membrane; sigma-1 receptor; stress granules
    DOI:  https://doi.org/10.1073/pnas.2315347120
  32. Dev Cell. 2023 Nov 08. pii: S1534-5807(23)00555-5. [Epub ahead of print]
    Transcription factor NFYa controls cardiomyocyte metabolism and proliferation during mouse fetal heart development.
    Miao Cui, Svetlana Bezprozvannaya, Tian Hao, Abdallah Elnwasany, Luke I Szweda, Ning Liu, Rhonda Bassel-Duby, Eric N Olson.
      Cardiomyocytes are highly metabolic cells responsible for generating the contractile force in the heart. During fetal development and regeneration, these cells actively divide but lose their proliferative activity in adulthood. The mechanisms that coordinate their metabolism and proliferation are not fully understood. Here, we study the role of the transcription factor NFYa in developing mouse hearts. Loss of NFYa alters cardiomyocyte composition, causing a decrease in immature regenerative cells and an increase in trabecular and mature cardiomyocytes, as identified by spatial and single-cell transcriptome analyses. NFYa-deleted cardiomyocytes exhibited reduced proliferation and impaired mitochondrial metabolism, leading to cardiac growth defects and embryonic death. NFYa, interacting with cofactor SP2, activates genes linking metabolism and proliferation at the transcription level. Our study identifies a nodal role of NFYa in regulating prenatal cardiac growth and a previously unrecognized transcriptional control mechanism of heart metabolism, highlighting the importance of mitochondrial metabolism during heart development and regeneration.
    Keywords:  cardiac metabolism; cardiomyocyte proliferation; heart development; nuclear transcription factor Y
    DOI:  https://doi.org/10.1016/j.devcel.2023.10.012
  33. Annu Rev Biochem. 2023 Nov 14.
    Lipid Quality Control and Ferroptosis: From Concept to Mechanism.
    Zhipeng Li, Mike Lange, Scott J Dixon, James A Olzmann.
      Cellular quality control systems sense and mediate homeostatic responses to prevent the buildup of aberrant macromolecules, which arise from errors during biosynthesis, damage by environmental insults, or imbalances in enzymatic and metabolic activity. Lipids are structurally diverse macromolecules that have many important cellular functions, ranging from structural roles in membranes to functions as signaling and energy-storage molecules. As with other macromolecules, lipids can be damaged (e.g., oxidized), and cells require quality control systems to ensure that nonfunctional and potentially toxic lipids do not accumulate. Ferroptosis is a form of cell death that results from the failure of lipid quality control and the consequent accumulation of oxidatively damaged phospholipids. In this review, we describe a framework for lipid quality control, using ferroptosis as an illustrative example to highlight concepts related to lipid damage, membrane remodeling, and suppression or detoxification of lipid damage via preemptive and damage-repair lipid quality control pathways. Expected final online publication date for the Annual Review of Biochemistry , Volume 93 is June 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
    DOI:  https://doi.org/10.1146/annurev-biochem-052521-033527
  34. Bio Protoc. 2023 Nov 05. 13(21): e4873
    Identification of Acetylation Sites of Fatty Acid Synthase (FASN) by Mass Spectrometry and FASN Activity Assay.
    Ting Miao, Hua Bai.
      Lysine acetylation is a conserved post-translational modification and a key regulatory mechanism for various cellular processes, including metabolic control, epigenetic regulation, and cellular signaling transduction. Recent advances in mass spectrometry (MS) enable the extensive identification of acetylated lysine residues of histone and non-histone proteins. However, protein enrichment before MS analysis may be necessary to improve the detection of low-abundant proteins or proteins that exhibit low acetylation levels. Fatty acid synthase (FASN), an essential enzyme catalyzing the de novo synthesis of fatty acids, has been found to be acetylated in various species, from fruit flies to humans. Here, we describe a step-by-step process of antibody-based protein enrichment and sample preparation for acetylation identification of endogenous FASN protein by MS-based proteomics analysis. Meanwhile, we provide a protocol for nicotinamide adenine dinucleotide phosphate (NADPH) absorbance assay for FASN activity measurement, which is one of the primary functional readouts of de novo lipogenesis. Key features • A comprehensive protocol for protein immunoprecipitation and sample preparation for acetylation site identification by mass spectrometry. • Step-by-step procedures for measurement of FASN activity of fruit fly larvae using an absorbance assay.
    Keywords:  Acetyl-CoA; Auto-acetylation; De novo lipogenesis; FASN activity; Mass spectrometry; Post-translational modification
    DOI:  https://doi.org/10.21769/BioProtoc.4873
  35. Cancer Res. 2023 Nov 14.
    Small cell lung cancer plasticity enables NFIB-independent metastasis.
    Julie H Ko, Kyle E Lambert, Debadrita Bhattacharya, Myung Chang Lee, Caterina I Colon, Haley Hauser, Julien Sage.
      Metastasis is a major cause of morbidity and mortality in patients with cancer, highlighting the need to identify improved treatment and prevention strategies. Previous observations in pre-clinical models and tumors from patients with small cell lung cancer (SCLC), a fatal form of lung cancer with high metastatic potential, identified the transcription factor NFIB as a driver of tumor growth and metastasis. However, investigation into the requirement for NFIB activity for tumor growth and metastasis in relevant in vivo models is needed to establish NFIB as a therapeutic target. Here, using conditional gene knockout strategies in genetically engineered mouse models of SCLC, we found that upregulation of NFIB contributes to tumor progression, but NFIB is not required for metastasis. Molecular studies in NFIB wild-type and knockout tumors identified the pioneer transcription factors FOXA1/2 as candidate drivers of metastatic progression. Thus, while NFIB upregulation is a frequent event in SCLC during tumor progression, SCLC tumors can employ NFIB-independent mechanisms for metastasis, further highlighting the plasticity of these tumors.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-23-1079
  36. Nat Cell Biol. 2023 Nov 13.
    Microglia promote anti-tumour immunity and suppress breast cancer brain metastasis.
    Katrina T Evans, Kerrigan Blake, Aaron Longworth, Morgan A Coburn, Jacob Insua-Rodríguez, Timothy P McMullen, Quy H Nguyen, Dennis Ma, Tatyana Lev, Grace A Hernandez, Armani K Oganyan, Davit Orujyan, Robert A Edwards, Clare Pridans, Kim N Green, S Armando Villalta, Mathew Blurton-Jones, Devon A Lawson.
      Breast cancer brain metastasis (BCBM) is a lethal disease with no effective treatments. Prior work has shown that brain cancers and metastases are densely infiltrated with anti-inflammatory, protumourigenic tumour-associated macrophages, but the role of brain-resident microglia remains controversial because they are challenging to discriminate from other tumour-associated macrophages. Using single-cell RNA sequencing, genetic and humanized mouse models, we specifically identify microglia and find that they play a distinct pro-inflammatory and tumour-suppressive role in BCBM. Animals lacking microglia show increased metastasis, decreased survival and reduced natural killer and T cell responses, showing that microglia are critical to promote anti-tumour immunity to suppress BCBM. We find that the pro-inflammatory response is conserved in human microglia, and markers of their response are associated with better prognosis in patients with BCBM. These findings establish an important role for microglia in anti-tumour immunity and highlight them as a potential immunotherapy target for brain metastasis.
    DOI:  https://doi.org/10.1038/s41556-023-01273-y
  37. Nat Struct Mol Biol. 2023 Nov;30(11): 1806-1815
    Integrated chemical and genetic screens unveil FSP1 mechanisms of ferroptosis regulation.
    Toshitaka Nakamura, Eikan Mishima, Naoya Yamada, André Santos Dias Mourão, Dietrich Trümbach, Sebastian Doll, Jonas Wanninger, Elena Lytton, Peter Sennhenn, Thamara Nishida Xavier da Silva, José Pedro Friedmann Angeli, Michael Sattler, Bettina Proneth, Marcus Conrad.
      Ferroptosis, marked by iron-dependent lipid peroxidation, may present an Achilles heel for the treatment of cancers. Ferroptosis suppressor protein-1 (FSP1), as the second ferroptosis mainstay, efficiently prevents lipid peroxidation via NAD(P)H-dependent reduction of quinones. Because its molecular mechanisms have remained obscure, we studied numerous FSP1 mutations present in cancer or identified by untargeted random mutagenesis. This mutational analysis elucidates the FAD/NAD(P)H-binding site and proton-transfer function of FSP1, which emerged to be evolutionarily conserved among different NADH quinone reductases. Using random mutagenesis screens, we uncover the mechanism of action of next-generation FSP1 inhibitors. Our studies identify the binding pocket of the first FSP1 inhibitor, iFSP1, and introduce the first species-independent FSP1 inhibitor, targeting the NAD(P)H-binding pocket. Conclusively, our study provides new insights into the molecular functions of FSP1 and enables the rational design of FSP1 inhibitors targeting cancer cells.
    DOI:  https://doi.org/10.1038/s41594-023-01136-y
  38. Physiology (Bethesda). 2023 Nov 14.
    MICROGLIA IN CENTRAL CONTROL OF METABOLISM.
    Jung Dae Kim, Francesca Copperi, Sabrina Diano.
      Beyond their role as brain immune cells, microglia act as metabolic sensors in response to changes in nutrient availability, thus playing a role in energy homeostasis. This review will highlight the evidence and challenges of studying the role of microglia in metabolism regulation.
    Keywords:  diet-induced obesity; glia; hypothalamus; metabolism
    DOI:  https://doi.org/10.1152/physiol.00021.2023
  39. iScience. 2023 Nov 17. 26(11): 108188
    Metabolic predictors of response to immune checkpoint blockade therapy.
    Ofir Shorer, Keren Yizhak.
      Metabolism of immune cells in the tumor microenvironment (TME) plays a critical role in cancer patient response to immune checkpoint inhibitors (ICI). Yet, a metabolic characterization of immune cells in the TME of patients treated with ICI is lacking. To bridge this gap we performed a semi-supervised analysis of ∼1700 metabolic genes using single-cell RNA-seq data of > 1 million immune cells from ∼230 samples of cancer patients treated with ICI. When clustering cells based on their metabolic gene expression, we found that similar immunological cellular states are found in different metabolic states. Most importantly, we found metabolic states that are significantly associated with patient response. We then built a metabolic predictor based on a dozen gene signature, which significantly differentiates between responding and non-responding patients across different cancer types (AUC = 0.8-0.92). Taken together, our results demonstrate the power of metabolism in predicting patient response to ICI.
    Keywords:  Cancer; Human metabolism; Immunology
    DOI:  https://doi.org/10.1016/j.isci.2023.108188
  40. Biochem Soc Trans. 2023 Nov 13. pii: BST20230735. [Epub ahead of print]
    Inorganic polyphosphate and the regulation of mitochondrial physiology.
    Renata T Da Costa, Lindsey M Riggs, Maria E Solesio.
      Inorganic polyphosphate (polyP) is an ancient polymer that is well-conserved throughout evolution. It is formed by multiple subunits of orthophosphates linked together by phosphoanhydride bonds. The presence of these bonds, which are structurally similar to those found in ATP, and the high abundance of polyP in mammalian mitochondria, suggest that polyP could be involved in the regulation of the physiology of the organelle, especially in the energy metabolism. In fact, the scientific literature shows an unequivocal role for polyP not only in directly regulating oxidative a phosphorylation; but also in the regulation of reactive oxygen species metabolism, mitochondrial free calcium homeostasis, and the formation and opening of mitochondrial permeability transitions pore. All these processes are closely interconnected with the status of mitochondrial bioenergetics and therefore play a crucial role in maintaining mitochondrial and cell physiology. In this invited review, we discuss the main scientific literature regarding the regulatory role of polyP in mammalian mitochondrial physiology, placing a particular emphasis on its impact on energy metabolism. Although the effects of polyP on the physiology of the organelle are evident; numerous aspects, particularly within mammalian cells, remain unclear and require further investigation. These aspects encompass, for example, advancing the development of more precise analytical methods, unraveling the mechanism responsible for sensing polyP levels, and understanding the exact molecular mechanism that underlies the effects of polyP on mitochondrial physiology. By increasing our understanding of the biology of this ancient and understudied polymer, we could unravel new pharmacological targets in diseases where mitochondrial dysfunction, including energy metabolism dysregulation, has been broadly described.
    Keywords:  cell biology; energy metabolism; inorganic polyphosphate; mitochondria; mitochondrial physiology; polyP
    DOI:  https://doi.org/10.1042/BST20230735
  41. Nat Struct Mol Biol. 2023 Nov;30(11): 1618-1619
    FSP1 inhibition: pick your pocket.
    Christina M Bebber, Silvia von Karstedt.
      
    DOI:  https://doi.org/10.1038/s41594-023-01145-x
  42. Nature. 2023 Nov 15.
    Single-cell CRISPR screens in vivo map T cell fate regulomes in cancer.
    Peipei Zhou, Hao Shi, Hongling Huang, Xiang Sun, Sujing Yuan, Nicole M Chapman, Jon P Connelly, Seon Ah Lim, Jordy Saravia, Anil Kc, Shondra M Pruett-Miller, Hongbo Chi.
      CD8+ cytotoxic T cells (CTLs) orchestrate antitumour immunity and exhibit inherent heterogeneity1,2, with precursor exhausted T (Tpex) cells but not terminally exhausted T (Tex) cells capable of responding to existing immunotherapies3-7. The gene regulatory network that underlies CTL differentiation and whether Tex cell responses can be functionally reinvigorated are incompletely understood. Here we systematically mapped causal gene regulatory networks using single-cell CRISPR screens in vivo and discovered checkpoints for CTL differentiation. First, the exit from quiescence of Tpex cells initiated successive differentiation into intermediate Tex cells. This process is differentially regulated by IKAROS and ETS1, the deficiencies of which dampened and increased mTORC1-associated metabolic activities, respectively. IKAROS-deficient cells accumulated as a metabolically quiescent Tpex cell population with limited differentiation potential following immune checkpoint blockade (ICB). Conversely, targeting ETS1 improved antitumour immunity and ICB efficacy by boosting differentiation of Tpex to intermediate Tex cells and metabolic rewiring. Mechanistically, TCF-1 and BATF are the targets for IKAROS and ETS1, respectively. Second, the RBPJ-IRF1 axis promoted differentiation of intermediate Tex to terminal Tex cells. Accordingly, targeting RBPJ enhanced functional and epigenetic reprogramming of Tex cells towards the proliferative state and improved therapeutic effects and ICB efficacy. Collectively, our study reveals that promoting the exit from quiescence of Tpex cells and enriching the proliferative Tex cell state act as key modalities for antitumour effects and provides a systemic framework to integrate cell fate regulomes and reprogrammable functional determinants for cancer immunity.
    DOI:  https://doi.org/10.1038/s41586-023-06733-x
  43. PLoS Biol. 2023 Nov;21(11): e3002367
    Carbon dioxide regulates cholesterol levels through SREBP2.
    Nityanand Bolshette, Saar Ezagouri, Vaishnavi Dandavate, Iuliia Karavaeva, Marina Golik, Hu Wang, Peter J Espenshade, Timothy F Osborne, Xianlin Han, Gad Asher.
      In mammals, O2 and CO2 levels are tightly regulated and are altered under various pathological conditions. While the molecular mechanisms that participate in O2 sensing are well characterized, little is known regarding the signaling pathways that participate in CO2 signaling and adaptation. Here, we show that CO2 levels control a distinct cellular transcriptional response that differs from mere pH changes. Unexpectedly, we discovered that CO2 regulates the expression of cholesterogenic genes in a SREBP2-dependent manner and modulates cellular cholesterol accumulation. Molecular dissection of the underlying mechanism suggests that CO2 triggers SREBP2 activation through changes in endoplasmic reticulum (ER) membrane cholesterol levels. Collectively, we propose that SREBP2 participates in CO2 signaling and that cellular cholesterol levels can be modulated by CO2 through SREBP2.
    DOI:  https://doi.org/10.1371/journal.pbio.3002367
  44. bioRxiv. 2023 Nov 03. pii: 2023.11.02.565386. [Epub ahead of print]
    Membrane potential mediates an ancient mechano-transduction mechanism for multi-cellular homeostasis.
    Avik Mukherjee, Yanqing Huang, Jens Elgeti, Seungeun Oh, Anjali Rebecca Neliat, Janik Schüttler, Nina Catherine Benites, Xili Liu, Mihail Barboiu, Hugo Stocker, Marc W Kirschner, Markus Basan.
      Membrane potential is a property of all living cells 1 . However, its physiological role in nonexcitable cells is poorly understood. Resting membrane potential is typically considered fixed for a given cell type and under tight homeostatic control 2 , akin to body temperature in mammals. Contrary to this widely accepted paradigm, we found that membrane potential is a dynamic property that directly reflects tissue density and mechanical forces acting on the cell. Serving as a quasi-instantaneous, global readout of density and mechanical pressure, membrane potential is integrated with signal transduction networks by affecting the conformation and clustering of proteins in the membrane 3,4 , as well as the transmembrane flux of key signaling ions 5,6 . Indeed, we show that important mechano-sensing pathways, YAP, Jnk and p38 7-121314 , are directly controlled by membrane potential. We further show that mechano-transduction via membrane potential plays a critical role in the homeostasis of epithelial tissues, setting tissue density by controlling proliferation and cell extrusion of cells. Moreover, a wave of depolarization triggered by mechanical stretch enhances the speed of wound healing. Mechano-transduction via membrane potential likely constitutes an ancient homeostatic mechanism in multi-cellular organisms, potentially serving as a steppingstone for the evolution of excitable tissues and neuronal mechano-sensing. The breakdown of membrane potential mediated homeostatic regulation may contribute to tumor growth.
    DOI:  https://doi.org/10.1101/2023.11.02.565386
  45. Semin Cell Dev Biol. 2023 Nov 15. pii: S1084-9521(23)00229-X. [Epub ahead of print]156 1-10
    Persister cell plasticity in tumour drug resistance.
    Paul C McDonald, Shoukat Dedhar.
      The emergence of therapeutic resistance remains a formidable barrier to durable responses by cancer patients and is a major cause of cancer-related deaths. It is increasingly recognized that non-genetic mechanisms of acquired resistance are important in many cancers. These mechanisms of resistance rely on inherent cellular plasticity where cancer cells can switch between multiple phenotypic states without genetic alterations, providing a dynamic, reversible resistance landscape. Such mechanisms underlie the generation of drug-tolerant persister (DTP) cells, a subpopulation of tumour cells that contributes to heterogeneity within tumours and that supports therapeutic resistance. In this review, we provide an overview of the major features of DTP cells, focusing on phenotypic and metabolic plasticity as two key drivers of tolerance and persistence. We discuss the link between DTP cell plasticity and the potential vulnerability of these cells to ferroptosis. We also discuss the relationship between DTP cells and cells that survive the induction of apoptosis, a process termed anastasis, and discuss the properties of such cells in the context of increased metastatic potential and sensitivity to cell death mechanisms such as ferroptosis.
    Keywords:  Anastasis; Drug tolerant persister cell; Epithelial-to-mesenchymal transition; Ferroptosis; Plasticity; Therapy resistance
    DOI:  https://doi.org/10.1016/j.semcdb.2023.11.003
  46. Nat Commun. 2023 Nov 14. 14(1): 7364
    Targeted suppression of mTORC2 reduces seizures across models of epilepsy.
    James Okoh, Jacqunae Mays, Alexandre Bacq, Juan A Oses-Prieto, Stefka Tyanova, Chien-Ju Chen, Khalel Imanbeyev, Marion Doladilhe, Hongyi Zhou, Paymaan Jafar-Nejad, Alma Burlingame, Jeffrey Noebels, Stephanie Baulac, Mauro Costa-Mattioli.
      Epilepsy is a neurological disorder that poses a major threat to public health. Hyperactivation of mTOR complex 1 (mTORC1) is believed to lead to abnormal network rhythmicity associated with epilepsy, and its inhibition is proposed to provide some therapeutic benefit. However, mTOR complex 2 (mTORC2) is also activated in the epileptic brain, and little is known about its role in seizures. Here we discover that genetic deletion of mTORC2 from forebrain neurons is protective against kainic acid-induced behavioral and EEG seizures. Furthermore, inhibition of mTORC2 with a specific antisense oligonucleotide robustly suppresses seizures in several pharmacological and genetic mouse models of epilepsy. Finally, we identify a target of mTORC2, Nav1.2, which has been implicated in epilepsy and neuronal excitability. Our findings, which are generalizable to several models of human seizures, raise the possibility that inhibition of mTORC2 may serve as a broader therapeutic strategy against epilepsy.
    DOI:  https://doi.org/10.1038/s41467-023-42922-y
  47. Elife. 2023 Nov 17. pii: e90298. [Epub ahead of print]12
    Disseminating cells in human oral tumours possess an EMT cancer stem cell marker profile that is predictive of metastasis in image-based machine learning.
    Gehad Youssef, Luke Gammon, Leah Ambler, Sophia Lunetto, Alice Scemama, Hannah Cottom, Kim Piper, Ian C Mackenzie, Michael P Philpott, Adrian Biddle.
      Cancer stem cells (CSCs) undergo epithelial-mesenchymal transition (EMT) to drive metastatic dissemination in experimental cancer models. However, tumour cells undergoing EMT have not been observed disseminating into the tissue surrounding human tumour specimens, leaving the relevance to human cancer uncertain. We have previously identified both EpCAM and CD24 as CSC markers that, alongside the mesenchymal marker Vimentin, identify EMT CSCs in human oral cancer cell lines. This afforded the opportunity to investigate whether the combination of these three markers can identify disseminating EMT CSCs in actual human tumours. Examining disseminating tumour cells in over 12,000 imaging fields from 74 human oral tumours, we see a significant enrichment of EpCAM, CD24 and Vimentin co-stained cells disseminating beyond the tumour body in metastatic specimens. Through training an artificial neural network, these predict metastasis with high accuracy (cross-validated accuracy of 87-89%). In this study, we have observed single disseminating EMT CSCs in human oral cancer specimens, and these are highly predictive of metastatic disease.
    Keywords:  cancer biology; human
    DOI:  https://doi.org/10.7554/eLife.90298
  48. Genes Chromosomes Cancer. 2023 Nov 11.
    Rethinking cancer initiation: The role of large-scale mutational events.
    Amil Shah.
      Cancer initiation is revisited in light of recent discoveries in cancer pathogenesis. Of note is the detection of mutated cancer genes in benign conditions. More significantly, somatic clones, which harbor mutations in cancer genes, arise in normal tissues from early development through adulthood, but seldom do they transform into cancer. Further, clustered mutational events-kataegis, chromothripsis and chromoplexy-are widespread in cancer, generating point mutations and chromosomal rearrangements in a single cellular catastrophe. These observations are contrary to the prevailing somatic mutation theory, which states that a cancer is caused by the gradual accumulation of mutations over time. A different perspective is proposed within the framework of Waddington's epigenetic landscape wherein tumorigenesis is viewed primarily as a disruption of cell development. Cell types are defined by their specific gene-expression profiles, determined by the gene regulatory network, and can be regarded as attractor states of the network dynamics: they represent specific, self-stabilizing patterns of gene activities across the genome. However, large-scale mutational events reshape the landscape topology, creating abnormal "unphysiological" attractors. This is the crux of the process of initiation. Initiation primes the cell for conversion into a tumor phenotype by oncogenes and tumor suppressor genes, which drive cell proliferation and clonal diversification. This view of tumorigenesis calls for a different approach to therapy.
    Keywords:  Waddington's epigenetic landscape; attractor state; cancer initiation; gene regulatory network; somatic mutation theory
    DOI:  https://doi.org/10.1002/gcc.23213
  49. Immunity. 2023 Nov 14. pii: S1074-7613(23)00455-7. [Epub ahead of print]56(11): 2459-2461
    SMPDL3A links cholesterol metabolism to the cGAS-STING pathway.
    Heegwon Shin, Hachung Chung.
      Liver X receptor (LXR), well known for its role in cholesterol metabolism, also has anti-inflammatory properties. In this issue of Immunity, Hou et al. demonstrate that LXR signaling induces SMPDL3A, a cGAMP-degrading enzyme that restricts cGAS-cGAMP-STING innate immune signaling, providing a mechanistic link between lipid metabolism and inflammation.
    DOI:  https://doi.org/10.1016/j.immuni.2023.10.015
  50. Aging Cell. 2023 Nov 13. e14009
    3D reconstruction of murine mitochondria reveals changes in structure during aging linked to the MICOS complex.
    Zer Vue, Edgar Garza-Lopez, Kit Neikirk, Prasanna Katti, Larry Vang, Heather Beasley, Jianqiang Shao, Andrea G Marshall, Amber Crabtree, Alexandria C Murphy, Brenita C Jenkins, Praveena Prasad, Chantell Evans, Brittany Taylor, Margaret Mungai, Mason Killion, Dominique Stephens, Trace A Christensen, Jacob Lam, Benjamin Rodriguez, Mark A Phillips, Nastaran Daneshgar, Ho-Jin Koh, Alice Koh, Jamaine Davis, Nina Devine, Saleem Muhammod, Estevão Scudese, Kenneth Ryan Arnold, Valeria Vanessa Chavarin, Ryan Daniel Robinson, Moumita Chakraborty, Jennifer A Gaddy, Mariya T Sweetwyne, Genesis Wilson, Elma Zaganjor, James Kezos, Cristiana Dondi, Anilkumar K Reddy, Brian Glancy, Annet Kirabo, Anita M Quintana, Dao-Fu Dai, Karen Ocorr, Sandra A Murray, Steven M Damo, Vernat Exil, Blake Riggs, Bret C Mobley, Jose A Gomez, Melanie R McReynolds, Antentor Hinton.
      During aging, muscle gradually undergoes sarcopenia, the loss of function associated with loss of mass, strength, endurance, and oxidative capacity. However, the 3D structural alterations of mitochondria associated with aging in skeletal muscle and cardiac tissues are not well described. Although mitochondrial aging is associated with decreased mitochondrial capacity, the genes responsible for the morphological changes in mitochondria during aging are poorly characterized. We measured changes in mitochondrial morphology in aged murine gastrocnemius, soleus, and cardiac tissues using serial block-face scanning electron microscopy and 3D reconstructions. We also used reverse transcriptase-quantitative PCR, transmission electron microscopy quantification, Seahorse analysis, and metabolomics and lipidomics to measure changes in mitochondrial morphology and function after loss of mitochondria contact site and cristae organizing system (MICOS) complex genes, Chchd3, Chchd6, and Mitofilin. We identified significant changes in mitochondrial size in aged murine gastrocnemius, soleus, and cardiac tissues. We found that both age-related loss of the MICOS complex and knockouts of MICOS genes in mice altered mitochondrial morphology. Given the critical role of mitochondria in maintaining cellular metabolism, we characterized the metabolomes and lipidomes of young and aged mouse tissues, which showed profound alterations consistent with changes in membrane integrity, supporting our observations of age-related changes in muscle tissues. We found a relationship between changes in the MICOS complex and aging. Thus, it is important to understand the mechanisms that underlie the tissue-dependent 3D mitochondrial phenotypic changes that occur in aging and the evolutionary conservation of these mechanisms between Drosophila and mammals.
    Keywords:   Drosophila ; 3D morphometry; MICOS; aging; mitochondria; mitochondrial disease; mitochondrion; reconstruction; reticulum; serial block-face SEM; skeletal muscle
    DOI:  https://doi.org/10.1111/acel.14009
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