bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2023–08–06
forty-two papers selected by
Christian Frezza, Universität zu Köln
  1. Investigation of hydrated channels and proton pathways in a high-resolution cryo-EM structure of mammalian complex I.
  2. Ketolysis drives CD8+ T cell effector function through effects on histone acetylation.
  3. Contact sites between endoplasmic reticulum sheets and mitochondria regulate mitochondrial DNA replication and segregation.
  4. O-GlcNAcylation of Raptor transduces glucose signals to mTORC1.
  5. Completion of mitochondrial division requires the intermembrane space protein Mdi1/Atg44.
  6. Inosine enhances tumor mitochondrial respiration by inducing Rag GTPases and nascent protein synthesis under nutrient starvation.
  7. Inter-tissue communication of mitochondrial stress and metabolic health.
  8. Phospholipids can regulate complex I assembly independent of their role in maintaining mitochondrial membrane integrity.
  9. cGAS-STING drives ageing-related inflammation and neurodegeneration.
  10. Metabolic switch from fatty acid oxidation to glycolysis in knock-in mouse model of Barth syndrome.
  11. Nanoscale details of mitochondrial constriction revealed by cryo-electron tomography.
  12. FBXO7/ntc and USP30 antagonistically set the ubiquitination threshold for basal mitophagy and provide a target for Pink1 phosphorylation in vivo.
  13. Drivers of de novo Serine/Glycine synthesis in acute leukemia.
  14. Methionine and H2S alter cancer-immune dialogue.
  15. Inhibition of the serotonin transporter induces dysfunction of human brown adipose tissue.
  16. Methionine restriction and antitumor immunity.
  17. Role of mitochondrial alterations in human cancer progression and cancer immunity.
  18. Cys-regulation: oxidized CHK1 controls cross-compartment circuit of chemoresistance.
  19. A mother to offspring metabolic link.
  20. Metabolic regulation of glucagon secretion.
  21. A widely distributed gene cluster compensates for uricase loss in hominids.
  22. Topography of mutational signatures in human cancer.
  23. A role for SETD2 loss in tumorigenesis through DNA methylation dysregulation.
  24. The circadian clock of the bacterium B. subtilis evokes properties of complex, multicellular circadian systems.
  25. A parallel glycolysis provides a selective advantage through rapid growth acceleration.
  26. Convergent and divergent mechanisms of peroxisomal and mitochondrial division.
  27. Fatty acid synthesis and oxidation regulate human endoderm differentiation by mediating SMAD3 nuclear localization via acetylation.
  28. The winner takes it all: Competition drives clonal selection in gliomagenesis.
  29. Central role of Tim17 in mitochondrial presequence protein translocation.
  30. The curious case of IDH mutant acute myeloid leukaemia: biochemistry and therapeutic approaches.
  31. Hepatic levels of S-adenosylmethionine regulate the adaptive response to fasting.
  32. DNA sensing in cancer: Pro-tumour and anti-tumour functions of cGAS-STING signalling.
  33. Senescent cells form nuclear foci that contain the 26S proteasome.
  34. CXCL9:SPP1 macrophage polarity identifies a network of cellular programs that control human cancers.
  35. Circadian regulation of metabolism across photosynthetic organisms.
  36. SF3B1 hotspot mutations confer sensitivity to PARP inhibition by eliciting a defective replication stress response.
  37. A novel theory of ageing independent of damage accumulation.
  38. Methionine restriction-induced sulfur deficiency impairs antitumour immunity partially through gut microbiota.
  39. Hallmarks of CD8+ T cell dysfunction are established within hours of tumor antigen encounter before cell division.
  40. An electrogenetic interface to program mammalian gene expression by direct current.
  41. 2-hydroxyglutarate rides the cancer-immunity cycle.
  42. Shared Gene Targets of the ATF4 and p53 Transcriptional Networks.
  1. Sci Adv. 2023 Aug 02. 9(31): eadi1359
    Investigation of hydrated channels and proton pathways in a high-resolution cryo-EM structure of mammalian complex I.
    Daniel N Grba, Injae Chung, Hannah R Bridges, Ahmed-Noor A Agip, Judy Hirst.
      Respiratory complex I, a key enzyme in mammalian metabolism, captures the energy released by reduction of ubiquinone by NADH to drive protons across the inner mitochondrial membrane, generating the proton-motive force for ATP synthesis. Despite remarkable advances in structural knowledge of this complicated membrane-bound enzyme, its mechanism of catalysis remains controversial. In particular, how ubiquinone reduction is coupled to proton pumping and the pathways and mechanisms of proton translocation are contested. We present a 2.4-Å resolution cryo-EM structure of complex I from mouse heart mitochondria in the closed, active (ready-to-go) resting state, with 2945 water molecules modeled. By analyzing the networks of charged and polar residues and water molecules present, we evaluate candidate pathways for proton transfer through the enzyme, for the chemical protons for ubiquinone reduction, and for the protons transported across the membrane. Last, we compare our data to the predictions of extant mechanistic models, and identify key questions to answer in future work to test them.
    DOI:  https://doi.org/10.1126/sciadv.adi1359
  2. Immunity. 2023 Jul 20. pii: S1074-7613(23)00314-X. [Epub ahead of print]
    Ketolysis drives CD8+ T cell effector function through effects on histone acetylation.
    Katarzyna M Luda, Joseph Longo, Susan M Kitchen-Goosen, Lauren R Duimstra, Eric H Ma, McLane J Watson, Brandon M Oswald, Zhen Fu, Zachary Madaj, Ariana Kupai, Bradley M Dickson, Lisa M DeCamp, Michael S Dahabieh, Shelby E Compton, Robert Teis, Irem Kaymak, Kin H Lau, Daniel P Kelly, Patrycja Puchalska, Kelsey S Williams, Connie M Krawczyk, Dominique Lévesque, François-Michel Boisvert, Ryan D Sheldon, Scott B Rothbart, Peter A Crawford, Russell G Jones.
      Environmental nutrient availability influences T cell metabolism, impacting T cell function and shaping immune outcomes. Here, we identified ketone bodies (KBs)-including β-hydroxybutyrate (βOHB) and acetoacetate (AcAc)-as essential fuels supporting CD8+ T cell metabolism and effector function. βOHB directly increased CD8+ T effector (Teff) cell cytokine production and cytolytic activity, and KB oxidation (ketolysis) was required for Teff cell responses to bacterial infection and tumor challenge. CD8+ Teff cells preferentially used KBs over glucose to fuel the tricarboxylic acid (TCA) cycle in vitro and in vivo. KBs directly boosted the respiratory capacity and TCA cycle-dependent metabolic pathways that fuel CD8+ T cell function. Mechanistically, βOHB was a major substrate for acetyl-CoA production in CD8+ T cells and regulated effector responses through effects on histone acetylation. Together, our results identify cell-intrinsic ketolysis as a metabolic and epigenetic driver of optimal CD8+ T cell effector responses.
    Keywords:  CD8(+) T cells; TCA cycle; acetyl-CoA; cancer immunology; effector function; epigenetics; ketolysis; ketone bodies; metabolism
    DOI:  https://doi.org/10.1016/j.immuni.2023.07.002
  3. iScience. 2023 Jul 21. 26(7): 107180
    Contact sites between endoplasmic reticulum sheets and mitochondria regulate mitochondrial DNA replication and segregation.
    Hema Saranya Ilamathi, Sara Benhammouda, Amel Lounas, Khalid Al-Naemi, Justine Desrochers-Goyette, Matthew A Lines, François J Richard, Jackie Vogel, Marc Germain.
      Mitochondria are multifaceted organelles crucial for cellular homeostasis that contain their own genome. Mitochondrial DNA (mtDNA) replication is a spatially regulated process essential for the maintenance of mitochondrial function, its defect causing mitochondrial diseases. mtDNA replication occurs at endoplasmic reticulum (ER)-mitochondria contact sites and is affected by mitochondrial dynamics: The absence of mitochondrial fusion is associated with mtDNA depletion whereas loss of mitochondrial fission causes the aggregation of mtDNA within abnormal structures termed mitobulbs. Here, we show that contact sites between mitochondria and ER sheets, the ER structure associated with protein synthesis, regulate mtDNA replication and distribution within mitochondrial networks. DRP1 loss or mutation leads to modified ER sheets and alters the interaction between ER sheets and mitochondria, disrupting RRBP1-SYNJ2BP interaction. Importantly, mtDNA distribution and replication were rescued by promoting ER sheets-mitochondria contact sites. Our work identifies the role of ER sheet-mitochondria contact sites in regulating mtDNA replication and distribution.
    Keywords:  Biochemistry; Biological sciences; Cell biology
    DOI:  https://doi.org/10.1016/j.isci.2023.107180
  4. Mol Cell. 2023 Jul 28. pii: S1097-2765(23)00526-9. [Epub ahead of print]
    O-GlcNAcylation of Raptor transduces glucose signals to mTORC1.
    Chenchen Xu, Xiaoqing Pan, Dong Wang, Yuanyuan Guan, Wenyu Yang, Xing Chen, Ying Liu.
      The mechanistic target of rapamycin complex 1 (mTORC1) regulates metabolism and cell growth in response to nutrient levels. Dysregulation of mTORC1 results in a broad spectrum of diseases. Glucose is the primary energy supply of cells, and therefore, glucose levels must be accurately conveyed to mTORC1 through highly responsive signaling mechanisms to control mTORC1 activity. Here, we report that glucose-induced mTORC1 activation is regulated by O-GlcNAcylation of Raptor, a core component of mTORC1, in HEK293T cells. Mechanistically, O-GlcNAcylation of Raptor at threonine 700 facilitates the interactions between Raptor and Rag GTPases and promotes the translocation of mTOR to the lysosomal surface, consequently activating mTORC1. In addition, we show that AMPK-mediated phosphorylation of Raptor suppresses Raptor O-GlcNAcylation and inhibits Raptor-Rags interactions. Our findings reveal an exquisitely controlled mechanism, which suggests how glucose coordinately regulates cellular anabolism and catabolism.
    Keywords:  O-GlcNAcylation; Raptor; glucose sensing; mTOR
    DOI:  https://doi.org/10.1016/j.molcel.2023.07.011
  5. J Cell Biol. 2023 Oct 02. pii: e202303147. [Epub ahead of print]222(10):
    Completion of mitochondrial division requires the intermembrane space protein Mdi1/Atg44.
    Olivia M Connor, Srujan K Matta, Jonathan R Friedman.
      Mitochondria are highly dynamic double membrane-bound organelles that maintain their shape in part through fission and fusion. Mitochondrial fission is performed by a dynamin-related protein, Dnm1 (Drp1 in humans), that constricts and divides the mitochondria in a GTP hydrolysis-dependent manner. However, it is unclear whether factors inside mitochondria help coordinate the process and if Dnm1/Drp1 activity is sufficient to complete the fission of both mitochondrial membranes. Here, we identify an intermembrane space protein required for mitochondrial fission in yeast, which we propose to name Mdi1 (also named Atg44). Loss of Mdi1 causes mitochondrial hyperfusion due to defects in fission, but not the lack of Dnm1 recruitment to mitochondria. Mdi1 is conserved in fungal species, and its homologs contain an amphipathic α-helix, mutations of which disrupt mitochondrial morphology. One model is that Mdi1 distorts mitochondrial membranes to enable Dnm1 to robustly complete fission. Our work reveals that Dnm1 cannot efficiently divide mitochondria without the coordinated function of Mdi1 inside mitochondria.
    DOI:  https://doi.org/10.1083/jcb.202303147
  6. Cell Death Dis. 2023 Aug 02. 14(8): 492
    Inosine enhances tumor mitochondrial respiration by inducing Rag GTPases and nascent protein synthesis under nutrient starvation.
    Mei-Xin Li, Xiao-Ting Wu, Wen-Qiang Jing, Wen-Kui Hou, Sheng Hu, Wei Yan.
      Metabolic heterogeneity of tumor microenvironment (TME) is a hallmark of cancer and a big barrier to cancer treatment. Cancer cells display diverse capacities to utilize alternative carbon sources, including nucleotides, under poor nutrient circumstances. However, whether and how purine, especially inosine, regulates mitochondrial metabolism to buffer nutrient starvation has not been well-defined yet. Here, we identify the induction of 5'-nucleotidase, cytosolic II (NT5C2) gene expression promotes inosine accumulation and maintains cancer cell survival in the nutrient-poor region. Inosine elevation further induces Rag GTPases abundance and mTORC1 signaling pathway by enhancing transcription factor SP1 level in the starved tumor. Besides, inosine supplementary stimulates the synthesis of nascent TCA cycle enzymes, including citrate synthesis (CS) and aconitase 1 (ACO1), to further enhance oxidative phosphorylation of breast cancer cells under glucose starvation, leading to the accumulation of iso-citric acid. Inhibition of the CS activity or knockdown of ACO1 blocks the rescue effect of inosine on cancer survival under starvation. Collectively, our finding highlights the vital signal role of inosine linking mitochondrial respiration and buffering starvation, beyond serving as direct energy carriers or building blocks for genetic code in TME, shedding light on future cancer treatment by targeting inosine metabolism.
    DOI:  https://doi.org/10.1038/s41419-023-06017-2
  7. Life Metab. 2023 Feb;pii: load001. [Epub ahead of print]2(1):
    Inter-tissue communication of mitochondrial stress and metabolic health.
    Hanlin Zhang, Xinyu Li, Wudi Fan, Sentibel Pandovski, Ye Tian, Andrew Dillin.
      Mitochondria function as a hub of the cellular metabolic network. Mitochondrial stress is closely associated with aging and a variety of diseases, including neurodegeneration and cancer. Cells autonomously elicit specific stress responses to cope with mitochondrial stress to maintain mitochondrial homeostasis. Interestingly, mitochondrial stress responses may also be induced in a non-autonomous manner in cells or tissues that are not directly experiencing such stress. Such non-autonomous mitochondrial stress responses are mediated by secreted molecules called mitokines. Due to their significant translational potential in improving human metabolic health, there has been a surge in mitokine-focused research. In this review, we summarize the findings regarding inter-tissue communication of mitochondrial stress in animal models. In addition, we discuss the possibility of mitokine-mediated intercellular mitochondrial communication originating from bacterial quorum sensing.
    Keywords:  inter-tissue communication; metabolic health; mitochondria; mitokine; quorum sensing
    DOI:  https://doi.org/10.1093/lifemeta/load001
  8. Cell Rep. 2023 Jul 29. pii: S2211-1247(23)00857-4. [Epub ahead of print]42(8): 112846
    Phospholipids can regulate complex I assembly independent of their role in maintaining mitochondrial membrane integrity.
    Anjaneyulu Murari, Shauna-Kay Rhooms, Divya Vimal, Kaniz Fatima Binte Hossain, Sanjay Saini, Maximino Villanueva, Michael Schlame, Edward Owusu-Ansah.
      Several phospholipid (PL) molecules are intertwined with some mitochondrial complex I (CI) subunits in the membrane domain of CI, but their function is unclear. We report that when the Drosophila melanogaster ortholog of the intramitochondrial PL transporter, STARD7, is severely disrupted, assembly of the oxidative phosphorylation (OXPHOS) system is impaired, and the biogenesis of several CI subcomplexes is hampered. However, intriguingly, a restrained knockdown of STARD7 impairs the incorporation of NDUFS5 and NDUFA1 into the proximal part of the CI membrane domain without directly affecting the incorporation of subunits in the distal part of the membrane domain, OXPHOS complexes already assembled, or mitochondrial cristae integrity. Importantly, the restrained knockdown of STARD7 appears to induce a modest amount of cardiolipin remodeling, indicating that there could be some alteration in the composition of the mitochondrial phospholipidome. We conclude that PLs can regulate CI biogenesis independent of their role in maintaining mitochondrial membrane integrity.
    Keywords:  CP: Molecular biology; Drosophila; NDUFA1; NDUFS5; OXPHOS; STARD7; complex I; mitochondria; phospholipid
    DOI:  https://doi.org/10.1016/j.celrep.2023.112846
  9. Nature. 2023 Aug 02.
    cGAS-STING drives ageing-related inflammation and neurodegeneration.
    Muhammet F Gulen, Natasha Samson, Alexander Keller, Marius Schwabenland, Chong Liu, Selene Glück, Vivek V Thacker, Lucie Favre, Bastien Mangeat, Lona J Kroese, Paul Krimpenfort, Marco Prinz, Andrea Ablasser.
      Low-grade inflammation is a hallmark of old age and a central driver of ageing-associated impairment and disease1. Multiple factors can contribute to ageing-associated inflammation2; however, the molecular pathways that transduce aberrant inflammatory signalling and their impact in natural ageing remain unclear. Here we show that the cGAS-STING signalling pathway, which mediates immune sensing of DNA3, is a critical driver of chronic inflammation and functional decline during ageing. Blockade of STING suppresses the inflammatory phenotypes of senescent human cells and tissues, attenuates ageing-related inflammation in multiple peripheral organs and the brain in mice, and leads to an improvement in tissue function. Focusing on the ageing brain, we reveal that activation of STING triggers reactive microglial transcriptional states, neurodegeneration and cognitive decline. Cytosolic DNA released from perturbed mitochondria elicits cGAS activity in old microglia, defining a mechanism by which cGAS-STING signalling is engaged in the ageing brain. Single-nucleus RNA-sequencing analysis of microglia and hippocampi of a cGAS gain-of-function mouse model demonstrates that engagement of cGAS in microglia is sufficient to direct ageing-associated transcriptional microglial states leading to bystander cell inflammation, neurotoxicity and impaired memory capacity. Our findings establish the cGAS-STING pathway as a driver of ageing-related inflammation in peripheral organs and the brain, and reveal blockade of cGAS-STING signalling as a potential strategy to halt neurodegenerative processes during old age.
    DOI:  https://doi.org/10.1038/s41586-023-06373-1
  10. EMBO Mol Med. 2023 Aug 03. e17399
    Metabolic switch from fatty acid oxidation to glycolysis in knock-in mouse model of Barth syndrome.
    Arpita Chowdhury, Angela Boshnakovska, Abhishek Aich, Aditi Methi, Ana Maria Vergel Leon, Ivan Silbern, Christian Lüchtenborg, Lukas Cyganek, Jan Prochazka, Radislav Sedlacek, Jiri Lindovsky, Dominic Wachs, Zuzana Nichtova, Dagmar Zudova, Gizela Koubkova, André Fischer, Henning Urlaub, Britta Brügger, Dörthe M Katschinski, Jan Dudek, Peter Rehling.
      Mitochondria are central for cellular metabolism and energy supply. Barth syndrome (BTHS) is a severe disorder, due to dysfunction of the mitochondrial cardiolipin acyl transferase tafazzin. Altered cardiolipin remodeling affects mitochondrial inner membrane organization and function of membrane proteins such as transporters and the oxidative phosphorylation (OXPHOS) system. Here, we describe a mouse model that carries a G197V exchange in tafazzin, corresponding to BTHS patients. TAZG197V mice recapitulate disease-specific pathology including cardiac dysfunction and reduced oxidative phosphorylation. We show that mutant mitochondria display defective fatty acid-driven oxidative phosphorylation due to reduced levels of carnitine palmitoyl transferases. A metabolic switch in ATP production from OXPHOS to glycolysis is apparent in mouse heart and patient iPSC cell-derived cardiomyocytes. An increase in glycolytic ATP production inactivates AMPK causing altered metabolic signaling in TAZG197V . Treatment of mutant cells with AMPK activator reestablishes fatty acid-driven OXPHOS and protects mice against cardiac dysfunction.
    Keywords:  Barth syndrome; cardiolipin; cardiomyopathy; mitochondria; tafazzin
    DOI:  https://doi.org/10.15252/emmm.202317399
  11. Biophys J. 2023 Aug 01. pii: S0006-3495(23)00481-2. [Epub ahead of print]
    Nanoscale details of mitochondrial constriction revealed by cryo-electron tomography.
    Shrawan Kumar Mageswaran, Danielle Ann Grotjahn, Xiangrui Zeng, Benjamin Asher Barad, Michaela Medina, My Hanh Hoang, Megan J Dobro, Yi-Wei Chang, Min Xu, Wei Yuan Yang, Grant J Jensen.
      Mitochondria adapt to changing cellular environments, stress stimuli, and metabolic demands through dramatic morphological remodeling of their shape, and thus function. Such mitochondrial dynamics is often dependent on cytoskeletal filament interactions. However, the precise organization of these filamentous assemblies remains speculative. Here, we apply cryogenic electron tomography to directly image the nanoscale architecture of the cytoskeletal-membrane interactions involved in mitochondrial dynamics in response to damage. We induced mitochondrial damage via membrane depolarization, a cellular stress associated with mitochondrial fragmentation and mitophagy. We find that, in response to acute membrane depolarization, mammalian mitochondria predominantly organize into tubular morphology that abundantly displays constrictions. We observe long bundles of both unbranched actin and septin filaments enriched at these constrictions. We also observed septin-microtubule interactions at these sites and elsewhere suggesting that these two filaments guide each other in the cytosolic space. Together, our results provide empirical parameters for the architecture of mitochondrial constriction factors to validate/refine existing models and inform the development of new ones.
    DOI:  https://doi.org/10.1016/j.bpj.2023.07.030
  12. PLoS Biol. 2023 Aug 03. 21(8): e3002244
    FBXO7/ntc and USP30 antagonistically set the ubiquitination threshold for basal mitophagy and provide a target for Pink1 phosphorylation in vivo.
    Alvaro Sanchez-Martinez, Aitor Martinez, Alexander J Whitworth.
      Functional analyses of genes linked to heritable forms of Parkinson's disease (PD) have revealed fundamental insights into the biological processes underpinning pathogenic mechanisms. Mutations in PARK15/FBXO7 cause autosomal recessive PD and FBXO7 has been shown to regulate mitochondrial homeostasis. We investigated the extent to which FBXO7 and its Drosophila orthologue, ntc, share functional homology and explored its role in mitophagy in vivo. We show that ntc mutants partially phenocopy Pink1 and parkin mutants and ntc overexpression supresses parkin phenotypes. Furthermore, ntc can modulate basal mitophagy in a Pink1- and parkin-independent manner by promoting the ubiquitination of mitochondrial proteins, a mechanism that is opposed by the deubiquitinase USP30. This basal ubiquitination serves as the substrate for Pink1-mediated phosphorylation that triggers stress-induced mitophagy. We propose that FBXO7/ntc works in equilibrium with USP30 to provide a checkpoint for mitochondrial quality control in basal conditions in vivo and presents a new avenue for therapeutic approaches.
    DOI:  https://doi.org/10.1371/journal.pbio.3002244
  13. FEBS Lett. 2023 Aug 01.
    Drivers of de novo Serine/Glycine synthesis in acute leukemia.
    Paulien Verstraete, Kim De Keersmaecker, Kim Rosalie Kampen.
      Cancer cells hijack metabolic pathways in order to provide themselves with building blocks to support their proliferation and survival. Upregulation and addiction to de novo serine/glycine synthesis is an example of metabolic rewiring in cancer cells whereby serine and glycine are synthesised via a side branch of glycolysis. In this review, we focus on upregulation of endogenous serine/glycine production in acute leukemia, namely T-cell acute leukemia (T-ALL) and acute myeloid leukemia (AML). Several genetic lesions directly driving the serine/glycine addiction in acute leukemia have been established. Additionally, indirect regulation of de novo serine/glycine synthesis is observed in acute leukemia.
    Keywords:  ALL; AML; DNMT3A; FLT3-ITD; NKX2-1; NOTCH1; RPL10; glycine; serine; sertraline
    DOI:  https://doi.org/10.1002/1873-3468.14700
  14. Nat Metab. 2023 Aug 03.
    Methionine and H2S alter cancer-immune dialogue.
    Emeline Joulia, Christian M Metallo.
      
    DOI:  https://doi.org/10.1038/s42255-023-00862-3
  15. Nat Metab. 2023 Aug 03.
    Inhibition of the serotonin transporter induces dysfunction of human brown adipose tissue.
      
    DOI:  https://doi.org/10.1038/s42255-023-00851-6
  16. Trends Cancer. 2023 Jul 28. pii: S2405-8033(23)00135-8. [Epub ahead of print]
    Methionine restriction and antitumor immunity.
    Fangchao Wei, Jason W Locasale.
      Fang et al. recently reported in Cancer Cell that methionine restriction increases antitumor immunity by enhancing cyclic GMP-AMP synthase (cGAS) activity and promoting its dissociation from chromatin. This finding identifies a potential strategy to target cGAS demethylation in cancer therapy by altering methionine metabolism.
    Keywords:  antitumor immunity; cGAS methylation; methionine restriction
    DOI:  https://doi.org/10.1016/j.trecan.2023.07.008
  17. J Biomed Sci. 2023 Jul 31. 30(1): 61
    Role of mitochondrial alterations in human cancer progression and cancer immunity.
    Sheng-Fan Wang, Ling-Ming Tseng, Hsin-Chen Lee.
      Dysregulating cellular metabolism is one of the emerging cancer hallmarks. Mitochondria are essential organelles responsible for numerous physiologic processes, such as energy production, cellular metabolism, apoptosis, and calcium and redox homeostasis. Although the "Warburg effect," in which cancer cells prefer aerobic glycolysis even under normal oxygen circumstances, was proposed a century ago, how mitochondrial dysfunction contributes to cancer progression is still unclear. This review discusses recent progress in the alterations of mitochondrial DNA (mtDNA) and mitochondrial dynamics in cancer malignant progression. Moreover, we integrate the possible regulatory mechanism of mitochondrial dysfunction-mediated mitochondrial retrograde signaling pathways, including mitochondrion-derived molecules (reactive oxygen species, calcium, oncometabolites, and mtDNA) and mitochondrial stress response pathways (mitochondrial unfolded protein response and integrated stress response) in cancer progression and provide the possible therapeutic targets. Furthermore, we discuss recent findings on the role of mitochondria in the immune regulatory function of immune cells and reveal the impact of the tumor microenvironment and metabolism remodeling on cancer immunity. Targeting the mitochondria and metabolism might improve cancer immunotherapy. These findings suggest that targeting mitochondrial retrograde signaling in cancer malignancy and modulating metabolism and mitochondria in cancer immunity might be promising treatment strategies for cancer patients and provide precise and personalized medicine against cancer.
    Keywords:  Cancer immunity; Cancer progression; Mitochondria; Retrograde signaling
    DOI:  https://doi.org/10.1186/s12929-023-00956-w
  18. Trends Cancer. 2023 Aug 01. pii: S2405-8033(23)00132-2. [Epub ahead of print]
    Cys-regulation: oxidized CHK1 controls cross-compartment circuit of chemoresistance.
    Nathan P Ward.
      In a recent study published in Cell, Zhang et al. integrate genome-wide CRISPRi screening with cysteine chemoproteomics to identify functionally relevant oxidation events associated with the cellular response to chemotherapy. This work uncovered checkpoint kinase 1 (CHK1) as a nuclear reactive oxygen species (ROS) sensor that mediates chemoresistance through the suppression of mitochondrial protein synthesis.
    Keywords:  CHK1; ROS; SSBP1; chemoresistance; redox
    DOI:  https://doi.org/10.1016/j.trecan.2023.07.005
  19. Nat Cell Biol. 2023 Aug 03.
    A mother to offspring metabolic link.
    Nicholas O Burton.
      
    DOI:  https://doi.org/10.1038/s41556-023-01189-7
  20. J Endocrinol. 2023 Jul 01. pii: JOE-23-0081. [Epub ahead of print]
    Metabolic regulation of glucagon secretion.
    Sarah L Armour, Jade E Stanley, James Cantley, E Danielle Dean, Jakob G Knudsen.
      Since the discovery of glucagon 100 years ago, the hormone, and the pancreatic islet alpha cells that produce it, have remained enigmatic relative to insulin producing beta cells. Canonically, alpha cells have been described in the context of glucagon's role on glucose metabolism in liver, with glucose as the primary nutrient signal regulating alpha cell function. However, current data reveal a more holistic model of metabolic signalling, involving glucagon-regulated metabolism of multiple nutrients by the liver and other tissues, with circulating nutrient availability, including amino acids and lipids, providing reciprocal feedback to regulate glucagon secretion and even alpha cell mass. Here we describe how various nutrients are sensed, transported, and metabolised in alpha cells, providing an integrative model for the metabolic regulation of glucagon secretion and action. Importantly, we discuss where these nutrient sensing pathways intersect to regulate alpha cell function and highlight key areas for future research.
    DOI:  https://doi.org/10.1530/JOE-23-0081
  21. Cell. 2023 Aug 03. pii: S0092-8674(23)00687-6. [Epub ahead of print]186(16): 3400-3413.e20
    A widely distributed gene cluster compensates for uricase loss in hominids.
    Yuanyuan Liu, J Bryce Jarman, Yen S Low, Hannah E Augustijn, Steven Huang, Haoqing Chen, Mary E DeFeo, Kazuma Sekiba, Bi-Huei Hou, Xiandong Meng, Allison M Weakley, Ashley V Cabrera, Zhiwei Zhou, Gilles van Wezel, Marnix H Medema, Calyani Ganesan, Alan C Pao, Saurabh Gombar, Dylan Dodd.
      Approximately 15% of US adults have circulating levels of uric acid above its solubility limit, which is causally linked to the disease gout. In most mammals, uric acid elimination is facilitated by the enzyme uricase. However, human uricase is a pseudogene, having been inactivated early in hominid evolution. Though it has long been known that uric acid is eliminated in the gut, the role of the gut microbiota in hyperuricemia has not been studied. Here, we identify a widely distributed bacterial gene cluster that encodes a pathway for uric acid degradation. Stable isotope tracing demonstrates that gut bacteria metabolize uric acid to xanthine or short chain fatty acids. Ablation of the microbiota in uricase-deficient mice causes severe hyperuricemia, and anaerobe-targeted antibiotics increase the risk of gout in humans. These data reveal a role for the gut microbiota in uric acid excretion and highlight the potential for microbiome-targeted therapeutics in hyperuricemia.
    Keywords:  gout; hyperuricemia; microbiome; microbiota; uric acid; uricase
    DOI:  https://doi.org/10.1016/j.cell.2023.06.010
  22. Cell Rep. 2023 Aug 03. pii: S2211-1247(23)00941-5. [Epub ahead of print]42(8): 112930
    Topography of mutational signatures in human cancer.
    Burçak Otlu, Marcos Díaz-Gay, Ian Vermes, Erik N Bergstrom, Maria Zhivagui, Mark Barnes, Ludmil B Alexandrov.
      The somatic mutations found in a cancer genome are imprinted by different mutational processes. Each process exhibits a characteristic mutational signature, which can be affected by the genome architecture. However, the interplay between mutational signatures and topographical genomic features has not been extensively explored. Here, we integrate mutations from 5,120 whole-genome-sequenced tumors from 40 cancer types with 516 topographical features from ENCODE to evaluate the effect of nucleosome occupancy, histone modifications, CTCF binding, replication timing, and transcription/replication strand asymmetries on the cancer-specific accumulation of mutations from distinct mutagenic processes. Most mutational signatures are affected by topographical features, with signatures of related etiologies being similarly affected. Certain signatures exhibit periodic behaviors or cancer-type-specific enrichments/depletions near topographical features, revealing further information about the processes that imprinted them. Our findings, disseminated via the COSMIC (Catalog of Somatic Mutations in Cancer) signatures database, provide a comprehensive online resource for exploring the interactions between mutational signatures and topographical features across human cancer.
    Keywords:  CP: Cancer; CP: Genomics; cancer genomics; genome topography; mutational signatures; somatic mutations
    DOI:  https://doi.org/10.1016/j.celrep.2023.112930
  23. BMC Cancer. 2023 Aug 01. 23(1): 721
    A role for SETD2 loss in tumorigenesis through DNA methylation dysregulation.
    Hira Javaid, Alessandro Barberis, Olga Chervova, Isar Nassiri, Vitaly Voloshin, Yusuke Sato, Seishi Ogawa, Benjamin Fairfax, Francesca Buffa, Timothy C Humphrey.
      SETD2-dependent H3 Lysine-36 trimethylation (H3K36me3) has been recently linked to the deposition of de-novo DNA methylation. SETD2 is frequently mutated in cancer, however, the functional impact of SETD2 loss and depletion on DNA methylation across cancer types and tumorigenesis is currently unknown. Here, we perform a pan-cancer analysis and show that both SETD2 mutation and reduced expression are associated with DNA methylation dysregulation across 21 out of the 24 cancer types tested. In renal cancer, these DNA methylation changes are associated with altered gene expression of oncogenes, tumour suppressors, and genes involved in neoplasm invasiveness, including TP53, FOXO1, and CDK4. This suggests a new role for SETD2 loss in tumorigenesis and cancer aggressiveness through DNA methylation dysregulation. Moreover, using a robust machine learning methodology, we develop and validate a 3-CpG methylation signature which is sufficient to predict SETD2 mutation status with high accuracy and correlates with patient prognosis.
    Keywords:  DNA methylation; H3K36me3; Machine learning biomarker; Renal cancer biomarker; SETD2
    DOI:  https://doi.org/10.1186/s12885-023-11162-0
  24. Sci Adv. 2023 Aug 04. 9(31): eadh1308
    The circadian clock of the bacterium B. subtilis evokes properties of complex, multicellular circadian systems.
    Francesca Sartor, Xinming Xu, Tanja Popp, Antony N Dodd, Ákos T Kovács, Martha Merrow.
      Circadian clocks are pervasive throughout nature, yet only recently has this adaptive regulatory program been described in nonphotosynthetic bacteria. Here, we describe an inherent complexity in the Bacillus subtilis circadian clock. We find that B. subtilis entrains to blue and red light and that circadian entrainment is separable from masking through fluence titration and frequency demultiplication protocols. We identify circadian rhythmicity in constant light, consistent with the Aschoff's rule, and entrainment aftereffects, both of which are properties described for eukaryotic circadian clocks. We report that circadian rhythms occur in wild isolates of this prokaryote, thus establishing them as a general property of this species, and that its circadian system responds to the environment in a complex fashion that is consistent with multicellular eukaryotic circadian systems.
    DOI:  https://doi.org/10.1126/sciadv.adh1308
  25. Nat Chem Biol. 2023 Aug 03.
    A parallel glycolysis provides a selective advantage through rapid growth acceleration.
    Richard C Law, Glenn Nurwono, Junyoung O Park.
      Glycolysis is a universal metabolic process that breaks down glucose to produce adenosine triphosphate (ATP) and biomass precursors. The Entner-Doudoroff (ED) pathway is a glycolytic pathway that parallels textbook glycolysis but yields half as much ATP. Accordingly, in organisms that possess both glycolytic pathways (for example, Escherichia coli), its raison d'être remains a mystery. In this study, we found that the ED pathway provides a selective advantage during growth acceleration. Upon carbon and nitrogen upshifts, E. coli accelerates growth faster with than without the ED pathway. Concurrent isotope tracing reveals that the ED pathway flux increases faster than that of textbook glycolysis. We attribute the fast response time of the ED pathway to its strong thermodynamic driving force and streamlining of glucose import. Intermittent nutrient supply manifests the evolutionary advantage of the parallel glycolysis; thus, the dynamic nature of an ostensibly redundant pathway's role in promoting rapid adaptation constitutes a metabolic design principle.
    DOI:  https://doi.org/10.1038/s41589-023-01395-2
  26. J Cell Biol. 2023 09 04. pii: e202304076. [Epub ahead of print]222(9):
    Convergent and divergent mechanisms of peroxisomal and mitochondrial division.
    Suresh Subramani, Nandini Shukla, Jean-Claude Farre.
      Organelle division and segregation are important in cellular homeostasis. Peroxisomes (POs) and mitochondria share a core division machinery and mechanism of membrane scission. The division of each organelle is interdependent not only on the other but also on other organelles, reflecting the dynamic communication between subcellular compartments, even as they coordinate the exchange of metabolites and signals. We highlight common and unique mechanisms involved in the fission of these organelles under the premise that much can be gleaned regarding the division of one organelle based on information available for the other.
    DOI:  https://doi.org/10.1083/jcb.202304076
  27. Dev Cell. 2023 Jul 25. pii: S1534-5807(23)00335-0. [Epub ahead of print]
    Fatty acid synthesis and oxidation regulate human endoderm differentiation by mediating SMAD3 nuclear localization via acetylation.
    Ying Yi, Xianchun Lan, Yinglei Li, Chenchao Yan, Jing Lv, Tianzhe Zhang, Wei Jiang.
      Metabolic remodeling is one of the earliest events that occur during cell differentiation. Here, we define fatty acid metabolism as a key player in definitive endoderm differentiation from human embryonic stem cells. Fatty acid β-oxidation is enhanced while lipogenesis is decreased, and this is due to the phosphorylation of lipogenic enzyme acetyl-CoA carboxylase by AMPK. More importantly, inhibition of fatty acid synthesis by either its inhibitors or AMPK agonist significantly promotes human endoderm differentiation, while blockade of fatty acid oxidation impairs differentiation. Mechanistically, reduced de novo fatty acid synthesis and enhanced fatty acid β-oxidation both contribute to the accumulation of intracellular acetyl-CoA, which guarantees the acetylation of SMAD3 and further causes nuclear localization to promote endoderm differentiation. Thus, our current study identifies a fatty acid synthesis/oxidation shift during early differentiation and presents an instructive role for fatty acid metabolism in regulating human endoderm differentiation.
    Keywords:  SMAD3 acetylation; embryonic stem cell; fatty acid metabolism; fatty acid synthesis; human endoderm differentiation
    DOI:  https://doi.org/10.1016/j.devcel.2023.07.005
  28. Cancer Cell. 2023 Jul 22. pii: S1535-6108(23)00243-X. [Epub ahead of print]
    The winner takes it all: Competition drives clonal selection in gliomagenesis.
    Frank Winkler.
      The exact mechanisms that govern clonal dynamics and selection during early tumorigenesis remain largely elusive. Ceresa et al. provide experimental and mathematical evidence that MYC-dependent competition between individual clones is one driving force of brain tumor evolution, adding a winner/loser aspect to the picture that complements existing concepts.
    DOI:  https://doi.org/10.1016/j.ccell.2023.07.003
  29. Nature. 2023 Aug 01.
    Central role of Tim17 in mitochondrial presequence protein translocation.
    Laura F Fielden, Jakob D Busch, Sandra G Merkt, Iniyan Ganesan, Conny Steiert, Hanna B Hasselblatt, Jon V Busto, Christophe Wirth, Nicole Zufall, Sibylle Jungbluth, Katja Noll, Julia M Dung, Ludmila Butenko, Karina von der Malsburg, Hans-Georg Koch, Carola Hunte, Martin van der Laan, Nils Wiedemann.
      The presequence translocase of the mitochondrial inner membrane (TIM23) represents the major route for the import of nuclear-encoded proteins into mitochondria1,2. About 60% of more than 1,000 different mitochondrial proteins are synthesised with amino-terminal targeting signals, termed presequences, which form positively charged amphiphilic α-helices3,4. TIM23 sorts the presequence proteins into the inner membrane or matrix. Various views including regulatory and coupling functions have been reported on the essential TIM23 subunit Tim175-7. We mapped the interaction of Tim17 with matrix-targeted and inner membrane-sorted preproteins during translocation in the native membrane environment. We show that Tim17 contains conserved negative charges close to the intermembrane space side of the bilayer, which are essential to initiate presequence protein translocation along a distinct transmembrane cavity of Tim17 for both classes of preproteins. The amphiphilic character of mitochondrial presequences directly matches this Tim17-dependent translocation mechanism. This mechanism permits direct lateral release of transmembrane segments of inner membrane-sorted precursors into the inner membrane.
    DOI:  https://doi.org/10.1038/s41586-023-06477-8
  30. Biochem Soc Trans. 2023 Aug 01. pii: BST20230017. [Epub ahead of print]
    The curious case of IDH mutant acute myeloid leukaemia: biochemistry and therapeutic approaches.
    Emily Gruber, Lev M Kats.
      Of the many genetic alterations that occur in cancer, relatively few have proven to be suitable for the development of targeted therapies. Mutations in isocitrate dehydrogenase (IDH) 1 and -2 increase the capacity of cancer cells to produce a normally scarce metabolite, D-2-hydroxyglutarate (2-HG), by several orders of magnitude. The discovery of the unusual biochemistry of IDH mutations spurred a flurry of activity that revealed 2-HG as an 'oncometabolite' with pleiotropic effects in malignant cells and consequences for anti-tumour immunity. Over the next decade, we learned that 2-HG dysregulates a wide array of molecular pathways, among them a large family of dioxygenases that utilise the closely related metabolite α-ketoglutarate (α-KG) as an essential co-substrate. 2-HG not only contributes to malignant transformation, but some cancer cells become addicted to it and sensitive to inhibitors that block its synthesis. Moreover, high 2-HG levels and loss of wild-type IDH1 or IDH2 activity gives rise to synthetic lethal vulnerabilities. Herein, we review the biology of IDH mutations with a particular focus on acute myeloid leukaemia (AML), an aggressive disease where selective targeting of IDH-mutant cells is showing significant promise.
    Keywords:  2-HG; IDH mutation; acute myeloid leukaemia; targeted therapies
    DOI:  https://doi.org/10.1042/BST20230017
  31. Cell Metab. 2023 Jul 31. pii: S1550-4131(23)00261-9. [Epub ahead of print]
    Hepatic levels of S-adenosylmethionine regulate the adaptive response to fasting.
    Alba Capelo-Diz, Sofía Lachiondo-Ortega, David Fernández-Ramos, Jorge Cañas-Martín, Naroa Goikoetxea-Usandizaga, Marina Serrano-Maciá, Maria J González-Rellan, Laura Mosca, Joan Blazquez-Vicens, Alberto Tinahones-Ruano, Marcos F Fondevila, Mason Buyan, Teresa C Delgado, Virginia Gutierrez de Juan, Paula Ayuso-García, Alejandro Sánchez-Rueda, Sergio Velasco-Avilés, Héctor Fernández-Susavila, Cristina Riobello-Suárez, Bartlomiej Dziechciarz, Cristina Montiel-Duarte, Fernando Lopitz-Otsoa, Maider Bizkarguenaga, Jon Bilbao-García, Ganeko Bernardo-Seisdedos, Ana Senra, Mario Soriano-Navarro, Oscar Millet, Ángel Díaz-Lagares, Ana B Crujeiras, Aida Bao-Caamano, Diana Cabrera, Sebastiaan van Liempd, Miguel Tamayo-Carro, Luigi Borzacchiello, Beatriz Gomez-Santos, Xabier Buqué, Diego Sáenz de Urturi, Francisco González-Romero, Jorge Simon, Rubén Rodríguez-Agudo, Asier Ruiz, Carlos Matute, Daniel Beiroa, Juan M Falcon-Perez, Patricia Aspichueta, Juan Rodríguez-Cuesta, Marina Porcelli, María A Pajares, Cristina Ameneiro, Miguel Fidalgo, Ana M Aransay, Tomas Lama-Díaz, Miguel G Blanco, Miguel López, Ricardo Villa-Bellosta, Timo D Müller, Rubén Nogueiras, Ashwin Woodhoo, María Luz Martínez-Chantar, Marta Varela-Rey.
      There has been an intense focus to uncover the molecular mechanisms by which fasting triggers the adaptive cellular responses in the major organs of the body. Here, we show that in mice, hepatic S-adenosylmethionine (SAMe)-the principal methyl donor-acts as a metabolic sensor of nutrition to fine-tune the catabolic-fasting response by modulating phosphatidylethanolamine N-methyltransferase (PEMT) activity, endoplasmic reticulum-mitochondria contacts, β-oxidation, and ATP production in the liver, together with FGF21-mediated lipolysis and thermogenesis in adipose tissues. Notably, we show that glucagon induces the expression of the hepatic SAMe-synthesizing enzyme methionine adenosyltransferase α1 (MAT1A), which translocates to mitochondria-associated membranes. This leads to the production of this metabolite at these sites, which acts as a brake to prevent excessive β-oxidation and mitochondrial ATP synthesis and thereby endoplasmic reticulum stress and liver injury. This work provides important insights into the previously undescribed function of SAMe as a new arm of the metabolic adaptation to fasting.
    Keywords:  S-adenosylmethionine; adipose tissue; caloric restriction; endoplasmic reticulum stress; fasting; liver; methionine adenosyltransferase a1; mitochondria-associated-membranes; phosphatidylethanolamine methyltransferase; β-oxidation
    DOI:  https://doi.org/10.1016/j.cmet.2023.07.002
  32. Essays Biochem. 2023 Aug 03. pii: EBC20220241. [Epub ahead of print]
    DNA sensing in cancer: Pro-tumour and anti-tumour functions of cGAS-STING signalling.
    Otto P G Wheeler, Leonie Unterholzner.
      The DNA sensor cGAS (cyclic GMP-AMP synthase) and its adaptor protein STING (Stimulator of Interferon Genes) detect the presence of cytosolic DNA as a sign of infection or damage. In cancer cells, this pathway can be activated through persistent DNA damage and chromosomal instability, which results in the formation of micronuclei and the exposure of DNA fragments to the cytosol. DNA damage from radio- or chemotherapy can further activate DNA sensing responses, which may occur in the cancer cells themselves or in stromal and immune cells in the tumour microenvironment (TME). cGAS-STING signalling results in the production of type I interferons, which have been linked to immune cell infiltration in 'hot' tumours that are susceptible to immunosurveillance and immunotherapy approaches. However, recent research has highlighted the complex nature of STING signalling, with tumours having developed mechanisms to evade and hijack this signalling pathway for their own benefit. In this mini-review we will explore how cGAS-STING signalling in different cells in the TME can promote both anti-tumour and pro-tumour responses. This includes the role of type I interferons and the second messenger cGAMP in the TME, and the influence of STING signalling on local immune cell populations. We examine how alternative signalling cascades downstream of STING can promote chronic interferon signalling, the activation of the transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and the production of inflammatory cytokines, which can have pro-tumour functions. An in-depth understanding of DNA sensing in different cell contexts will be required to harness the anti-tumour functions of STING signalling.
    Keywords:  DNA sensing; STING; cGAS; cancer; immunology; innate immunity
    DOI:  https://doi.org/10.1042/EBC20220241
  33. Cell Rep. 2023 Aug 01. pii: S2211-1247(23)00891-4. [Epub ahead of print] 112880
    Senescent cells form nuclear foci that contain the 26S proteasome.
    Tomohiro Iriki, Hiroaki Iio, Shu Yasuda, Shun Masuta, Masakazu Kato, Hidetaka Kosako, Shoshiro Hirayama, Akinori Endo, Fumiaki Ohtake, Mako Kamiya, Yasuteru Urano, Yasushi Saeki, Jun Hamazaki, Shigeo Murata.
      The proteasome plays a central role in intracellular protein degradation. Age-dependent decline in proteasome activity is associated with cellular senescence and organismal aging; however, the mechanism by which the proteasome plays a role in senescent cells remains elusive. Here, we show that nuclear foci that contain the proteasome and exhibit liquid-like properties are formed in senescent cells. The formation of senescence-associated nuclear proteasome foci (SANPs) is dependent on ubiquitination and RAD23B, similar to previously known nuclear proteasome foci, but also requires proteasome activity. RAD23B knockdown suppresses SANP formation and increases mitochondrial activity, leading to reactive oxygen species production without affecting other senescence traits such as cell-cycle arrest and cell morphology. These findings suggest that SANPs are an important feature of senescent cells and uncover a mechanism by which the proteasome plays a role in senescent cells.
    Keywords:  CP: Cell biology; CP: Molecular biology; cell senescence; liquid-liquid phase separation; mitochondria; nuclear body; proteasome; ubiquitin
    DOI:  https://doi.org/10.1016/j.celrep.2023.112880
  34. Science. 2023 Aug 04. 381(6657): 515-524
    CXCL9:SPP1 macrophage polarity identifies a network of cellular programs that control human cancers.
    Ruben Bill, Pratyaksha Wirapati, Marius Messemaker, Whijae Roh, Beatrice Zitti, Florent Duval, Máté Kiss, Jong Chul Park, Talia M Saal, Jan Hoelzl, David Tarussio, Fabrizio Benedetti, Stéphanie Tissot, Lana Kandalaft, Marco Varrone, Giovanni Ciriello, Thomas A McKee, Yan Monnier, Maxime Mermod, Emily M Blaum, Irena Gushterova, Anna L K Gonye, Nir Hacohen, Gad Getz, Thorsten R Mempel, Allon M Klein, Ralph Weissleder, William C Faquin, Peter M Sadow, Derrick Lin, Sara I Pai, Moshe Sade-Feldman, Mikael J Pittet.
      Tumor microenvironments (TMEs) influence cancer progression but are complex and often differ between patients. Considering that microenvironment variations may reveal rules governing intratumoral cellular programs and disease outcome, we focused on tumor-to-tumor variation to examine 52 head and neck squamous cell carcinomas. We found that macrophage polarity-defined by CXCL9 and SPP1 (CS) expression but not by conventional M1 and M2 markers-had a noticeably strong prognostic association. CS macrophage polarity also identified a highly coordinated network of either pro- or antitumor variables, which involved each tumor-associated cell type and was spatially organized. We extended these findings to other cancer indications. Overall, these results suggest that, despite their complexity, TMEs coordinate coherent responses that control human cancers and for which CS macrophage polarity is a relevant yet simple variable.
    DOI:  https://doi.org/10.1126/science.ade2292
  35. Plant J. 2023 Aug 02.
    Circadian regulation of metabolism across photosynthetic organisms.
    Luíza Lane de Barros Dantas, Bethany M Eldridge, Jack Dorling, Richard Dekeya, Deirdre A Lynch, Antony N Dodd.
      Circadian regulation produces a biological measure of time within cells. The daily cycle in the availability of light for photosynthesis causes dramatic changes in biochemical processes in photosynthetic organisms, with the circadian clock having crucial roles in adaptation to these fluctuating conditions. Correct alignment between the circadian clock and environmental day-night cycles maximizes plant productivity through its regulation of metabolism. Therefore, the processes that integrate circadian regulation with metabolism are key to understanding how the circadian clock contributes to plant productivity. This forms an important part of exploiting knowledge of circadian regulation to enhance sustainable crop production. Here, we examine the roles of circadian regulation in metabolic processes in source and sink organ structures of Arabidopsis. We also evaluate possible roles for circadian regulation in root exudation processes that deposit carbon into the soil, and the nature of the rhythmic interactions between plants and their associated microbial communities. Finally, we examine shared and differing aspects of the circadian regulation of metabolism between Arabidopsis and other model photosynthetic organisms, and between circadian control of metabolism in photosynthetic and non-photosynthetic organisms. This synthesis identifies a variety of future research topics, including a focus on metabolic processes that underlie biotic interactions within ecosystems.
    Keywords:  Arabidopsis thaliana; Bacillus subtilis; Chlamydomonas reinhardtii; Ostreococcus tauri; Synechococcus elongatus PCC7942; circadian regulation; cyanobacteria; metabolism; rhizosphere; starch
    DOI:  https://doi.org/10.1111/tpj.16405
  36. Nat Genet. 2023 Jul 31.
    SF3B1 hotspot mutations confer sensitivity to PARP inhibition by eliciting a defective replication stress response.
    Philip Bland, Harry Saville, Patty T Wai, Lucinda Curnow, Gareth Muirhead, Jadwiga Nieminuszczy, Nivedita Ravindran, Marie Beatrix John, Somaieh Hedayat, Holly E Barker, James Wright, Lu Yu, Ioanna Mavrommati, Abigail Read, Barrie Peck, Mark Allen, Patrycja Gazinska, Helen N Pemberton, Aditi Gulati, Sarah Nash, Farzana Noor, Naomi Guppy, Ioannis Roxanis, Guy Pratt, Ceri Oldreive, Tatjana Stankovic, Samantha Barlow, Helen Kalirai, Sarah E Coupland, Ronan Broderick, Samar Alsafadi, Alexandre Houy, Marc-Henri Stern, Stephen Pettit, Jyoti S Choudhary, Syed Haider, Wojciech Niedzwiedz, Christopher J Lord, Rachael Natrajan.
      SF3B1 hotspot mutations are associated with a poor prognosis in several tumor types and lead to global disruption of canonical splicing. Through synthetic lethal drug screens, we identify that SF3B1 mutant (SF3B1MUT) cells are selectively sensitive to poly (ADP-ribose) polymerase inhibitors (PARPi), independent of hotspot mutation and tumor site. SF3B1MUT cells display a defective response to PARPi-induced replication stress that occurs via downregulation of the cyclin-dependent kinase 2 interacting protein (CINP), leading to increased replication fork origin firing and loss of phosphorylated CHK1 (pCHK1; S317) induction. This results in subsequent failure to resolve DNA replication intermediates and G2/M cell cycle arrest. These defects are rescued through CINP overexpression, or further targeted by a combination of ataxia-telangiectasia mutated and PARP inhibition. In vivo, PARPi produce profound antitumor effects in multiple SF3B1MUT cancer models and eliminate distant metastases. These data provide the rationale for testing the clinical efficacy of PARPi in a biomarker-driven, homologous recombination proficient, patient population.
    DOI:  https://doi.org/10.1038/s41588-023-01460-5
  37. Aging (Albany NY). 2023 Jul 28. undefined
    A novel theory of ageing independent of damage accumulation.
    James Wordsworth, Daryl Shanley.
      
    Keywords:  ageing; cell competition; damage; evolution; metabolic slowdown
    DOI:  https://doi.org/10.18632/aging.204956
  38. Nat Metab. 2023 Aug 03.
    Methionine restriction-induced sulfur deficiency impairs antitumour immunity partially through gut microbiota.
    Ming Ji, Xiaojiang Xu, Qing Xu, Yun-Chung Hsiao, Cody Martin, Svetlana Ukraintseva, Vladimir Popov, Konstantin G Arbeev, Tom A Randall, Xiaoyue Wu, Liz M Garcia-Peterson, Juan Liu, Xin Xu, M Andrea Azcarate-Peril, Yisong Wan, Anatoliy I Yashin, Karthik Anantharaman, Kun Lu, Jian-Liang Li, Igor Shats, Xiaoling Li.
      Restriction of methionine (MR), a sulfur-containing essential amino acid, has been reported to repress cancer growth and improve therapeutic responses in several preclinical settings. However, how MR impacts cancer progression in the context of the intact immune system is unknown. Here we report that while inhibiting cancer growth in immunocompromised mice, MR reduces T cell abundance, exacerbates tumour growth and impairs tumour response to immunotherapy in immunocompetent male and female mice. Mechanistically, MR reduces microbial production of hydrogen sulfide, which is critical for immune cell survival/activation. Dietary supplementation of a hydrogen sulfide donor or a precursor, or methionine, stimulates antitumour immunity and suppresses tumour progression. Our findings reveal an unexpected negative interaction between MR, sulfur deficiency and antitumour immunity and further uncover a vital role of gut microbiota in mediating this interaction. Our study suggests that any possible anticancer benefits of MR require careful consideration of both the microbiota and the immune system.
    DOI:  https://doi.org/10.1038/s42255-023-00854-3
  39. Nat Immunol. 2023 Aug 03.
    Hallmarks of CD8+ T cell dysfunction are established within hours of tumor antigen encounter before cell division.
    Michael W Rudloff, Paul Zumbo, Natalie R Favret, Jessica J Roetman, Carlos R Detrés Román, Megan M Erwin, Kristen A Murray, Sriya T Jonnakuti, Friederike Dündar, Doron Betel, Mary Philip.
      Tumor-specific CD8+ T cells (TST) in patients with cancer are dysfunctional and unable to halt cancer progression. TST dysfunction, also known as exhaustion, is thought to be driven by chronic T cell antigen receptor (TCR) stimulation over days to weeks. However, we know little about the interplay between CD8+ T cell function, cell division and epigenetic remodeling within hours of activation. Here, we assessed early CD8+ T cell differentiation, cell division, chromatin accessibility and transcription in tumor-bearing mice and acutely infected mice. Surprisingly, despite robust activation and proliferation, TST had near complete effector function impairment even before undergoing cell division and had acquired hallmark chromatin accessibility features previously associated with later dysfunction/exhaustion. Moreover, continued tumor/antigen exposure drove progressive epigenetic remodeling, 'imprinting' the dysfunctional state. Our study reveals the rapid divergence of T cell fate choice before cell division in the context of tumors versus infection.
    DOI:  https://doi.org/10.1038/s41590-023-01578-y
  40. Nat Metab. 2023 Jul 31.
    An electrogenetic interface to program mammalian gene expression by direct current.
    Jinbo Huang, Shuai Xue, Peter Buchmann, Ana Palma Teixeira, Martin Fussenegger.
      Wearable electronic devices are playing a rapidly expanding role in the acquisition of individuals' health data for personalized medical interventions; however, wearables cannot yet directly program gene-based therapies because of the lack of a direct electrogenetic interface. Here we provide the missing link by developing an electrogenetic interface that we call direct current (DC)-actuated regulation technology (DART), which enables electrode-mediated, time- and voltage-dependent transgene expression in human cells using DC from batteries. DART utilizes a DC supply to generate non-toxic levels of reactive oxygen species that act via a biosensor to reversibly fine-tune synthetic promoters. In a proof-of-concept study in a type 1 diabetic male mouse model, a once-daily transdermal stimulation of subcutaneously implanted microencapsulated engineered human cells by energized acupuncture needles (4.5 V DC for 10 s) stimulated insulin release and restored normoglycemia. We believe this technology will enable wearable electronic devices to directly program metabolic interventions.
    DOI:  https://doi.org/10.1038/s42255-023-00850-7
  41. Curr Opin Biotechnol. 2023 Jul 27. pii: S0958-1669(23)00086-1. [Epub ahead of print]83 102976
    2-hydroxyglutarate rides the cancer-immunity cycle.
    Iosifina P Foskolou, Lukas Bunse, Jan Van den Bossche.
      2-hydroxyglutarate (2HG) is a biproduct of the Krebs cycle, which exists in a D- and L- enantiomer and is structurally similar to α-ketoglutarate. Both 2HG enantiomers have been described to accumulate in diverse cancer and immune cells and can influence cell fate and function. While D-2HG was originally considered as an 'oncometabolite' that aberrantly builds up in certain cancers, it is becoming clear that it also physiologically accumulates in immune cells and regulates immune function. Conversely, L-2HG is considered as an 'immunometabolite' due to its induction and regulatory function in T cells, but it can also be induced in certain cancers. Here, the authors review the effects of both 2HG enantiomers on immune cells within the tumor microenvironment.
    DOI:  https://doi.org/10.1016/j.copbio.2023.102976
  42. Mol Cell Biol. 2023 Aug 02. 1-24
    Shared Gene Targets of the ATF4 and p53 Transcriptional Networks.
    Gabriele Baniulyte, Serene A Durham, Lauren E Merchant, Morgan A Sammons.
      The master tumor suppressor p53 regulates multiple cell fate decisions, such as cell cycle arrest and apoptosis, via transcriptional control of a broad gene network. Dysfunction in the p53 network is common in cancer, often through mutations that inactivate p53 or other members of the pathway. Induction of tumor-specific cell death by restoration of p53 activity without off-target effects has gained significant interest in the field. In this study, we explore the gene regulatory mechanisms underlying a putative anticancer strategy involving stimulation of the p53-independent integrated stress response (ISR). Our data demonstrate the p53 and ISR pathways converge to independently regulate common metabolic and proapoptotic genes. We investigated the architecture of multiple gene regulatory elements bound by p53 and the ISR effector ATF4 controlling this shared regulation. We identified additional key transcription factors that control basal and stress-induced regulation of these shared p53 and ATF4 target genes. Thus, our results provide significant new molecular and genetic insight into gene regulatory networks and transcription factors that are the target of numerous antitumor therapies.
    Keywords:  ATF4; cis-regulation; enhancers; genomics; p53; transcription; transcription factors
    DOI:  https://doi.org/10.1080/10985549.2023.2229225
This page is being maintained by Thomas Krichel. It was last updated on 2024‒11‒22 at 4:13.