bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2021‒10‒17
43 papers selected by
Christian Frezza,

  1. Autophagy and cancer metabolism-The two-way interplay.
  2. The Role of Non-essential Amino Acids in T Cell Function and Anti-tumour Immunity.
  3. p107 mediated mitochondrial function controls muscle stem cell proliferative fates.
  4. Generating stable isolated mitochondrial recipient clones in mammalian cells using MitoPunch mitochondrial transfer.
  5. Mechanisms Governing Metabolic Heterogeneity in Breast Cancer and Other Tumors.
  6. Nutrients in the fate of pluripotent stem cells.
  7. Mitochondrial translation is required for sustained killing by cytotoxic T cells.
  8. Mutant clones in normal epithelium outcompete and eliminate emerging tumours.
  9. Enhancement of O-GlcNAcylation on Mitochondrial Proteins with 2-(4-Methoxyphenyl)ethyl-2-acetamido-2-deoxy-β-d-pyranoside, Contributes to the Mitochondrial Network, Cellular Bioenergetics and Stress Response in Neuronal Cells under Ischemic-like Conditions.
  10. Metabolic remodelling during early mouse embryo development.
  11. Simulations reveal that different responses to cell crowding determine the expansion of p53 and Notch mutant clones in squamous epithelia.
  12. mTOR-dependent immunometabolism as Achilles' heel of anticancer therapy.
  13. Diminished YAP1 affects mitochondrial dynamics in IDH1 mutant glioma.
  14. An anaplerotic approach to correct the mitochondrial dysfunction in ataxia-telangiectasia (A-T).
  15. Role of the Mitochondrial Protein Import Machinery and Protein Processing in Heart Disease.
  16. Non-canonical glutamine transamination sustains efferocytosis by coupling redox buffering to oxidative phosphorylation.
  17. Hepatocyte nuclear factor-1β shapes the energetic homeostasis of kidney tubule cells.
  18. Redox Regulation in Cancer Cells during Metastasis.
  19. Signatures of plasticity, metastasis, and immunosuppression in an atlas of human small cell lung cancer.
  20. Selective targeting of MYC mRNA by stabilized antisense oligonucleotides.
  21. SLC1A5 provides glutamine and asparagine necessary for bone development in mice.
  22. Fasting-mimicking diet prevents high-fat diet effect on cardiometabolic risk and lifespan.
  23. Metabolic Messengers: tumour necrosis factor.
  24. Emerging Roles of Energy Metabolism in Ferroptosis Regulation of Tumor Cells.
  25. A leucine-derived fatty acid unlocks the mTOR to development.
  26. Exploiting cancer's drinking problem: regulation and therapeutic potential of macropinocytosis.
  27. Methylglyoxal disrupts the functionality of rat liver mitochondria.
  28. Glutamine gluttony of efferocytes.
  29. Cancer gene mutation frequencies for the U.S. population.
  30. Metabolomics atlas of oral 13C-glucose tolerance test in mice.
  31. Inhibition of Mitochondrial Metabolism Leads to Selective Eradication of Cells Adapted to Acidic Microenvironment.
  32. GLUT4-overexpressing engineered muscle constructs as a therapeutic platform to normalize glycemia in diabetic mice.
  33. Convergent somatic mutations in metabolism genes in chronic liver disease.
  34. Metabolic turnover and dynamics of modified ribonucleosides by 13C labeling.
  35. Mapping the cellular response to electron transport chain inhibitors reveals selective signaling networks triggered by mitochondrial perturbation.
  36. Tryptophan metabolism is inversely regulated in the tumor and blood of patients with glioblastoma.
  37. p53-mediated redox control promotes liver regeneration and maintains liver function in response to CCl4.
  38. Proteomics reveal cap-dependent translation inhibitors remodel the translation machinery and translatome.
  39. Enhanced vulnerability of LKB1-deficient NSCLC to disruption of ATP pools and redox homeostasis by 8-Cl-Ado.
  40. ULK1 promotes mitophagy via phosphorylation and stabilization of BNIP3.
  41. Downregulation of mitochondrial biogenesis by virus infection triggers antiviral responses by cyclic GMP-AMP synthase.
  42. The RNA N6-Methyladenosine Methyltransferase METTL3 Promotes the Progression of Kidney Cancer via N6-Methyladenosine-Dependent Translational Enhancement of ABCD1.
  43. Compensatory ion transport buffers daily protein rhythms to regulate osmotic balance and cellular physiology.
  1. IUBMB Life. 2021 Oct 15.
    Autophagy and cancer metabolism-The two-way interplay.
    Reui-Liang Yan, Ruey-Hwa Chen.
      Autophagy is an intracellular catabolic process that degrades cytoplasmic components for recycling in response to stressed conditions, such as nutrient deprivation. Dysregulation of autophagy is associated with various diseases, including cancer. Although autophagy plays dichotomous and context-dependent roles in cancer, evidence has emerged that cancer cells exploit autophagy for metabolic adaptation. Autophagy is upregulated in many cancer types through tumor cell-intrinsic proliferation demands and the hypoxic and nutrient-limited tumor microenvironment (TME). Autophagy-induced breakdown products then fuel into various metabolic pathways to supply tumor cells with energy and building blocks for biosynthesis and survival. This bidirectional regulation between autophagy and tumor constitutes a vicious cycle to potentiate tumor growth and therapy resistance. In addition, the pro-tumor functions of autophagy are expanded to host, including cells in TME and distant organs. Thus, inhibition of autophagy or autophagy-mediated metabolic reprogramming may be a promising strategy for anticancer therapy. Better understanding the metabolic rewiring mechanisms of autophagy for its pro-tumor effects will provide insights into patient treatment.
    Keywords:  anticancer therapy; autophagy; cancer; metabolism; tumor microenvironment
    DOI:  https://doi.org/10.1002/iub.2569
  2. Arch Immunol Ther Exp (Warsz). 2021 Oct 12. 69(1): 29
    The Role of Non-essential Amino Acids in T Cell Function and Anti-tumour Immunity.
    Helen Carrasco Hope, Robert J Salmond.
      T cell activation, differentiation and proliferation is dependent upon and intrinsically linked to a capacity to modulate and adapt cellular metabolism. Antigen-induced activation stimulates a transcriptional programme that results in metabolic reprogramming, enabling T cells to fuel anabolic metabolic pathways and provide the nutrients to sustain proliferation and effector responses. Amino acids are key nutrients for T cells and have essential roles as building blocks for protein synthesis as well as in numerous metabolic pathways. In this review, we discuss the roles for uptake and biosynthesis of non-essential amino acids in T cell metabolism, activation and effector function. Furthermore, we highlight the effects of amino acid metabolism and depletion by cancer cells on T cell anti-tumour function and discuss approaches to modulate and improve T cell metabolism for improved anti-tumour function in these nutrient-depleted microenvironments.
    Keywords:  Immunotherapy; Metabolism; Non-essential amino acid; T cell; Tumour microenvironment
    DOI:  https://doi.org/10.1007/s00005-021-00633-6
  3. Nat Commun. 2021 Oct 13. 12(1): 5977
    p107 mediated mitochondrial function controls muscle stem cell proliferative fates.
    Debasmita Bhattacharya, Vicky Shah, Oreoluwa Oresajo, Anthony Scimè.
      Muscle diseases and aging are associated with impaired myogenic stem cell self-renewal and fewer proliferating progenitors (MPs). Importantly, distinct metabolic states induced by glycolysis or oxidative phosphorylation have been connected to MP proliferation and differentiation. However, how these energy-provisioning mechanisms cooperate remain obscure. Herein, we describe a mechanism by which mitochondrial-localized transcriptional co-repressor p107 regulates MP proliferation. We show p107 directly interacts with the mitochondrial DNA, repressing mitochondrial-encoded gene transcription. This reduces ATP production by limiting electron transport chain complex formation. ATP output, controlled by the mitochondrial function of p107, is directly associated with the cell cycle rate. Sirt1 activity, dependent on the cytoplasmic glycolysis product NAD+, directly interacts with p107, impeding its mitochondrial localization. The metabolic control of MP proliferation, driven by p107 mitochondrial function, establishes a cell cycle paradigm that might extend to other dividing cell types.
    DOI:  https://doi.org/10.1038/s41467-021-26176-0
  4. STAR Protoc. 2021 Dec 17. 2(4): 100850
    Generating stable isolated mitochondrial recipient clones in mammalian cells using MitoPunch mitochondrial transfer.
    Alexander J Sercel, Alexander J Napior, Alexander N Patananan, Ting-Hsiang Wu, Pei-Yu Chiou, Michael A Teitell.
      This protocol describes the assembly and use of MitoPunch to deliver mitochondria containing mitochondrial DNA (mtDNA) into cells lacking mtDNA (ρ0 cells). MitoPunch generates stable isolated mitochondrial recipient clones with restored mtDNA and recovered respiration, enabling investigation of mtDNA mutations and mtDNA-nuclear DNA interactions in a range of cell types. For complete details on the use and execution of this protocol, please refer to Sercel et al. (2021) and Patananan et al. (2020).
    Keywords:  Biotechnology and bioengineering; Cell Biology; Cell culture; Cell-based Assays; Metabolism
    DOI:  https://doi.org/10.1016/j.xpro.2021.100850
  5. Front Oncol. 2021 ;11 700629
    Mechanisms Governing Metabolic Heterogeneity in Breast Cancer and Other Tumors.
    Sayani Patra, Naveed Elahi, Aaron Armorer, Swathi Arunachalam, Joshua Omala, Iman Hamid, Anthony W Ashton, David Joyce, Xuanmao Jiao, Richard G Pestell.
      Reprogramming of metabolic priorities promotes tumor progression. Our understanding of the Warburg effect, based on studies of cultured cancer cells, has evolved to a more complex understanding of tumor metabolism within an ecosystem that provides and catabolizes diverse nutrients provided by the local tumor microenvironment. Recent studies have illustrated that heterogeneous metabolic changes occur at the level of tumor type, tumor subtype, within the tumor itself, and within the tumor microenvironment. Thus, altered metabolism occurs in cancer cells and in the tumor microenvironment (fibroblasts, immune cells and fat cells). Herein we describe how these growth advantages are obtained through either "convergent" genetic changes, in which common metabolic properties are induced as a final common pathway induced by diverse oncogene factors, or "divergent" genetic changes, in which distinct factors lead to subtype-selective phenotypes and thereby tumor heterogeneity. Metabolic heterogeneity allows subtyping of cancers and further metabolic heterogeneity occurs within the same tumor mass thought of as "microenvironmental metabolic nesting". Furthermore, recent findings show that mutations of metabolic genes arise in the majority of tumors providing an opportunity for the development of more robust metabolic models of an individual patient's tumor. The focus of this review is on the mechanisms governing this metabolic heterogeneity in breast cancer.
    Keywords:  Cyclin D1; PPAR-γ; Warburg effect; aerobic glycolysis; breast cancer; epigenetics; metabolism; reverse Warburg effect
    DOI:  https://doi.org/10.3389/fonc.2021.700629
  6. Cell Metab. 2021 Oct 06. pii: S1550-4131(21)00432-0. [Epub ahead of print]
    Nutrients in the fate of pluripotent stem cells.
    Vivian Lu, Irena J Roy, Michael A Teitell.
      Pluripotent stem cells model certain features of early mammalian development ex vivo. Medium-supplied nutrients can influence self-renewal, lineage specification, and earliest differentiation of pluripotent stem cells. However, which specific nutrients support these distinct outcomes, and their mechanisms of action, remain under active investigation. Here, we evaluate the available data on nutrients and their metabolic conversion that influence pluripotent stem cell fates. We also discuss key questions open for investigation in this rapidly expanding area of increasing fundamental and practical importance.
    Keywords:  development; differentiation; fate; metabolism; nutrients; pluripotent stem cell
    DOI:  https://doi.org/10.1016/j.cmet.2021.09.013
  7. Science. 2021 Oct 15. 374(6565): eabe9977
    Mitochondrial translation is required for sustained killing by cytotoxic T cells.
    Miriam Lisci, Philippa R Barton, Lyra O Randzavola, Claire Y Ma, Julia M Marchingo, Doreen A Cantrell, Vincent Paupe, Julien Prudent, Jane C Stinchcombe, Gillian M Griffiths.
      [Figure: see text].
    DOI:  https://doi.org/10.1126/science.abe9977
  8. Nature. 2021 Oct 13.
    Mutant clones in normal epithelium outcompete and eliminate emerging tumours.
    B Colom, A Herms, M W J Hall, S C Dentro, C King, R K Sood, M P Alcolea, G Piedrafita, D Fernandez-Antoran, S H Ong, J C Fowler, K T Mahbubani, K Saeb-Parsy, M Gerstung, B A Hall, P H Jones.
      Human epithelial tissues accumulate cancer-driver mutations with age1-9, yet tumour formation remains rare. The positive selection of these mutations suggests that they alter the behaviour and fitness of proliferating cells10-12. Thus, normal adult tissues become a patchwork of mutant clones competing for space and survival, with the fittest clones expanding by eliminating their less competitive neighbours11-14. However, little is known about how such dynamic competition in normal epithelia influences early tumorigenesis. Here we show that the majority of newly formed oesophageal tumours are eliminated through competition with mutant clones in the adjacent normal epithelium. We followed the fate of nascent, microscopic, pre-malignant tumours in a mouse model of oesophageal carcinogenesis and found that most were rapidly lost with no indication of tumour cell death, decreased proliferation or an anti-tumour immune response. However, deep sequencing of ten-day-old and one-year-old tumours showed evidence of selection on the surviving neoplasms. Induction of highly competitive clones in transgenic mice increased early tumour removal, whereas pharmacological inhibition of clonal competition reduced tumour loss. These results support a model in which survival of early neoplasms depends on their competitive fitness relative to that of mutant clones in the surrounding normal tissue. Mutant clones in normal epithelium have an unexpected anti-tumorigenic role in purging early tumours through cell competition, thereby preserving tissue integrity.
    DOI:  https://doi.org/10.1038/s41586-021-03965-7
  9. Molecules. 2021 Sep 28. pii: 5883. [Epub ahead of print]26(19):
    Enhancement of O-GlcNAcylation on Mitochondrial Proteins with 2-(4-Methoxyphenyl)ethyl-2-acetamido-2-deoxy-β-d-pyranoside, Contributes to the Mitochondrial Network, Cellular Bioenergetics and Stress Response in Neuronal Cells under Ischemic-like Conditions.
    Hui Xu, Mingzhi Du, Yuntian Shen, Yumin Yang, Fei Ding, Shu Yu.
      O-GlcNAcylation is a nutrient-driven post-translational modification known as a metabolic sensor that links metabolism to cellular function. Recent evidences indicate that the activation of O-GlcNAc pathway is a potential pro-survival pathway and that acute enhancement of this response is conducive to the survival of cells and tissues. 2-(4-Methoxyphenyl)ethyl-2-acetamido-2-deoxy-β-d-pyranoside (SalA-4g), is a salidroside analogue synthesized in our laboratory by chemical structure-modification, with a phenyl ring containing a para-methoxy group and a sugar ring consisting of N-acetylglucosamine. We have previously shown that SalA-4g elevates levels of protein O-GlcNAc and improves neuronal tolerance to ischemia. However, the specific target of SalA-4g regulating O-GlcNAcylation remains unknown. To address these questions, in this study, we have focused on mitochondrial network homeostasis mediated by O-GlcNAcylation in SalA-4g's neuroprotection in primary cortical neurons under ischemic-like conditions. O-GlcNAc-modified mitochondria induced by SalA-4g demonstrated stronger neuroprotection under oxygen glucose deprivation and reoxygenation stress, including the improvement of mitochondrial homeostasis and bioenergy, and inhibition of mitochondrial apoptosis pathway. Blocking mitochondrial protein O-GlcNAcylation with OSMI-1 disrupted mitochondrial network homeostasis and antagonized the protective effects of SalA-4g. Collectively, these data demonstrate that mitochondrial homeostasis mediated by mitochondrial protein O-GlcNAcylation is critically involved in SalA-4g neuroprotection.
    Keywords:  2-(4-methoxyphenyl)ethyl-2-acetamido-2-deoxy-b-d-pyranoside; O-GlcNAcylation; cellular bioenergetics; mitochondrial homeostasis; neuroprotection; oxygen glucose deprivation/reoxygenation stress
    DOI:  https://doi.org/10.3390/molecules26195883
  10. Nat Metab. 2021 Oct 14.
    Metabolic remodelling during early mouse embryo development.
    Jing Zhao, Ke Yao, Hua Yu, Ling Zhang, Yuyan Xu, Lang Chen, Zhen Sun, Yuqing Zhu, Cheng Zhang, Yuli Qian, Shuyan Ji, Hongru Pan, Min Zhang, Jie Chen, Cristina Correia, Taylor Weiskittel, Da-Wei Lin, Yuzheng Zhao, Sriram Chandrasekaran, Xudong Fu, Dan Zhang, Heng-Yu Fan, Wei Xie, Hu Li, Zeping Hu, Jin Zhang.
      During early mammalian embryogenesis, changes in cell growth and proliferation depend on strict genetic and metabolic instructions. However, our understanding of metabolic reprogramming and its influence on epigenetic regulation in early embryo development remains elusive. Here we show a comprehensive metabolomics profiling of key stages in mouse early development and the two-cell and blastocyst embryos, and we reconstructed the metabolic landscape through the transition from totipotency to pluripotency. Our integrated metabolomics and transcriptomics analysis shows that while two-cell embryos favour methionine, polyamine and glutathione metabolism and stay in a more reductive state, blastocyst embryos have higher metabolites related to the mitochondrial tricarboxylic acid cycle, and present a more oxidative state. Moreover, we identify a reciprocal relationship between α-ketoglutarate (α-KG) and the competitive inhibitor of α-KG-dependent dioxygenases, L-2-hydroxyglutarate (L-2-HG), where two-cell embryos inherited from oocytes and one-cell zygotes display higher L-2-HG, whereas blastocysts show higher α-KG. Lastly, increasing 2-HG availability impedes erasure of global histone methylation markers after fertilization. Together, our data demonstrate dynamic and interconnected metabolic, transcriptional and epigenetic network remodelling during early mouse embryo development.
    DOI:  https://doi.org/10.1038/s42255-021-00464-x
  11. J R Soc Interface. 2021 Oct;18(183): 20210607
    Simulations reveal that different responses to cell crowding determine the expansion of p53 and Notch mutant clones in squamous epithelia.
    Vasiliki Kostiou, Michael W J Hall, Philip H Jones, Benjamin A Hall.
      During ageing, normal epithelial tissues progressively accumulate clones carrying mutations that increase mutant cell fitness above that of wild-type cells. Such mutants spread widely through the tissues, yet despite this cellular homeostasis and functional integrity of the epithelia are maintained. Two of the genes most commonly mutated in human skin and oesophagus are p53 and Notch1, both of which are also recurrently mutated in cancers of these tissues. From observations taken in human and mouse epithelia, we find that clones carrying p53 and Notch pathway mutations have different clone dynamics which can be explained by their different responses to local cell crowding. p53 mutant clone growth in mouse epidermis approximates a logistic curve, but feedbacks responding to local crowding are required to maintain tissue homeostasis. We go on to show that the observed ability of Notch pathway mutant cells to displace the wild-type population in the mouse oesophageal epithelium reflects a local density feedback that affects both mutant and wild-type cells equally. We then show how these distinct feedbacks are consistent with the distribution of mutations observed in human datasets and are suggestive of a putative mechanism to constrain these cancer-associated mutants.
    Keywords:  cell competition; clonal evolution; epithelial dynamics; somatic mutation; spatial modelling
    DOI:  https://doi.org/10.1098/rsif.2021.0607
  12. Eur J Immunol. 2021 Oct 14.
    mTOR-dependent immunometabolism as Achilles' heel of anticancer therapy.
    Clarissa Braun, Thomas Weichhart.
      Immune cells are important constituents of the tumor microenvironment and essential in eradicating tumor cells during conventional therapies or novel immunotherapies. The mechanistic target of rapamycin (mTOR) signaling pathway senses the intra- and extracellular nutrient status, growth factor supply and cell stress-related changes to coordinate cellular metabolism and activation dictating effector and memory functions in mainly all hematopoietic immune cells. In addition, the mTOR complex 1 (mTORC1) and mTORC2 are frequently deregulated and become activated in cancer cells to drive cell transformation, survival, neovascularization, and invasion. In this review we provide an overview of the influence of mTOR complexes on immune and cancer cell function and metabolism. We discuss how mTOR inhibitors aiming to target cancer cells will influence immunometabolic cell functions participating either in anti-tumor responses or favoring tumor cell progression in individual immune cells. We suggest immunometabolism as the weak spot of anticancer therapy and propose to evaluate patients according to their predominant immune cell subtype in the cancer tissue. Advances in metabolic drug development that hold promise for more effective treatments in different types of cancer will have to consider their effects on the immune system. This article is protected by copyright. All rights reserved.
    Keywords:  Immunometabolism; cancer treatment; immunotherapy; mTORC1; tumor microenvironment
    DOI:  https://doi.org/10.1002/eji.202149270
  13. J Cell Sci. 2021 Oct 15. pii: jcs.259188. [Epub ahead of print]
    Diminished YAP1 affects mitochondrial dynamics in IDH1 mutant glioma.
    Shruti Patrick, Pruthvi Gowda, Kirti Lathoria, Vaishali Suri, Ellora Sen.
      Mutation in isocitrate dehydrogenase 1 (IDH1) gene, leading to the production of oncometabolite D-2-hydroxyglutarate (2-HG) from α-ketoglutarate, is associated with better prognosis in glioma. As Yes-associated protein 1 (YAP1) is an important regulator of tumor progression, its role in glioma expressing IDH1 R132H mutation was investigated. Diminished nuclear YAP1 in IDH1 mutant patient gliomas and cell lines was accompanied by decreased TFAM levels. Luciferase reporter assays and chromatin immunoprecipitation indicated the functionality of TEAD2 site on TFAM promoter in mediating its YAP1-dependent expression. YAP1-dependent mitochondrial fragmentation and ROS generation was accompanied by decreased TERT levels and increased mitochondrial TERT localization in IDH1 R132H cells. Treatment with Bosutinib that prevents extranuclear TERT shuttle, further elevated ROS in IDH1 R132H cells and triggered apoptosis. Importantly, Bosutinib elevated ROS levels and induced apoptosis in IDH1 WT cells upon concurrent depletion of YAP1. These findings highlight the involvement of YAP1 in coupling mitochondrial dysfunction with TERT mitochondrial shuttle to constitute an essential non-canonical function of YAP1 in regulating redox homeostasis.
    Keywords:  Glioma; IDH1; Mitochondria; TERT; TFAM; YAP1
    DOI:  https://doi.org/10.1242/jcs.259188
  14. Mol Metab. 2021 Oct 09. pii: S2212-8778(21)00201-5. [Epub ahead of print] 101354
    An anaplerotic approach to correct the mitochondrial dysfunction in ataxia-telangiectasia (A-T).
    A J Yeo, G N Subramanian, K L Chong, M Gatei, R G Parton, D Coman, M F Lavin.
      OBJECTIVE: ATM, the protein defective in the human genetic disorder, ataxia telangiectasia (A-T) plays a central role in the response to DNA double strand breaks (DSBs) and in protecting the cell against oxidative stress. We recently showed that A-T cells are hypersensitive to metabolic stress which can be accounted for by a failure to exhibit efficient endoplasmic reticulum (ER)-mitochondrial signalling and Ca2+ transfer in response to nutrient deprivation resulting in mitochondrial dysfunction. The objective of the current study is to use an anaplerotic approach using the fatty acid, heptanoate (C7), a metabolic product of the triglyceride, triheptanoin to correct the defect in ER-mitochondrial signalling and enhance cell survival of A-T cells in response to metabolic stress.METHODS: We treated control cells and A-T cells with the anaplerotic agent, heptanoate to determine their sensitivity to metabolic stress induced by inhibition of glycolysis with 2 deoxyglucose (2DG) using live-cell imaging to monitor cell survival for 72 hours using the Incucyte system. We examined ER-mitochondrial signalling in A-T cells exposed to metabolic stress using a suite of techniques including immunofluorescence staining of Grp75, ER-mitochondrial Ca2+ channel, the VAPB-PTPIP51 ER-mitochondrial tether complexes as well as proximity ligation assays between Grp75-IP3R1 and VAPB1-PTPIP51 to establish a functional interaction between ER and mitochondria. Finally, we also performed metabolomic analysis using LC-MS/MS to determine altered levels of TCA intermediates A-T cells compared to healthy control cells.
    RESULTS: We demonstrate here that heptanoate corrects all aspects of the defective ER-mitochondrial signalling observed in A-T cells. Heptanoate enhances ER-mitochondrial contacts; increases the flow of calcium from the ER to the mitochondrion; restores normal mitochondrial function and mitophagy and increases resistance of ATM-deficient cells and cells from A-T patients to metabolic stress-induced killing. The defect in mitochondrial function in ATM-deficient cells was accompanied by more reliance on aerobic glycolysis as shown by increased lactate dehydrogenase A (LDHA), accumulation of lactate and reduced levels of both acetyl CoA and ATP which are all restored by heptanoate.
    CONCLUSIONS: These data together show that heptanoate corrects metabolic stress in A-T cells by restoring ER-mitochondria signalling and mitochondrial function and suggest that the parent compound, triheptanoin, has great potential as a novel therapeutic agent for patients with A-T.
    Keywords:  ATM; Ataxia-telangiectasia; endoplasmic reticulum; heptanoate (C7); mitochondrial dysfunction; mitochondrial interaction; nutrient deprivation
    DOI:  https://doi.org/10.1016/j.molmet.2021.101354
  15. Front Cardiovasc Med. 2021 ;8 749756
    Role of the Mitochondrial Protein Import Machinery and Protein Processing in Heart Disease.
    Fujie Zhao, Ming-Hui Zou.
      Mitochondria are essential organelles for cellular energy production, metabolic homeostasis, calcium homeostasis, cell proliferation, and apoptosis. About 99% of mammalian mitochondrial proteins are encoded by the nuclear genome, synthesized as precursors in the cytosol, and imported into mitochondria by mitochondrial protein import machinery. Mitochondrial protein import systems function not only as independent units for protein translocation, but also are deeply integrated into a functional network of mitochondrial bioenergetics, protein quality control, mitochondrial dynamics and morphology, and interaction with other organelles. Mitochondrial protein import deficiency is linked to various diseases, including cardiovascular disease. In this review, we describe an emerging class of protein or genetic variations of components of the mitochondrial import machinery involved in heart disease. The major protein import pathways, including the presequence pathway (TIM23 pathway), the carrier pathway (TIM22 pathway), and the mitochondrial intermembrane space import and assembly machinery, related translocases, proteinases, and chaperones, are discussed here. This review highlights the importance of mitochondrial import machinery in heart disease, which deserves considerable attention, and further studies are urgently needed. Ultimately, this knowledge may be critical for the development of therapeutic strategies in heart disease.
    Keywords:  CHCHD4 (MIA40); TIM22 complex; TIM23 complex; TOM complex; heart disease; mitochondrial protein import machinery
    DOI:  https://doi.org/10.3389/fcvm.2021.749756
  16. Nat Metab. 2021 Oct 14.
    Non-canonical glutamine transamination sustains efferocytosis by coupling redox buffering to oxidative phosphorylation.
    Johanna Merlin, Stoyan Ivanov, Adélie Dumont, Alexey Sergushichev, Julie Gall, Marion Stunault, Marion Ayrault, Nathalie Vaillant, Alexia Castiglione, Amanda Swain, Francois Orange, Alexandre Gallerand, Thierry Berton, Jean-Charles Martin, Stefania Carobbio, Justine Masson, Inna Gaisler-Salomon, Pierre Maechler, Stephen Rayport, Judith C Sluimer, Erik A L Biessen, Rodolphe R Guinamard, Emmanuel L Gautier, Edward B Thorp, Maxim N Artyomov, Laurent Yvan-Charvet.
      Macrophages rely on tightly integrated metabolic rewiring to clear dying neighboring cells by efferocytosis during homeostasis and disease. Here we reveal that glutaminase-1-mediated glutaminolysis is critical to promote apoptotic cell clearance by macrophages during homeostasis in mice. In addition, impaired macrophage glutaminolysis exacerbates atherosclerosis, a condition during which, efficient apoptotic cell debris clearance is critical to limit disease progression. Glutaminase-1 expression strongly correlates with atherosclerotic plaque necrosis in patients with cardiovascular diseases. High-throughput transcriptional and metabolic profiling reveals that macrophage efferocytic capacity relies on a non-canonical transaminase pathway, independent from the traditional requirement of glutamate dehydrogenase to fuel ɑ-ketoglutarate-dependent immunometabolism. This pathway is necessary to meet the unique requirements of efferocytosis for cellular detoxification and high-energy cytoskeletal rearrangements. Thus, we uncover a role for non-canonical glutamine metabolism for efficient clearance of dying cells and maintenance of tissue homeostasis during health and disease in mouse and humans.
    DOI:  https://doi.org/10.1038/s42255-021-00471-y
  17. FASEB J. 2021 Nov;35(11): e21931
    Hepatocyte nuclear factor-1β shapes the energetic homeostasis of kidney tubule cells.
    Alexis Piedrafita, Stéphane Balayssac, Audrey Casemayou, Jean-Sébastien Saulnier-Blache, Alexandre Lucas, Jason S Iacovoni, Benjamin Breuil, Dominique Chauveau, Stéphane Decramer, Myriam Malet-Martino, Joost P Schanstra, Stanislas Faguer.
      Energetic metabolism controls key steps of kidney development, homeostasis, and epithelial repair following acute kidney injury (AKI). Hepatocyte nuclear factor-1β (HNF-1β) is a master transcription factor that controls mitochondrial function in proximal tubule (PT) cells. Patients with HNF1B pathogenic variant display a wide range of kidney developmental abnormalities and progressive kidney fibrosis. Characterizing the metabolic changes in PT cells with HNF-1β deficiency may help to identify new targetable molecular hubs involved in HNF1B-related kidney phenotypes and AKI. Here, we combined 1 H-NMR-based metabolomic analysis in a murine PT cell line with CrispR/Cas9-induced Hnf1b invalidation (Hnf1b-/- ), clustering analysis, targeted metabolic assays, and datamining of published RNA-seq and ChIP-seq dataset to identify the role of HNF-1β in metabolism. Hnf1b-/- cells grown in normoxic conditions display intracellular ATP depletion, increased cytosolic lactate concentration, increased lipid droplet content, failure to use pyruvate for energetic purposes, increased levels of tricarboxylic acid (TCA) cycle intermediates and oxidized glutathione, and a reduction of TCA cycle byproducts, all features consistent with mitochondrial dysfunction and an irreversible switch toward glycolysis. Unsupervised clustering analysis showed that Hnf1b-/- cells mimic a hypoxic signature and that they cannot furthermore increase glycolysis-dependent energetic supply during hypoxic challenge. Metabolome analysis also showed alteration of phospholipid biosynthesis in Hnf1b-/- cells leading to the identification of Chka, the gene coding for choline kinase α, as a new putative target of HNF-1β. HNF-1β shapes the energetic metabolism of PT cells and HNF1B deficiency in patients could lead to a hypoxia-like metabolic state precluding further adaptation to ATP depletion following AKI.
    Keywords:  HNF-1β; hypoxia; kidney tubule; metabolism
    DOI:  https://doi.org/10.1096/fj.202100782RR
  18. Cancer Discov. 2021 Oct 14.
    Redox Regulation in Cancer Cells during Metastasis.
    Alpaslan Tasdogan, Jessalyn M Ubellacker, Sean J Morrison.
      Metastasis is an inefficient process in which the vast majority of cancer cells are fated to die, partly because they experience oxidative stress. Metastasizing cancer cells migrate through diverse environments that differ dramatically from their tumor of origin, leading to redox imbalances. The rare metastasizing cells that survive undergo reversible metabolic changes that confer oxidative stress resistance. We review the changes in redox regulation that cancer cells undergo during metastasis. By better understanding these mechanisms, it may be possible to develop pro-oxidant therapies that block disease progression by exacerbating oxidative stress in cancer cells. SIGNIFICANCE: Oxidative stress often limits cancer cell survival during metastasis, raising the possibility of inhibiting cancer progression with pro-oxidant therapies. This is the opposite strategy of treating patients with antioxidants, an approach that worsened outcomes in large clinical trials.
    DOI:  https://doi.org/10.1158/2159-8290.CD-21-0558
  19. Cancer Cell. 2021 Oct 12. pii: S1535-6108(21)00497-9. [Epub ahead of print]
    Signatures of plasticity, metastasis, and immunosuppression in an atlas of human small cell lung cancer.
    Joseph M Chan, Álvaro Quintanal-Villalonga, Vianne Ran Gao, Yubin Xie, Viola Allaj, Ojasvi Chaudhary, Ignas Masilionis, Jacklynn Egger, Andrew Chow, Thomas Walle, Marissa Mattar, Dig V K Yarlagadda, James L Wang, Fathema Uddin, Michael Offin, Metamia Ciampricotti, Besnik Qeriqi, Amber Bahr, Elisa de Stanchina, Umesh K Bhanot, W Victoria Lai, Matthew J Bott, David R Jones, Arvin Ruiz, Marina K Baine, Yanyun Li, Natasha Rekhtman, John T Poirier, Tal Nawy, Triparna Sen, Linas Mazutis, Travis J Hollmann, Dana Pe'er, Charles M Rudin.
      Small cell lung cancer (SCLC) is an aggressive malignancy that includes subtypes defined by differential expression of ASCL1, NEUROD1, and POU2F3 (SCLC-A, -N, and -P, respectively). To define the heterogeneity of tumors and their associated microenvironments across subtypes, we sequenced 155,098 transcriptomes from 21 human biospecimens, including 54,523 SCLC transcriptomes. We observe greater tumor diversity in SCLC than lung adenocarcinoma, driven by canonical, intermediate, and admixed subtypes. We discover a PLCG2-high SCLC phenotype with stem-like, pro-metastatic features that recurs across subtypes and predicts worse overall survival. SCLC exhibits greater immune sequestration and less immune infiltration than lung adenocarcinoma, and SCLC-N shows less immune infiltrate and greater T cell dysfunction than SCLC-A. We identify a profibrotic, immunosuppressive monocyte/macrophage population in SCLC tumors that is particularly associated with the recurrent, PLCG2-high subpopulation.
    Keywords:  PLCG2; SCLC; metastasis; myeloid; scRNA-seq; single cell; tumor atlas
    DOI:  https://doi.org/10.1016/j.ccell.2021.09.008
  20. Oncogene. 2021 Oct 14.
    Selective targeting of MYC mRNA by stabilized antisense oligonucleotides.
    Taylor Gill, Haichuan Wang, Raj Bandaru, Matthew Lawlor, Chenyue Lu, Linda T Nieman, Junyan Tao, Yixian Zhang, Daniel G Anderson, David T Ting, Xin Chen, James E Bradner, Christopher J Ott.
      MYC is a prolific proto-oncogene driving the malignant behaviors of numerous common cancers, yet potent and selective cell-permeable inhibitors of MYC remain elusive. In order to ultimately realize the goal of therapeutic MYC inhibition in cancer, we have initiated discovery chemistry efforts aimed at inhibiting MYC translation. Here we describe a series of conformationally stabilized synthetic antisense oligonucleotides designed to target MYC mRNA (MYCASOs). To support bioactivity, we designed and synthesized this focused library of MYCASOs incorporating locked nucleic acid (LNA) bases at the 5'- and 3'-ends, a phosphorothioate backbone, and internal DNA bases. Treatment of MYC-expressing cancer cells with MYCASOs leads to a potent decrease in MYC mRNA and protein levels. Cleaved MYC mRNA in MYCASO-treated cells is detected with a sensitive 5' Rapid Amplification of cDNA Ends (RACE) assay. MYCASO treatment of cancer cell lines leads to significant inhibition of cellular proliferation while specifically perturbing MYC-driven gene expression signatures. In a MYC-induced model of hepatocellular carcinoma, MYCASO treatment decreases MYC protein levels within tumors, decreases tumor burden, and improves overall survival. MYCASOs represent a new chemical tool for in vitro and in vivo modulation of MYC activity, and promising therapeutic agents for MYC-addicted tumors.
    DOI:  https://doi.org/10.1038/s41388-021-02053-4
  21. Elife. 2021 Oct 14. pii: e71595. [Epub ahead of print]10
    SLC1A5 provides glutamine and asparagine necessary for bone development in mice.
    Deepika Sharma, Yilin Yu, Leyao Shen, Guo-Fang Zhang, Courtney M Karner.
      Osteoblast differentiation is sequentially characterized by high rates of proliferation followed by increased protein and matrix synthesis, processes that require substantial amino acid acquisition and production. How osteoblasts obtain or maintain intracellular amino acid production is poorly understood. Here we identify SLC1A5 as a critical amino acid transporter during bone development. Using a genetic and metabolomic approach, we show SLC1A5 acts cell autonomously to regulate protein synthesis and osteoblast differentiation. SLC1A5 provides both glutamine and asparagine which are essential for osteoblast differentiation. Mechanistically, glutamine and to a lesser extent asparagine support amino acid biosynthesis. Thus, osteoblasts depend on Slc1a5 to provide glutamine and asparagine, which are subsequently used to produce non-essential amino acids and support osteoblast differentiation and bone development.
    Keywords:  cell biology; developmental biology; mouse
    DOI:  https://doi.org/10.7554/eLife.71595
  22. Nat Metab. 2021 Oct 14.
    Fasting-mimicking diet prevents high-fat diet effect on cardiometabolic risk and lifespan.
    Amrendra Mishra, Hamed Mirzaei, Novella Guidi, Manlio Vinciguerra, Alice Mouton, Marina Linardic, Francesca Rappa, Rosario Barone, Gerardo Navarrete, Min Wei, Sebastian Brandhorst, Stefano Di Biase, Todd E Morgan, S Ram Kumar, Peter S Conti, Matteo Pellegrini, Michel Bernier, Rafael de Cabo, Valter D Longo.
      Diet-induced obesity is a major risk factor for metabolic syndrome, diabetes and cardiovascular disease. Here, we show that a 5-d fasting-mimicking diet (FMD), administered every 4 weeks for a period of 2 years, ameliorates the detrimental changes caused by consumption of a high-fat, high-calorie diet (HFCD) in female mice. We demonstrate that monthly FMD cycles inhibit HFCD-mediated obesity by reducing the accumulation of visceral and subcutaneous fat without causing loss of lean body mass. FMD cycles increase cardiac vascularity and function and resistance to cardiotoxins, prevent HFCD-dependent hyperglycaemia, hypercholesterolaemia and hyperleptinaemia and ameliorate impaired glucose and insulin tolerance. The effect of monthly FMD cycles on gene expression associated with mitochondrial metabolism and biogenesis in adipocytes and the sustained ketogenesis in HFCD-fed mice indicate a role for fat cell reprogramming in obesity prevention. These effects of an FMD on adiposity and cardiac ageing could explain the protection from HFCD-dependent early mortality.
    DOI:  https://doi.org/10.1038/s42255-021-00469-6
  23. Nat Metab. 2021 Oct 14.
    Metabolic Messengers: tumour necrosis factor.
    Jaswinder K Sethi, Gökhan S Hotamisligil.
      Tumour necrosis factor (TNF) is a classical, pleiotropic pro-inflammatory cytokine. It is also the first 'adipokine' described to be produced from adipose tissue, regulated in obesity and proposed to contribute to obesity-associated metabolic disease. In this review, we provide an overview of TNF in the context of metabolic inflammation or metaflammation, its discovery as a metabolic messenger, its sites and mechanisms of action and some critical considerations for future research. Although we focus on TNF and the studies that elucidated its immunometabolic actions, we highlight a conceptual framework, generated by these studies, that is equally applicable to the complex network of pro-inflammatory signals, their biological activity and their integration with metabolic regulation, and to the field of immunometabolism more broadly.
    DOI:  https://doi.org/10.1038/s42255-021-00470-z
  24. Adv Sci (Weinh). 2021 Oct 10. e2100997
    Emerging Roles of Energy Metabolism in Ferroptosis Regulation of Tumor Cells.
    Xuemei Yao, Wei Li, De Fang, Chuyu Xiao, Xiao Wu, Menghuan Li, Zhong Luo.
      Ferroptosis is a new form of regulated cell death, which is characterized by the iron-dependent accumulation of lethal lipid peroxides and involved in many critical diseases. Recent reports revealed that cellular energy metabolism activities such as glycolysis, pentose phosphate pathway (PPP), and tricarboxylic acid cycle are involved in the regulation of key ferroptosis markers such as reduced nicotinamide adenine dinucleotide phosphate (NADPH), glutathione (GSH), and reactive oxygen species (ROS), therefore imposing potential regulatory roles in ferroptosis. Remarkably, tumor cells can activate adaptive metabolic responses to inhibit ferroptosis for self-preservation such as the upregulation of glycolysis and PPP. Due to the rapid proliferation of tumor cells and the intensified metabolic rate, tumor energy metabolism has become a target for disrupting the redox homeostasis and induce ferroptosis. Based on these emerging insights, regulatory impact of those-tumor specific metabolic aberrations is systematically characterized, such as rewired glucose metabolism and metabolic compensation through glutamine utilization on ferroptosis and analyzed the underlying molecular mechanisms. Additionally, those ferroptosis-based therapeutic strategies are also discussed by exploiting those metabolic vulnerabilities, which may open up new avenues for tumor treatment in a clinical context.
    Keywords:  cellular energy metabolism; ferroptosis; glucose; glutamine
    DOI:  https://doi.org/10.1002/advs.202100997
  25. Dev Cell. 2021 Oct 11. pii: S1534-5807(21)00735-8. [Epub ahead of print]56(19): 2681-2682
    A leucine-derived fatty acid unlocks the mTOR to development.
    Chung-Yang Yeh, Dudley W Lamming.
      Understanding how nutrient-sensitive signaling pathways regulate development and aging is an active area of research. In this issue of Developmental Cell,Zhu and colleagues (2021) identify a specific monomethylated branched-chain fatty acid that overrides nutrient deprivation signaling and activates mTORC1 in C. elegans and mammalian cells.
    DOI:  https://doi.org/10.1016/j.devcel.2021.09.017
  26. Trends Cancer. 2021 Oct 11. pii: S2405-8033(21)00194-1. [Epub ahead of print]
    Exploiting cancer's drinking problem: regulation and therapeutic potential of macropinocytosis.
    Joseph Puccini, Michael Alexander Badgley, Dafna Bar-Sagi.
      Macropinocytosis, an evolutionarily conserved endocytic mechanism that mediates non-specific fluid-phase uptake, is potently upregulated by various oncogenic pathways. It is now well appreciated that high macropinocytic activity is a hallmark of many human tumors, which use this adaptation to scavenge extracellular nutrients for fueling cell growth. In the context of the nutrient-scarce tumor microenvironment, this process provides tumor cells with metabolic flexibility. However, dependence on this scavenging mechanism also illuminates a potential metabolic vulnerability. As such, there is a great deal of interest in understanding the molecular underpinnings of macropinocytosis. In this review, we will discuss the most recent advances in characterizing macropinocytosis: the pathways that regulate it, its contribution to the metabolic fitness of cancer cells, and its therapeutic potential.
    Keywords:  RAS; macropinocytosis; membrane ruffling; metabolic fitness; nutrient scavenging
    DOI:  https://doi.org/10.1016/j.trecan.2021.09.004
  27. Chem Biol Interact. 2021 Oct 08. pii: S0009-2797(21)00315-X. [Epub ahead of print] 109677
    Methylglyoxal disrupts the functionality of rat liver mitochondria.
    Alessandro de Souza Prestes, Matheus Mulling Dos Santos, Jean Paul Kamdem, Gianni Mancini, Luana Caroline Schüler, Andreza Fabro de Bem, Nilda Vargas Barbosa.
      Methylglyoxal (MG) is a reactive metabolite derived from different physiological pathways. Its production can be harmful to cells via glycation reactions of lipids, DNA, and proteins. But, the effects of MG on mitochondrial functioning and bioenergetic responses are still elusive. Then, the effects of MG on key parameters of mitochondrial functionality were examined here. Isolated rat liver mitochondria were exposed to 0.1-10 mM of MG to determine its toxicity in the mitochondrial viability, membrane potential (Δψm), swelling and the superoxide (O2•-) production. Besides, mitochondrial oxidative phosphorylation parameters were analyzed by high-resolution respiratory (HRR) assay. In this set of experiments, routine state, PM state (pyruvate/malate), oxidative phosphorylation (OXPHOS), LEAK respiration, electron transport system (ETS) and oxygen residual (ROX) states were evaluated. HRR showed that PM state, OXPHOS CI-Linked, LEAK respiration, ETS CI/CII-Linked and ETS CII-Linked/ROX were significantly inhibited by MG exposure. MG also inhibited the complex II activity, and decreased Δψm and the viability of mitochondria. Taken together, our data indicates that MG is an inductor of mitochondrial dysfunctions and impairs important steps of respiratory chain, effects that can alter bioenergetics responses.
    Keywords:  High-resolution respirometry; Methylglyoxal; Mitochondria; Oxidative stress
    DOI:  https://doi.org/10.1016/j.cbi.2021.109677
  28. Nat Metab. 2021 Oct 14.
    Glutamine gluttony of efferocytes.
    Alison Jaccard, Xiaoyun Li, Ping-Chih Ho.
      
    DOI:  https://doi.org/10.1038/s42255-021-00462-z
  29. Nat Commun. 2021 Oct 13. 12(1): 5961
    Cancer gene mutation frequencies for the U.S. population.
    Gaurav Mendiratta, Eugene Ke, Meraj Aziz, David Liarakos, Melinda Tong, Edward C Stites.
      Mutations play a fundamental role in the development of cancer, and many create targetable vulnerabilities. There are both public health and basic science benefits from the determination of the proportion of all cancer cases within a population that include a mutant form of a gene. Here, we provide the first such estimates by combining genomic and epidemiological data. We estimate KRAS is mutated in only 11% of all cancers, which is less than PIK3CA (13%) and marginally higher than BRAF (8%). TP53 is the most commonly mutated gene (35%), and KMT2C, KMT2D, and ARID1A are among the ten most commonly mutated driver genes, highlighting the role of epigenetic dysregulation in cancer. Analysis of major cancer subclassifications highlighted varying dependencies upon individual cancer drivers. Overall, we find that cancer genetics is less dominated by high-frequency, high-profile cancer driver genes than studies limited to a subset of cancer types have suggested.
    DOI:  https://doi.org/10.1038/s41467-021-26213-y
  30. Cell Rep. 2021 Oct 12. pii: S2211-1247(21)01297-3. [Epub ahead of print]37(2): 109833
    Metabolomics atlas of oral 13C-glucose tolerance test in mice.
    Magno Lopes, Kristyna Brejchova, Martin Riecan, Michaela Novakova, Martin Rossmeisl, Tomas Cajka, Ondrej Kuda.
      Glucose tolerance represents a complex phenotype in which many tissues play important roles and interact to regulate metabolic homeostasis. Here, we perform an analysis of 13C6-glucose tissue distribution, which maps the metabolome and lipidome across 12 metabolically relevant mouse organs and plasma, with integrated 13C6-glucose-derived carbon tracing during oral glucose tolerance test (OGTT). We measure time profiles of water-soluble metabolites and lipids and integrate the global metabolite response into metabolic pathways. During the OGTT, glucose use is turned on with specific kinetics at the organ level, but fasting substrates like β-hydroxybutyrate are switched off in all organs simultaneously. Timeline profiling of 13C-labeled fatty acids and triacylglycerols across tissues suggests that brown adipose tissue may contribute to the circulating fatty acid pool at maximal plasma glucose levels. The GTTAtlas interactive web application serves as a unique resource for the exploration of whole-body glucose metabolism and time profiles of tissue and plasma metabolites during the OGTT.
    Keywords:  13C; brown adipose tissue; de novo lipogenesis; glucose tolerance; lipidomics; metabolite cycling; metabolomics; metabolomics atlas; pathway analysis; tracer analysis
    DOI:  https://doi.org/10.1016/j.celrep.2021.109833
  31. Int J Mol Sci. 2021 Oct 06. pii: 10790. [Epub ahead of print]22(19):
    Inhibition of Mitochondrial Metabolism Leads to Selective Eradication of Cells Adapted to Acidic Microenvironment.
    Martina Koncošová, Nikola Vrzáčková, Ivana Křížová, Petra Tomášová, Silvie Rimpelová, Aleš Dvořák, Libor Vítek, Michaela Rumlová, Tomáš Ruml, Jaroslav Zelenka.
      Metabolic transformation of cancer cells leads to the accumulation of lactate and significant acidification in the tumor microenvironment. Both lactate and acidosis have a well-documented impact on cancer progression and negative patient prognosis. Here, we report that cancer cells adapted to acidosis are significantly more sensitive to oxidative damage induced by hydrogen peroxide, high-dose ascorbate, and photodynamic therapy. Higher lactate concentrations abrogate the sensitization. Mechanistically, acidosis leads to a drop in antioxidant capacity caused by a compromised supply of nicotinamide adenine dinucleotide phosphate (NADPH) derived from glucose metabolism. However, lactate metabolism in the Krebs cycle restores NADPH supply and antioxidant capacity. CPI-613 (devimistat), an anticancer drug candidate, selectively eradicates the cells adapted to acidosis through inhibition of the Krebs cycle and induction of oxidative stress while completely abrogating the protective effect of lactate. Simultaneous cell treatment with tetracycline, an inhibitor of the mitochondrial proteosynthesis, further enhances the cytotoxic effect of CPI-613 under acidosis and in tumor spheroids. While there have been numerous attempts to treat cancer by neutralizing the pH of the tumor microenvironment, we alternatively suggest considering tumor acidosis as the Achilles' heel of cancer as it enables selective therapeutic induction of lethal oxidative stress.
    Keywords:  CPI-613; acidosis; bioenergetics; cancer; lactate; mitochondria; photodynamic therapy; tetracycline; therapy; tumor microenvironment
    DOI:  https://doi.org/10.3390/ijms221910790
  32. Sci Adv. 2021 Oct 15. 7(42): eabg3947
    GLUT4-overexpressing engineered muscle constructs as a therapeutic platform to normalize glycemia in diabetic mice.
    Margarita Beckerman, Chava Harel, Inbal Michael, Amira Klip, Philip J Bilan, Emily J Gallagher, Derek LeRoith, Eli C Lewis, Eddy Karnieli, Shulamit Levenberg.
      [Figure: see text].
    DOI:  https://doi.org/10.1126/sciadv.abg3947
  33. Nature. 2021 Oct 13.
    Convergent somatic mutations in metabolism genes in chronic liver disease.
    Stanley W K Ng, Foad J Rouhani, Simon F Brunner, Natalia Brzozowska, Sarah J Aitken, Ming Yang, Federico Abascal, Luiza Moore, Efterpi Nikitopoulou, Lia Chappell, Daniel Leongamornlert, Aleksandra Ivovic, Philip Robinson, Timothy Butler, Mathijs A Sanders, Nicholas Williams, Tim H H Coorens, Jon Teague, Keiran Raine, Adam P Butler, Yvette Hooks, Beverley Wilson, Natalie Birtchnell, Huw Naylor, Susan E Davies, Michael R Stratton, Iñigo Martincorena, Raheleh Rahbari, Christian Frezza, Matthew Hoare, Peter J Campbell.
      The progression of chronic liver disease to hepatocellular carcinoma is caused by the acquisition of somatic mutations that affect 20-30 cancer genes1-8. Burdens of somatic mutations are higher and clonal expansions larger in chronic liver disease9-13 than in normal liver13-16, which enables positive selection to shape the genomic landscape9-13. Here we analysed somatic mutations from 1,590 genomes across 34 liver samples, including healthy controls, alcohol-related liver disease and non-alcoholic fatty liver disease. Seven of the 29 patients with liver disease had mutations in FOXO1, the major transcription factor in insulin signalling. These mutations affected a single hotspot within the gene, impairing the insulin-mediated nuclear export of FOXO1. Notably, six of the seven patients with FOXO1S22W hotspot mutations showed convergent evolution, with variants acquired independently by up to nine distinct hepatocyte clones per patient. CIDEB, which regulates lipid droplet metabolism in hepatocytes17-19, and GPAM, which produces storage triacylglycerol from free fatty acids20,21, also had a significant excess of mutations. We again observed frequent convergent evolution: up to fourteen independent clones per patient with CIDEB mutations and up to seven clones per patient with GPAM mutations. Mutations in metabolism genes were distributed across multiple anatomical segments of the liver, increased clone size and were seen in both alcohol-related liver disease and non-alcoholic fatty liver disease, but rarely in hepatocellular carcinoma. Master regulators of metabolic pathways are a frequent target of convergent somatic mutation in alcohol-related and non-alcoholic fatty liver disease.
    DOI:  https://doi.org/10.1038/s41586-021-03974-6
  34. J Biol Chem. 2021 Oct 08. pii: S0021-9258(21)01099-1. [Epub ahead of print] 101294
    Metabolic turnover and dynamics of modified ribonucleosides by 13C labeling.
    Paulo A Gameiro, Vesela Encheva, Mariana Silva Dos Santos, James I MacRae, Jernej Ule.
      Tandem mass spectrometry (MS/MS) is an accurate tool to assess modified ribonucleosides and their dynamics in mammalian cells. However, MS/MS quantification of lowly abundant modifications in non-ribosomal RNAs is unreliable, and the dynamic features of various modifications poorly understood. Here, we developed a 13C labeling approach, called 13C-dynamods, to quantify the turnover of base modifications in newly transcribed RNA. This turnover-based approach helped to resolve mRNA from ncRNA modifications in purified RNA or free ribonucleoside samples, and showed the distinct kinetics of the N6-methyladenosine (m6A) versus 7-methylguanosine (m7G) modification in polyA+-purified RNA. We uncovered that N6,N6-dimethyladenosine (m62A) exhibits distinct turnover in small RNAs and free ribonucleosides when compared to known m62A-modified large rRNAs. Finally, combined measurements of turnover and abundance of these modifications informed on the transcriptional versus posttranscriptional sensitivity of modified ncRNAs and mRNAs, respectively, to stress conditions. Thus, 13C-dynamods enables studies of the origin of modified RNAs at steady-state and subsequent dynamics under non-stationary conditions. These results open new directions to probe the presence and biological regulation of modifications in particular RNAs.
    Keywords:  7-methylguanosine; Isotopic labeling; N6,N6-dimethyladenosine; N6-methyladenosine; RNA modifications; RNA turnover; mass spectrometry; metabolic stress; metabolism; methylation dynamics
    DOI:  https://doi.org/10.1016/j.jbc.2021.101294
  35. Arch Toxicol. 2021 Oct 13.
    Mapping the cellular response to electron transport chain inhibitors reveals selective signaling networks triggered by mitochondrial perturbation.
    Wanda van der Stel, Huan Yang, Nanette G Vrijenhoek, Johannes P Schimming, Giulia Callegaro, Giada Carta, Salihanur Darici, Johannes Delp, Anna Forsby, Andrew White, Sylvia le Dévédec, Marcel Leist, Paul Jennings, Joost B Beltman, Bob van de Water, Erik H J Danen.
      Mitochondrial perturbation is a key event in chemical-induced organ toxicities that is incompletely understood. Here, we studied how electron transport chain (ETC) complex I, II, or III (CI, CII and CIII) inhibitors affect mitochondrial functionality, stress response activation, and cell viability using a combination of high-content imaging and TempO-Seq in HepG2 hepatocyte cells. CI and CIII inhibitors perturbed mitochondrial membrane potential (MMP) and mitochondrial and cellular ATP levels in a concentration- and time-dependent fashion and, under conditions preventing a switch to glycolysis attenuated cell viability, whereas CII inhibitors had no effect. TempO-Seq analysis of changes in mRNA expression pointed to a shared cellular response to CI and CIII inhibition. First, to define specific ETC inhibition responses, a gene set responsive toward ETC inhibition (and not to genotoxic, oxidative, or endoplasmic reticulum stress) was identified using targeted TempO-Seq in HepG2. Silencing of one of these genes, NOS3, exacerbated the impact of CI and CIII inhibitors on cell viability, indicating its functional implication in cellular responses to mitochondrial stress. Then by monitoring dynamic responses to ETC inhibition using a HepG2 GFP reporter panel for different classes of stress response pathways and applying pathway and gene network analysis to TempO-Seq data, we looked for downstream cellular events of ETC inhibition and identified the amino acid response (AAR) as being triggered in HepG2 by ETC inhibition. Through in silico approaches we provide evidence indicating that a similar AAR is associated with exposure to mitochondrial toxicants in primary human hepatocytes. Altogether, we (i) unravel quantitative, time- and concentration-resolved cellular responses to mitochondrial perturbation, (ii) identify a gene set associated with adaptation to exposure to active ETC inhibitors, and (iii) show that ER stress and an AAR accompany ETC inhibition in HepG2 and primary hepatocytes.
    Keywords:  DILI; ETC complex inhibitors; High-content imaging; Mitochondrial toxicity; TempO-Seq
    DOI:  https://doi.org/10.1007/s00204-021-03160-7
  36. Theranostics. 2021 ;11(19): 9217-9233
    Tryptophan metabolism is inversely regulated in the tumor and blood of patients with glioblastoma.
    Verena Panitz, Saša Končarević, Ahmed Sadik, Dennis Friedel, Tobias Bausbacher, Saskia Trump, Vadim Farztdinov, Sandra Schulz, Philipp Sievers, Stefan Schmidt, Ina Jürgenson, Stephan Jung, Karsten Kuhn, Irada Pflüger, Suraj Sharma, Antje Wick, Pauline Pfänder, Stefan Selzer, Philipp Vollmuth, Felix Sahm, Andreas von Deimling, Ines Heiland, Carsten Hopf, Peter Schulz-Knappe, Ian Pike, Michael Platten, Wolfgang Wick, Christiane A Opitz.
      Tryptophan (Trp)-catabolic enzymes (TCEs) produce metabolites that activate the aryl hydrocarbon receptor (AHR) and promote tumor progression and immunosuppression in glioblastoma. As therapies targeting TCEs or AHR become available, a better understanding of Trp metabolism is required. Methods: The combination of LC-MS/MS with chemical isobaric labeling enabled the simultaneous quantitative comparison of Trp and its amino group-bearing metabolites in multiple samples. We applied this method to the sera of a cohort of 43 recurrent glioblastoma patients and 43 age- and sex-matched healthy controls. Tumor volumes were measured in MRI data using an artificial neural network-based approach. MALDI MSI visualized Trp and its direct metabolite N-formylkynurenine (FK) in glioblastoma tissue. Analysis of scRNA-seq data was used to detect the presence of Trp metabolism and AHR activity in different cell types in glioblastoma. Results: Compared to healthy controls, glioblastoma patients showed decreased serum Trp levels. Surprisingly, the levels of Trp metabolites were also reduced. The decrease became smaller with more enzymatic steps between Trp and its metabolites, suggesting that Trp availability controls the levels of its systemic metabolites. High tumor volume associated with low systemic metabolite levels and low systemic kynurenine levels associated with worse overall survival. MALDI MSI demonstrated heterogeneity of Trp catabolism across glioblastoma tissues. Analysis of scRNA-seq data revealed that genes involved in Trp metabolism were expressed in almost all the cell types in glioblastoma and that most cell types, in particular macrophages and T cells, exhibited AHR activation. Moreover, high AHR activity associated with reduced overall survival in the glioblastoma TCGA dataset. Conclusion: The novel techniques we developed could support the identification of patients that may benefit from therapies targeting TCEs or AHR activation.
    Keywords:  AHR; Glioblastoma; MALDI MSI; mass spectrometry; tryptophan
    DOI:  https://doi.org/10.7150/thno.60679
  37. Cell Death Differ. 2021 Oct 09.
    p53-mediated redox control promotes liver regeneration and maintains liver function in response to CCl4.
    Timothy J Humpton, Holly Hall, Christos Kiourtis, Colin Nixon, William Clark, Ann Hedley, Robin Shaw, Thomas G Bird, Karen Blyth, Karen H Vousden.
      The p53 transcription factor coordinates wide-ranging responses to stress that contribute to its function as a tumour suppressor. The responses to p53 induction are complex and range from mediating the elimination of stressed or damaged cells to promoting survival and repair. These activities of p53 can modulate tumour development but may also play a role in pathological responses to stress such as tissue damage and repair. Using a p53 reporter mouse, we have previously detected strong induction of p53 activity in the liver of mice treated with the hepatotoxin carbon tetrachloride (CCl4). Here, we show that p53 functions to support repair and recovery from CCl4-mediated liver damage, control reactive oxygen species (ROS) and limit the development of hepatocellular carcinoma (HCC), in part through the activation of a detoxification cytochrome P450, CYP2A5 (CYP2A6 in humans). Our work demonstrates an important role for p53-mediated redox control in facilitating the hepatic regenerative response after damage and identifies CYP2A5/CYP2A6 as a mediator of this pathway with potential prognostic utility in human HCC.
    DOI:  https://doi.org/10.1038/s41418-021-00871-3
  38. Cell Rep. 2021 10 12. pii: S2211-1247(21)01266-3. [Epub ahead of print]37(2): 109806
    Proteomics reveal cap-dependent translation inhibitors remodel the translation machinery and translatome.
    J J David Ho, Tyler A Cunningham, Paola Manara, Caroline A Coughlin, Artavazd Arumov, Evan R Roberts, Ashanti Osteen, Preet Kumar, Daniel Bilbao, Jonathan R Krieger, Stephen Lee, Jonathan H Schatz.
      Tactical disruption of protein synthesis is an attractive therapeutic strategy, with the first-in-class eIF4A-targeting compound zotatifin in clinical evaluation for cancer and COVID-19. The full cellular impact and mechanisms of these potent molecules are undefined at a proteomic level. Here, we report mass spectrometry analysis of translational reprogramming by rocaglates, cap-dependent initiation disruptors that include zotatifin. We find effects to be far more complex than simple "translational inhibition" as currently defined. Translatome analysis by TMT-pSILAC (tandem mass tag-pulse stable isotope labeling with amino acids in cell culture mass spectrometry) reveals myriad upregulated proteins that drive hitherto unrecognized cytotoxic mechanisms, including GEF-H1-mediated anti-survival RHOA/JNK activation. Surprisingly, these responses are not replicated by eIF4A silencing, indicating a broader translational adaptation than currently understood. Translation machinery analysis by MATRIX (mass spectrometry analysis of active translation factors using ribosome density fractionation and isotopic labeling experiments) identifies rocaglate-specific dependence on specific translation factors including eEF1ε1 that drive translatome remodeling. Our proteome-level interrogation reveals that the complete cellular response to these historical "translation inhibitors" is mediated by comprehensive translational landscape remodeling.
    Keywords:  DDX17; GEF-H1; JNK; RHOA; eEF1ε1; eIF4A; rocaglate; silvestrol; translation; zotatifin
    DOI:  https://doi.org/10.1016/j.celrep.2021.109806
  39. Mol Cancer Res. 2021 Oct 15. pii: molcanres.0448.2021. [Epub ahead of print]
    Enhanced vulnerability of LKB1-deficient NSCLC to disruption of ATP pools and redox homeostasis by 8-Cl-Ado.
    Ana Galan-Cobo, Christine M Stellrecht, Emrullah Yilmaz, Chao Yang, Yu Qian, Xiao Qu, Ishita Akhter, Mary L Ayres, Youhong Fan, Pan Tong, Lixia Diao, Jie Ding, Uma Giri, Jayanthi Gudikote, Monique Nilsson, William G Wierda, Jing Wang, Ferdinandos Skoulidis, John D Minna, Varsha Gandhi, John V Heymach.
      Loss of function somatic mutations of STK11, a tumor suppressor gene encoding LKB1 that contributes to the altered metabolic phenotype of cancer cells, is the second most common event in lung adenocarcinomas and often co-occurs with activating KRAS mutations. Tumor cells lacking LKB1 display an aggressive phenotype, with uncontrolled cell growth and higher energetic and redox stress due to its failure to balance ATP and NADPH levels in response to cellular stimulus. The identification of effective therapeutic regimens for LKB1-deficient non-small cell lung cancer (NSCLC) patients remains a major clinical need. Here, we report that LKB1-deficient NSCLC tumor cells displayed reduced basal levels of ATP and to a lesser extent other nucleotides, and markedly enhanced sensitivity to 8-Cl-adenosine (8-Cl-Ado), an energy-depleting nucleoside analogue. Treatment with 8-Cl-Ado depleted intracellular ATP levels, raised redox stress and induced cell death leading to a compensatory suppression of mTOR signaling in LKB1-intact, but not LKB1-deficient, cells. Proteomic analysis revealed that the MAPK/MEK/ERK and PI3K/AKT pathways were activated in response to 8-Cl-Ado treatment and targeting these pathways enhanced the anti-tumor efficacy of 8-Cl-Ado. Implications: Together, our findings demonstrate that LKB1-deficient tumor cells are selectively sensitive to 8-Cl-Ado and suggest that therapeutic approaches targeting vulnerable energy stores combined with signaling pathway inhibitors merit further investigation for this patient population.
    DOI:  https://doi.org/10.1158/1541-7786.MCR-21-0448
  40. Sci Rep. 2021 Oct 15. 11(1): 20526
    ULK1 promotes mitophagy via phosphorylation and stabilization of BNIP3.
    Logan P Poole, Althea Bock-Hughes, Damian E Berardi, Kay F Macleod.
      UNC51-like kinase-1 (ULK1) is the catalytic component of the autophagy pre-initiation complex that stimulates autophagy via phosphorylation of ATG14, BECLN1 and other autophagy proteins. ULK1 has also been shown to specifically promote mitophagy but the mechanistic basis of how has remained unclear. Here we show that ULK1 phosphorylates the BNIP3 mitochondrial cargo receptor on a critical serine residue (S17) adjacent to its amino terminal LIR motif. ULK1 similarly phosphorylates BNIP3L on S35. Phosphorylation of BNIP3 on S17 by ULK1 promotes interaction with LC3 and mitophagy. ULK1 interaction also promotes BNIP3 protein stability by limiting its turnover at the proteasome. The ability of ULK1 to regulate BNIP3 protein stability depends on an intact "BH3" domain and deletion of its "BH3" domain reduces BNIP3 turnover and increases BNIP3 protein levels independent of ULK1. In summary ULK1 promotes mitophagy by both stabilization of BNIP3 protein and via phosphorylation of S17 to stimulate interaction with LC3.
    DOI:  https://doi.org/10.1038/s41598-021-00170-4
  41. PLoS Pathog. 2021 Oct;17(10): e1009841
    Downregulation of mitochondrial biogenesis by virus infection triggers antiviral responses by cyclic GMP-AMP synthase.
    Hiroki Sato, Miho Hoshi, Fusako Ikeda, Tomoko Fujiyuki, Misako Yoneda, Chieko Kai.
      In general, in mammalian cells, cytosolic DNA viruses are sensed by cyclic GMP-AMP synthase (cGAS), and RNA viruses are recognized by retinoic acid-inducible gene I (RIG-I)-like receptors, triggering a series of downstream innate antiviral signaling steps in the host. We previously reported that measles virus (MeV), which possesses an RNA genome, induces rapid antiviral responses, followed by comprehensive downregulation of host gene expression in epithelial cells. Interestingly, gene ontology analysis indicated that genes encoding mitochondrial proteins are enriched among the list of downregulated genes. To evaluate mitochondrial stress after MeV infection, we first observed the mitochondrial morphology of infected cells and found that significantly elongated mitochondrial networks with a hyperfused phenotype were formed. In addition, an increased amount of mitochondrial DNA (mtDNA) in the cytosol was detected during progression of infection. Based on these results, we show that cytosolic mtDNA released from hyperfused mitochondria during MeV infection is captured by cGAS and causes consequent priming of the DNA sensing pathway in addition to canonical RNA sensing. We also ascertained the contribution of cGAS to the in vivo pathogenicity of MeV. In addition, we found that other viruses that induce downregulation of mitochondrial biogenesis as seen for MeV cause similar mitochondrial hyperfusion and cytosolic mtDNA-priming antiviral responses. These findings indicate that the mtDNA-activated cGAS pathway is critical for full innate control of certain viruses, including RNA viruses that cause mitochondrial stress.
    DOI:  https://doi.org/10.1371/journal.ppat.1009841
  42. Front Cell Dev Biol. 2021 ;9 737498
    The RNA N6-Methyladenosine Methyltransferase METTL3 Promotes the Progression of Kidney Cancer via N6-Methyladenosine-Dependent Translational Enhancement of ABCD1.
    Yue Shi, Yanliang Dou, Jianye Zhang, Jie Qi, Zijuan Xin, Mingxin Zhang, Yu Xiao, Weimin Ci.
      The role of N6-methyladenosine (m6A)-modifying proteins in cancer progression depends on the cell type and mRNA affected. However, the biological role and underlying mechanism of m6A in kidney cancer is limited. Here, we discovered the variability in m6A methyltransferase METTL3 expression was significantly increased in clear cell renal cell carcinoma (ccRCC) the most common subtype of renal cell carcinoma (RCC), and high METTL3 expression predicts poor prognosis in ccRCC patients using a dataset from The Cancer Genome Atlas (TCGA). Importantly, knockdown of METTL3 in ccRCC cell line impaired both cell migration capacity and tumor spheroid formation in soft fibrin gel, a mechanical method for selecting stem-cell-like tumorigenic cells. Consistently, overexpression of METTL3 but not methyltransferase activity mutant METTL3 can promote cell migration, spheroid formation in cell line and tumor growth in xenograft model. Transcriptional profiling of m6A in ccRCC tissues identified the aberrant m6A transcripts were enriched in cancer-related pathways. Further m6A-sequencing of METTL3 knockdown cells and functional studies confirmed that translation of ABCD1, an ATP-binding cassette (ABC) transporter of fatty acids, was inhibited by METTL3 in m6A-dependent manner. Moreover, knockdown of ABCD1 in ccRCC cells decreased cancer cell migration and spheroid formation, and upregulation of ABCD1 acts as an adverse prognosis factor of kidney cancer patients. In summary, our study identifies that METTL3 promotes ccRCC progression through m6A modification-mediated translation of ABCD1, providing an epitranscriptional insight into the molecular mechanism in kidney cancer.
    Keywords:  ABCD1; METTL3; cancer progression; kidney cancer; m6A
    DOI:  https://doi.org/10.3389/fcell.2021.737498
  43. Nat Commun. 2021 Oct 15. 12(1): 6035
    Compensatory ion transport buffers daily protein rhythms to regulate osmotic balance and cellular physiology.
    Alessandra Stangherlin, Joseph L Watson, David C S Wong, Silvia Barbiero, Aiwei Zeng, Estere Seinkmane, Sew Peak Chew, Andrew D Beale, Edward A Hayter, Alina Guna, Alison J Inglis, Marrit Putker, Eline Bartolami, Stefan Matile, Nicolas Lequeux, Thomas Pons, Jason Day, Gerben van Ooijen, Rebecca M Voorhees, David A Bechtold, Emmanuel Derivery, Rachel S Edgar, Peter Newham, John S O'Neill.
      Between 6-20% of the cellular proteome is under circadian control and tunes mammalian cell function with daily environmental cycles. For cell viability, and to maintain volume within narrow limits, the daily variation in osmotic potential exerted by changes in the soluble proteome must be counterbalanced. The mechanisms and consequences of this osmotic compensation have not been investigated before. In cultured cells and in tissue we find that compensation involves electroneutral active transport of Na+, K+, and Cl- through differential activity of SLC12A family cotransporters. In cardiomyocytes ex vivo and in vivo, compensatory ion fluxes confer daily variation in electrical activity. Perturbation of soluble protein abundance has commensurate effects on ion composition and cellular function across the circadian cycle. Thus, circadian regulation of the proteome impacts ion homeostasis with substantial consequences for the physiology of electrically active cells such as cardiomyocytes.
    DOI:  https://doi.org/10.1038/s41467-021-25942-4
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