bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2019‒12‒15
48 papers selected by
Christian Frezza,

  1. Activation of Oxidative Stress Response in Cancer Generates a Druggable Dependency on Exogenous Non-essential Amino Acids.
  2. Regulation of Tumor Initiation by the Mitochondrial Pyruvate Carrier.
  3. Small-Molecule Modulators of Mitochondrial Channels as Chemotherapeutic Agents.
  4. Metabolic reprogramming and the role of mitochondria in polycystic kidney disease.
  5. Aconitase 2 inhibits the proliferation of MCF-7 cells promoting mitochondrial oxidative metabolism and ROS/FoxO1-mediated autophagic response.
  6. New aspects of amino acid metabolism in cancer.
  7. Bioenergetic consequences from xenotopic expression of a tunicate AOX in mouse mitochondria: Switch from RET and ROS to FET.
  8. A sensitive mass spectrometric assay for mitochondrial CoQ pool redox state in vivo.
  9. Bioenergetics and translational metabolism: implications for genetics, physiology and precision medicine.
  10. Defining a metabolic landscape of tumours: genome meets metabolism.
  11. Mutant IDH1 confers resistance to energy stress in normal biliary cells through PFKP-induced aerobic glycolysis and AMPK activation.
  12. Rescue of TCA Cycle Dysfunction for Cancer Therapy.
  13. TGFβ-induced metabolic reprogramming during epithelial-to-mesenchymal transition in cancer.
  14. KRAS4A directly regulates hexokinase 1.
  15. Power to the daughters - mitochondrial and mtDNA transmission during cell division.
  16. Forcing contacts between mitochondria and the endoplasmic reticulum extends lifespan in a Drosophila model of Alzheimer's disease.
  17. The Metabolite Repair Enzyme Phosphoglycolate Phosphatase Regulates Central Carbon Metabolism and Fosmidomycin Sensitivity in Plasmodium falciparum.
  18. Oncogenic pathways and the electron transport chain: a dangeROS liaison.
  19. NAMPT maintains mitochondria content via NRF2-PPARα/AMPKα pathway to promote cell survival under oxidative stress.
  20. Reprogramming of fatty acid metabolism in cancer.
  21. Mutant p53 drives clonal hematopoiesis through modulating epigenetic pathway.
  22. Mitochondrial 4-HNE derived from MAO-A promotes mitoCa2+ overload in chronic postischemic cardiac remodeling.
  23. Glycolytic suppression dramatically changes the intracellular metabolic profile of multiple cancer cell lines in a mitochondrial metabolism-dependent manner.
  24. Metabolism and cancer: the future is now.
  25. Prohibitin levels regulate OMA1 activity and turnover in neurons.
  26. Kinetic modelling of quantitative proteome data predicts metabolic reprogramming of liver cancer.
  27. Metabolic Regulation of Macrophage Polarization in Cancer.
  28. Greasing the Wheels of the Cancer Machine: The Role of Lipid Metabolism in Cancer.
  29. ATP citrate lyase: a central metabolic enzyme in cancer.
  30. LRRK2 regulates endoplasmic reticulum-mitochondrial tethering through the PERK-mediated ubiquitination pathway.
  31. Targeting Mitochondrial Fission to Trigger Cancer Cell Death.
  32. Window of opportunity clinical trial designs to study cancer metabolism.
  33. FOXA1 upregulation promotes enhancer and transcriptional reprogramming in endocrine-resistant breast cancer.
  34. A Systems Chemoproteomic Analysis of Acyl-CoA/Protein Interaction Networks.
  35. The clock is ticking: the impact of ageing on T cell metabolism.
  36. The "mitochondrial contact site and cristae organising system" (MICOS) in health and human disease.
  37. The Metabolic Interplay between Cancer and Other Diseases.
  38. CASP9 (caspase 9) is essential for autophagosome maturation through regulation of mitochondrial homeostasis.
  39. Techniques for investigating mitochondrial gene expression.
  40. Multiphoton NAD(P)H FLIM reveals metabolic changes in individual cell types of the intact cochlea upon sensorineural hearing loss.
  41. p53-Mediated Tumor Suppression: DNA-Damage Response and Alternative Mechanisms.
  42. MFN1-dependent alteration of mitochondrial dynamics drives hepatocellular carcinoma metastasis by glucose metabolic reprogramming.
  43. Targeting Succinate Metabolism in Ischemia/Reperfusion Injury.
  44. Metabolism remodeling in pancreatic ductal adenocarcinoma.
  45. Plasma membrane V-ATPase controls oncogenic RAS-induced macropinocytosis.
  46. The Role of Iron Regulation in Immunometabolism and Immune-Related Disease.
  47. Ten-Hour Time-Restricted Eating Reduces Weight, Blood Pressure, and Atherogenic Lipids in Patients with Metabolic Syndrome.
  48. LDHA Suppression Altering Metabolism Inhibits Tumor Progress by an Organic Arsenical.
  1. Cell Metab. 2019 Nov 28. pii: S1550-4131(19)30619-9. [Epub ahead of print]
    Activation of Oxidative Stress Response in Cancer Generates a Druggable Dependency on Exogenous Non-essential Amino Acids.
    Sarah E LeBoeuf, Warren L Wu, Triantafyllia R Karakousi, Burcu Karadal, S RaElle Jackson, Shawn M Davidson, Kwok-Kin Wong, Sergei B Koralov, Volkan I Sayin, Thales Papagiannakopoulos.
      Rewiring of metabolic pathways is a hallmark of tumorigenesis as cancer cells acquire novel nutrient dependencies to support oncogenic growth. A major genetic subtype of lung adenocarcinoma with KEAP1/NRF2 mutations, which activates the endogenous oxidative stress response, undergoes significant metabolic rewiring to support enhanced antioxidant production. We demonstrate that cancers with high antioxidant capacity exhibit a general dependency on exogenous non-essential amino acids (NEAAs) that is driven by the Nrf2-dependent secretion of glutamate through system xc- (XCT), which limits intracellular glutamate pools that are required for NEAA synthesis. This dependency can be therapeutically targeted by dietary restriction or enzymatic depletion of individual NEAAs. Importantly, limiting endogenous glutamate levels by glutaminase inhibition can sensitize tumors without alterations in the Keap1/Nrf2 pathway to dietary restriction of NEAAs. Our findings identify a metabolic strategy to therapeutically target cancers with genetic or pharmacologic activation of the Nrf2 antioxidant response pathway by restricting exogenous sources of NEAAs.
    Keywords:  Keap1; NRF2; amino acid synthesis; asparaginase; glutamate; glutaminase; lung cancer; metabolism; non-essential amino acids; oxidative stress; system x(c)(−)
    DOI:  https://doi.org/10.1016/j.cmet.2019.11.012
  2. Cell Metab. 2019 Dec 02. pii: S1550-4131(19)30609-6. [Epub ahead of print]
    Regulation of Tumor Initiation by the Mitochondrial Pyruvate Carrier.
    Claire L Bensard, Dona R Wisidigama, Kristofor A Olson, Jordan A Berg, Nathan M Krah, John C Schell, Sara M Nowinski, Sarah Fogarty, Alex J Bott, Peng Wei, Katja K Dove, Jason M Tanner, Vanja Panic, Ahmad Cluntun, Sandra Lettlova, Christian S Earl, David F Namnath, Karina Vázquez-Arreguín, Claudio J Villanueva, Dean Tantin, L Charles Murtaugh, Kimberley J Evason, Gregory S Ducker, Carl S Thummel, Jared Rutter.
      Although metabolic adaptations have been demonstrated to be essential for tumor cell proliferation, the metabolic underpinnings of tumor initiation are poorly understood. We found that the earliest stages of colorectal cancer (CRC) initiation are marked by a glycolytic metabolic signature, including downregulation of the mitochondrial pyruvate carrier (MPC), which couples glycolysis and glucose oxidation through mitochondrial pyruvate import. Genetic studies in Drosophila suggest that this downregulation is required because hyperplasia caused by loss of the Apc or Notch tumor suppressors in intestinal stem cells can be completely blocked by MPC overexpression. Moreover, in two distinct CRC mouse models, loss of Mpc1 prior to a tumorigenic stimulus doubled the frequency of adenoma formation and produced higher grade tumors. MPC loss was associated with a glycolytic metabolic phenotype and increased expression of stem cell markers. These data suggest that changes in cellular pyruvate metabolism are necessary and sufficient to promote cancer initiation.
    Keywords:  cancer metabolism; carbohydrate metabolism; colon cancer; mitochondria; pyruvate metabolism; stem cell metabolism; tumor initiation
    DOI:  https://doi.org/10.1016/j.cmet.2019.11.002
  3. Cell Physiol Biochem. 2019 ;53(S1): 11-43
    Small-Molecule Modulators of Mitochondrial Channels as Chemotherapeutic Agents.
    Sofia Parrasia, Andrea Mattarei, Alberto Furlan, Mario Zoratti, Lucia Biasutto.
      Ion channels residing in the inner (IMM) and outer (OMM) mitochondrial membranes are emerging as noteworthy pharmacological targets in oncology. While these aspects have not been investigated for all of them, a role in cancer growth and/or metastasis and/or drug resistance has been shown at least for the IMM-residing Ca2+ uniporter complex and K+- selective mtKV1.3, mtIKCa, mtSKCa and mtTASK-3, and for the OMM Voltage-Dependent Anion Channel (mitochondrial porin). A special case is that of the Mitochondrial Permeability Transition Pore, a large pore which forms in the IMM of severely stressed cells, and which may be exploited to precipitate the death of cancerous cells. Here we briefly discuss the oncological relevance of mitochondria and their channels, and summarize the methods that can be adopted to selectively target these intracellular organelles. We then present an updated list of known mitochondrial channels, and review the pharmacology of those with proven relevance for cancer.
    Keywords:  Mitochondrial channels; Cancer; Channel modulators; Mitochondria-targeting
    DOI:  https://doi.org/10.33594/000000192
  4. Cell Signal. 2019 Dec 06. pii: S0898-6568(19)30291-8. [Epub ahead of print] 109495
    Metabolic reprogramming and the role of mitochondria in polycystic kidney disease.
    Christine Podrini, Laura Cassina, Alessandra Boletta.
      Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a slowly progressive disease characterized by the relentless growth of renal cysts throughout the life of affected individuals. Early evidence suggested that the epithelia lining the cysts share neoplastic features, leading to the definition of PKD as a "neoplasm in disguise". Recent work from our and other laboratories has identified a profound metabolic reprogramming in PKD, similar to the one reported in cancer and consistent with the reported increased proliferation. Multiple lines of evidence suggest that aerobic glycolysis (a Warburg-like effect) is present in the disease, along with other metabolic dysfunctions such as an increase in the pentose phosphate pathway, in glutamine anaplerosis and fatty acid biosynthesis, while fatty acid oxidation and oxidative phosphorylation (OXPHOS) are decreased. In addition to glutamine, other amino acid-related pathways appear altered, including asparagine and arginine. The precise origin of the metabolic alterations is not entirely clear, but two hypotheses can be formulated, not mutually exclusive. First, the polycystins have been recently shown to regulate directly mitochondrial function and structure either by regulating Ca2+ uptake in mitochondria at the Mitochondria Associated Membranes (MAMs) of the Endoplasmic Reticulum, or by a direct translocation of a small fragment of the protein into the matrix of mitochondria. One alternative possibility is that metabolic and mitochondrial dysfunctions in ADPKD are secondary to the de-regulation of proliferation, driven by the multiple signaling pathways identified in the disease, which include mTORC1 and AMPK among the most relevant. While the precise mechanisms underlying these novel alterations identified in ADPKD will need further investigation, it is evident that they offer a great opportunity for novel interventions in the disease.
    Keywords:  Cell Signaling; Glucose; Lipids; Metabolism; Mitochondria; OXPHOS; Polycystic kidney disease
    DOI:  https://doi.org/10.1016/j.cellsig.2019.109495
  5. Br J Cancer. 2019 Dec 10.
    Aconitase 2 inhibits the proliferation of MCF-7 cells promoting mitochondrial oxidative metabolism and ROS/FoxO1-mediated autophagic response.
    Fabio Ciccarone, Luca Di Leo, Giacomo Lazzarino, Giuseppe Maulucci, Flavio Di Giacinto, Barbara Tavazzi, Maria Rosa Ciriolo.
      BACKGROUND: Deregulation of the tricarboxylic acid cycle (TCA) due to mutations in specific enzymes or defective aerobic metabolism is associated with tumour growth. Aconitase 2 (ACO2) participates in the TCA cycle by converting citrate to isocitrate, but no evident demonstrations of its involvement in cancer metabolism have been provided so far.METHODS: Biochemical assays coupled with molecular biology, in silico, and cellular tools were applied to circumstantiate the impact of ACO2 in the breast cancer cell line MCF-7 metabolism. Fluorescence lifetime imaging microscopy (FLIM) of NADH was used to corroborate the changes in bioenergetics.
    RESULTS: We showed that ACO2 levels are decreased in breast cancer cell lines and human tumour biopsies. We generated ACO2- overexpressing MCF-7 cells and employed comparative analyses to identify metabolic adaptations. We found that increased ACO2 expression impairs cell proliferation and commits cells to redirect pyruvate to mitochondria, which weakens Warburg-like bioenergetic features. We also demonstrated that the enhancement of oxidative metabolism was supported by mitochondrial biogenesis and FoxO1-mediated autophagy/mitophagy that sustains the increased ROS burst.
    CONCLUSIONS: This work identifies ACO2 as a relevant gene in cancer metabolic rewiring of MCF-7 cells, promoting a different utilisation of pyruvate and revealing the potential metabolic vulnerability of ACO2-associated malignancies.
    DOI:  https://doi.org/10.1038/s41416-019-0641-0
  6. Br J Cancer. 2019 Dec 10.
    New aspects of amino acid metabolism in cancer.
    Lisa Vettore, Rebecca L Westbrook, Daniel A Tennant.
      An abundant supply of amino acids is important for cancers to sustain their proliferative drive. Alongside their direct role as substrates for protein synthesis, they can have roles in energy generation, driving the synthesis of nucleosides and maintenance of cellular redox homoeostasis. As cancer cells exist within a complex and often nutrient-poor microenvironment, they sometimes exist as part of a metabolic community, forming relationships that can be both symbiotic and parasitic. Indeed, this is particularly evident in cancers that are auxotrophic for particular amino acids. This review discusses the stromal/cancer cell relationship, by using examples to illustrate a number of different ways in which cancer cells can rely on and contribute to their microenvironment - both as a stable network and in response to therapy. In addition, it examines situations when amino acid synthesis is driven through metabolic coupling to other reactions, and synthesis is in excess of the cancer cell's proliferative demand. Finally, it highlights the understudied area of non-proteinogenic amino acids in cancer metabolism and their potential role.
    DOI:  https://doi.org/10.1038/s41416-019-0620-5
  7. Biochim Biophys Acta Bioenerg. 2019 Dec 08. pii: S0005-2728(19)30191-4. [Epub ahead of print] 148137
    Bioenergetic consequences from xenotopic expression of a tunicate AOX in mouse mitochondria: Switch from RET and ROS to FET.
    Marten Szibor, Timur Gainutdinov, Erika Fernandez-Vizarra, Eric Dufour, Zemfira Gizatullina, Grazyna Debska-Vielhaber, Juliana Heidler, Ilka Wittig, Carlo Viscomi, Frank Gellerich, Anthony L Moore.
      Electron transfer from all respiratory chain dehydrogenases of the electron transport chain (ETC) converges at the level of the quinone (Q) pool. The Q redox state is thus a function of electron input (reduction) and output (oxidation) and closely reflects the mitochondrial respiratory state. Disruption of electron flux at the level of the cytochrome bc1 complex (cIII) or cytochrome c oxidase (cIV) shifts the Q redox poise to a more reduced state which is generally sensed as respiratory stress. To cope with respiratory stress, many species, but not insects and vertebrates, express alternative oxidase (AOX) which acts as an electron sink for reduced Q and by-passes cIII and cIV. Here, we used Ciona intestinalis AOX xenotopically expressed in mouse mitochondria to study how respiratory states impact the Q poise and how AOX may be used to restore respiration. Particularly interesting is our finding that electron input through succinate dehydrogenase (cII), but not NADH:ubiquinone oxidoreductase (cI), reduces the Q pool almost entirely (>90%) irrespective of the respiratory state. AOX enhances the forward electron transport (FET) from cII thereby decreasing reverse electron transport (RET) and ROS specifically when non-phosphorylating. AOX is not engaged with cI substrates, however, unless a respiratory inhibitor is added. This sheds new light on Q poise signaling, the biological role of cII which enigmatically is the only ETC complex absent from respiratory supercomplexes but yet participates in the tricarboxylic acid (TCA) cycle. Finally, we delineate potential risks and benefits arising from therapeutic AOX transfer.
    Keywords:  Alternative oxidase (AOX); Mitochondria; OXPHOS; Quinone pool; ROS; Xenotopic expression
    DOI:  https://doi.org/10.1016/j.bbabio.2019.148137
  8. Free Radic Biol Med. 2019 Dec 05. pii: S0891-5849(19)31565-5. [Epub ahead of print]
    A sensitive mass spectrometric assay for mitochondrial CoQ pool redox state in vivo.
    Nils Burger, Angela Logan, Tracy A Prime, Amin Mottahedin, Stuart T Caldwell, Thomas Krieg, Richard C Hartley, Andrew M James, Michael P Murphy.
      Coenzyme Q (CoQ) is an essential cofactor, primarily found in the mitochondrial inner membrane where it functions as an electron carrier in the respiratory chain, and a lipophilic antioxidant. The redox state of the CoQ pool is the ratio of its oxidised (ubiquinone) and reduced (ubiquinol) forms, and is a key indicator of mitochondrial bioenergetic and antioxidant status. However, the role of CoQ redox state in vivo is poorly understood, because determining its value is technically challenging due to redox changes during isolation, extraction and analysis. To address these problems, we have developed a sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay that enables us to extract and analyse both the CoQ redox state and the magnitude of the CoQ pool with negligible changes to redox state from small amounts of tissue. This will enable the physiological and pathophysiological roles of the CoQ redox state to be investigated in vivo.
    Keywords:  CoQ(10); CoQ(9); Coenzyme Q; Mass spectrometry; Mitochondria; Oxidative stress; Redox state
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2019.11.028
  9. Biol Chem. 2019 Dec 18. pii: /j/bchm.2020.401.issue-1/hsz-2019-0268/hsz-2019-0268.xml. [Epub ahead of print]401(1): 3-29
    Bioenergetics and translational metabolism: implications for genetics, physiology and precision medicine.
    Bradford G Hill, Sruti Shiva, Scott Ballinger, Jianhua Zhang, Victor M Darley-Usmar.
      It is now becoming clear that human metabolism is extremely plastic and varies substantially between healthy individuals. Understanding the biochemistry that underlies this physiology will enable personalized clinical interventions related to metabolism. Mitochondrial quality control and the detailed mechanisms of mitochondrial energy generation are central to understanding susceptibility to pathologies associated with aging including cancer, cardiac and neurodegenerative diseases. A precision medicine approach is also needed to evaluate the impact of exercise or caloric restriction on health. In this review, we discuss how technical advances in assessing mitochondrial genetics, cellular bioenergetics and metabolomics offer new insights into developing metabolism-based clinical tests and metabolotherapies. We discuss informatics approaches, which can define the bioenergetic-metabolite interactome and how this can help define healthy energetics. We propose that a personalized medicine approach that integrates metabolism and bioenergetics with physiologic parameters is central for understanding the pathophysiology of diseases with a metabolic etiology. New approaches that measure energetics and metabolomics from cells isolated from human blood or tissues can be of diagnostic and prognostic value to precision medicine. This is particularly significant with the development of new metabolotherapies, such as mitochondrial transplantation, which could help treat complex metabolic diseases.
    Keywords:  bioenergetic-metabolite interactome; metabolomics; mitochondria; personalized medicine; translational research
    DOI:  https://doi.org/10.1515/hsz-2019-0268
  10. Br J Cancer. 2019 Dec 10.
    Defining a metabolic landscape of tumours: genome meets metabolism.
    Chandan Seth Nanda, Sharavan Vishaan Venkateswaran, Neill Patani, Mariia Yuneva.
      Cancer is a complex disease of multiple alterations occuring at the epigenomic, genomic, transcriptomic, proteomic and/or metabolic levels. The contribution of genetic mutations in cancer initiation, progression and evolution is well understood. However, although metabolic changes in cancer have long been acknowledged and considered a plausible therapeutic target, the crosstalk between genetic and metabolic alterations throughout cancer types is not clearly defined. In this review, we summarise the present understanding of the interactions between genetic drivers of cellular transformation and cancer-associated metabolic changes, and how these interactions contribute to metabolic heterogeneity of tumours. We discuss the essential question of whether changes in metabolism are a cause or a consequence in the formation of cancer. We highlight two modes of how metabolism contributes to tumour formation. One is when metabolic reprogramming occurs downstream of oncogenic mutations in signalling pathways and supports tumorigenesis. The other is where metabolic reprogramming initiates transformation being either downstream of mutations in oncometabolite genes or induced by chronic wounding, inflammation, oxygen stress or metabolic diseases. Finally, we focus on the factors that can contribute to metabolic heterogeneity in tumours, including genetic heterogeneity, immunomodulatory factors and tissue architecture. We believe that an in-depth understanding of cancer metabolic reprogramming, and the role of metabolic dysregulation in tumour initiation and progression, can help identify cellular vulnerabilities that can be exploited for therapeutic use.
    DOI:  https://doi.org/10.1038/s41416-019-0663-7
  11. Sci Rep. 2019 Dec 11. 9(1): 18859
    Mutant IDH1 confers resistance to energy stress in normal biliary cells through PFKP-induced aerobic glycolysis and AMPK activation.
    Hiroaki Fujiwara, Keisuke Tateishi, Kento Misumi, Akimasa Hayashi, Kaori Igarashi, Hiroyuki Kato, Takuma Nakatsuka, Nobumi Suzuki, Keisuke Yamamoto, Yotaro Kudo, Yoku Hayakawa, Hayato Nakagawa, Yasuo Tanaka, Hideaki Ijichi, Hirofumi Kogure, Yosuke Nakai, Hiroyuki Isayama, Kiyoshi Hasegawa, Masashi Fukayama, Tomoyoshi Soga, Kazuhiko Koike.
      Metabolism is a critical regulator of cell fate determination. Recently, the significance of metabolic reprogramming in environmental adaptation during tumorigenesis has attracted much attention in cancer research. Recurrent mutations in the isocitrate dehydrogenase (IDH) 1 or 2 genes have been identified in several cancers, including intrahepatic cholangiocarcinoma (ICC). Mutant IDHs convert α-ketoglutarate (α-KG) to 2-hydroxyglutarate (2-HG), which affects the activity of multiple α-KG-dependent dioxygenases including histone lysine demethylases. Although mutant IDH can be detected even in the early stages of neoplasia, how IDH mutations function as oncogenic drivers remains unclear. In this study, we aimed to address the biological effects of IDH1 mutation using intrahepatic biliary organoids (IBOs). We demonstrated that mutant IDH1 increased the formation of IBOs as well as accelerated glucose metabolism. Gene expression analysis and ChIP results revealed the upregulation of platelet isoform of phosphofructokinase-1 (PFKP), which is a rate-limiting glycolytic enzyme, through the alteration of histone modification. Knockdown of the Pfkp gene alleviated the mutant IDH1-induced increase in IBO formation. Notably, the high expression of PFKP was observed more frequently in patients with IDH-mutant ICC compared to in those with wild-type IDH (p < 0.01, 80.9% vs. 42.5%, respectively). Furthermore, IBOs expressing mutant IDH1 survived the suppression of ATP production caused by growth factor depletion and matrix detachment by retaining high ATP levels through 5' adenosine monophosphate-activated protein kinase (AMPK) activation. Our findings provide a systematic understanding as to how mutant IDH induces tumorigenic preconditioning by metabolic rewiring in intrahepatic cholangiocytes.
    DOI:  https://doi.org/10.1038/s41598-019-55211-w
  12. J Clin Med. 2019 Dec 06. pii: E2161. [Epub ahead of print]8(12):
    Rescue of TCA Cycle Dysfunction for Cancer Therapy.
    Jubert Marquez, Jessa Flores, Amy Hyein Kim, Bayalagmaa Nyamaa, Anh Thi Tuyet Nguyen, Nammi Park, Jin Han.
      Mitochondrion, a maternally hereditary, subcellular organelle, is the site of the tricarboxylic acid (TCA) cycle, electron transport chain (ETC), and oxidative phosphorylation (OXPHOS)-the basic processes of ATP production. Mitochondrial function plays a pivotal role in the development and pathology of different cancers. Disruption in its activity, like mutations in its TCA cycle enzymes, leads to physiological imbalances and metabolic shifts of the cell, which contributes to the progression of cancer. In this review, we explored the different significant mutations in the mitochondrial enzymes participating in the TCA cycle and the diseases, especially cancer types, that these malfunctions are closely associated with. In addition, this paper also discussed the different therapeutic approaches which are currently being developed to address these diseases caused by mitochondrial enzyme malfunction.
    Keywords:  mitochondria, TCA, cancer, IDH, SDH, FH, MDH, CRISPR/Cas9, miRNA
    DOI:  https://doi.org/10.3390/jcm8122161
  13. Cell Mol Life Sci. 2019 Dec 10.
    TGFβ-induced metabolic reprogramming during epithelial-to-mesenchymal transition in cancer.
    Wan Hua, Peter Ten Dijke, Sarantos Kostidis, Martin Giera, Marten Hornsveld.
      Metastasis is the most frequent cause of death in cancer patients. Epithelial-to-mesenchymal transition (EMT) is the process in which cells lose epithelial integrity and become motile, a critical step for cancer cell invasion, drug resistance and immune evasion. The transforming growth factor-β (TGFβ) signaling pathway is a major driver of EMT. Increasing evidence demonstrates that metabolic reprogramming is a hallmark of cancer and extensive metabolic changes are observed during EMT. The aim of this review is to summarize and interconnect recent findings that illustrate how changes in glycolysis, mitochondrial, lipid and choline metabolism coincide and functionally contribute to TGFβ-induced EMT. We describe TGFβ signaling is involved in stimulating both glycolysis and mitochondrial respiration. Interestingly, the subsequent metabolic consequences for the redox state and lipid metabolism in cancer cells are found to be in favor of EMT as well. Combined we illustrate that a better understanding of the mechanistic links between TGFβ signaling, cancer metabolism and EMT holds promising strategies for cancer therapy, some of which are already actively being explored in the clinic.
    Keywords:  Cancer; Choline metabolism; EMT; Glycolysis; Lipid metabolism; Mitochondrial metabolism; Signal transduction; TGFβ
    DOI:  https://doi.org/10.1007/s00018-019-03398-6
  14. Nature. 2019 Dec 11.
    KRAS4A directly regulates hexokinase 1.
    Caroline R Amendola, James P Mahaffey, Seth J Parker, Ian M Ahearn, Wei-Ching Chen, Mo Zhou, Helen Court, Jie Shi, Sebastian L Mendoza, Michael J Morten, Eli Rothenberg, Eyal Gottlieb, Youssef Z Wadghiri, Richard Possemato, Stevan R Hubbard, Allan Balmain, Alec C Kimmelman, Mark R Philips.
      The most frequently mutated oncogene in cancer is KRAS, which uses alternative fourth exons to generate two gene products (KRAS4A and KRAS4B) that differ only in their C-terminal membrane-targeting region1. Because oncogenic mutations occur in exons 2 or 3, two constitutively active KRAS proteins-each capable of transforming cells-are encoded when KRAS is activated by mutation2. No functional distinctions among the splice variants have so far been established. Oncogenic KRAS alters the metabolism of tumour cells3 in several ways, including increased glucose uptake and glycolysis even in the presence of abundant oxygen4 (the Warburg effect). Whereas these metabolic effects of oncogenic KRAS have been explained by transcriptional upregulation of glucose transporters and glycolytic enzymes3-5, it is not known whether there is direct regulation of metabolic enzymes. Here we report a direct, GTP-dependent interaction between KRAS4A and hexokinase 1 (HK1) that alters the activity of the kinase, and thereby establish that HK1 is an effector of KRAS4A. This interaction is unique to KRAS4A because the palmitoylation-depalmitoylation cycle of this RAS isoform enables colocalization with HK1 on the outer mitochondrial membrane. The expression of KRAS4A in cancer may drive unique metabolic vulnerabilities that can be exploited therapeutically.
    DOI:  https://doi.org/10.1038/s41586-019-1832-9
  15. Biol Chem. 2019 Dec 09. pii: /j/bchm.ahead-of-print/hsz-2019-0337/hsz-2019-0337.xml. [Epub ahead of print]
    Power to the daughters - mitochondrial and mtDNA transmission during cell division.
    Ina Aretz, Christopher Jakubke, Christof Osman.
      Mitochondria supply virtually all eukaryotic cells with energy through ATP production by oxidative phosphoryplation (OXPHOS). Accordingly, maintenance of mitochondrial function is fundamentally important to sustain cellular health and various diseases have been linked to mitochondrial dysfunction. Biogenesis of OXPHOS complexes crucially depends on mitochondrial DNA (mtDNA) that encodes essential subunits of the respiratory chain and is distributed in multiple copies throughout the mitochondrial network. During cell division, mitochondria, including mtDNA, need to be accurately apportioned to daughter cells. This process requires an intimate and coordinated interplay between the cell cycle, mitochondrial dynamics and the replication and distribution of mtDNA. Recent years have seen exciting advances in the elucidation of the mechanisms that facilitate these processes and essential key players have been identified. Moreover, segregation of qualitatively distinct mitochondria during asymmetric cell division is emerging as an important quality control step, which secures the maintenance of a healthy cell population.
    Keywords:  asymmetric cell division; cell cycle; mammals; mitochondria; quality control; yeast
    DOI:  https://doi.org/10.1515/hsz-2019-0337
  16. Biol Open. 2019 Dec 10. pii: bio.047530. [Epub ahead of print]
    Forcing contacts between mitochondria and the endoplasmic reticulum extends lifespan in a Drosophila model of Alzheimer's disease.
    Juan Garrido-Maraver, Samantha H Y Loh, L Miguel Martins.
      Eukaryotic cells are complex systems containing internal compartments with specialised functions. Among these compartments, the endoplasmic reticulum (ER) plays a major role in processing proteins for modification and delivery to other organelles, whereas mitochondria generate energy in the form of ATP. Mitochondria and the ER form physical interactions, defined as mitochondria-ER contact sites (MERCs) to exchange metabolites such as calcium ions (Ca2+) and lipids. Sites of contact between mitochondria and the ER can regulate biological processes such as ATP generation and mitochondrial division. The interactions between mitochondria and the ER are dynamic and respond to the metabolic state of cells. Changes in MERCs have been linked to metabolic pathologies such as diabetes, neurodegenerative diseases and sleep disruption.Here we explored the consequences of increasing contacts between mitochondria and the ER in flies using a synthetic linker. We showed that enhancing MERCs increases locomotion and extends lifespan. We also showed that, in a Drosophila model of Alzheimer's disease linked to toxic amyloid beta (Aβ), linker expression can suppress motor impairment and extend lifespan. We conclude that strategies for increasing contacts between mitochondria and the ER may improve symptoms of diseases associated with mitochondria dysfunction.
    Keywords:  Alzheimer's disease; Drosophila; Endoplasmic reticulum; Mitochondria; Organelle contacts
    DOI:  https://doi.org/10.1242/bio.047530
  17. MBio. 2019 Dec 10. pii: e02060-19. [Epub ahead of print]10(6):
    The Metabolite Repair Enzyme Phosphoglycolate Phosphatase Regulates Central Carbon Metabolism and Fosmidomycin Sensitivity in Plasmodium falciparum.
    Laure Dumont, Mark B Richardson, Phillip van der Peet, Danushka S Marapana, Tony Triglia, Matthew W A Dixon, Alan F Cowman, Spencer J Williams, Leann Tilley, Malcolm J McConville, Simon A Cobbold.
      Members of the haloacid dehalogenase (HAD) family of metabolite phosphatases play an important role in regulating multiple pathways in Plasmodium falciparum central carbon metabolism. We show that the P. falciparum HAD protein, phosphoglycolate phosphatase (PGP), regulates glycolysis and pentose pathway flux in asexual blood stages via detoxifying the damaged metabolite 4-phosphoerythronate (4-PE). Disruption of the P. falciparum pgp gene caused accumulation of two previously uncharacterized metabolites, 2-phospholactate and 4-PE. 4-PE is a putative side product of the glycolytic enzyme, glyceraldehyde-3-phosphate dehydrogenase, and its accumulation inhibits the pentose phosphate pathway enzyme, 6-phosphogluconate dehydrogenase (6-PGD). Inhibition of 6-PGD by 4-PE leads to an unexpected feedback response that includes increased flux into the pentose phosphate pathway as a result of partial inhibition of upper glycolysis, with concomitant increased sensitivity to antimalarials that target pathways downstream of glycolysis. These results highlight the role of metabolite detoxification in regulating central carbon metabolism and drug sensitivity of the malaria parasite.IMPORTANCE The malaria parasite has a voracious appetite, requiring large amounts of glucose and nutrients for its rapid growth and proliferation inside human red blood cells. The host cell is resource rich, but this is a double-edged sword; nutrient excess can lead to undesirable metabolic reactions and harmful by-products. Here, we demonstrate that the parasite possesses a metabolite repair enzyme (PGP) that suppresses harmful metabolic by-products (via substrate dephosphorylation) and allows the parasite to maintain central carbon metabolism. Loss of PGP leads to the accumulation of two damaged metabolites and causes a domino effect of metabolic dysregulation. Accumulation of one damaged metabolite inhibits an essential enzyme in the pentose phosphate pathway, leading to substrate accumulation and secondary inhibition of glycolysis. This work highlights how the parasite coordinates metabolic flux by eliminating harmful metabolic by-products to ensure rapid proliferation in its resource-rich niche.
    Keywords:  CRISPR; Plasmodium falciparum ; antimalarial; fosmidomycin; glycolysis; isoprenoid; metabolic regulation; metabolism; metabolomics; parasitology; pentose
    DOI:  https://doi.org/10.1128/mBio.02060-19
  18. Br J Cancer. 2019 Dec 10.
    Oncogenic pathways and the electron transport chain: a dangeROS liaison.
    Vittoria Raimondi, Francesco Ciccarese, Vincenzo Ciminale.
      Driver mutations in oncogenic pathways, rewiring of cellular metabolism and altered ROS homoeostasis are intimately connected hallmarks of cancer. Electrons derived from different metabolic processes are channelled into the mitochondrial electron transport chain (ETC) to fuel the oxidative phosphorylation process. Electrons leaking from the ETC can prematurely react with oxygen, resulting in the generation of reactive oxygen species (ROS). Several signalling pathways are affected by ROS, which act as second messengers controlling cell proliferation and survival. On the other hand, oncogenic pathways hijack the ETC, enhancing its ROS-producing capacity by increasing electron flow or by impinging on the structure and organisation of the ETC. In this review, we focus on the ETC as a source of ROS and its modulation by oncogenic pathways, which generates a vicious cycle that resets ROS levels to a higher homoeostatic set point, sustaining the cancer cell phenotype.
    DOI:  https://doi.org/10.1038/s41416-019-0651-y
  19. Cell Signal. 2019 Dec 06. pii: S0898-6568(19)30292-X. [Epub ahead of print]66 109496
    NAMPT maintains mitochondria content via NRF2-PPARα/AMPKα pathway to promote cell survival under oxidative stress.
    An Yu, Ronghua Zhou, Benzeng Xia, Weiwei Dang, Zaiqing Yang, Xiaodong Chen.
      Mitochondria plays a key role in regulating cell death process under stress conditions and it has been indicated that NAMPT overexpression promotes cell survival under genotoxic stress by maintaining mitochondrial NAD+ level. NAMPT is a rate-limiting enzyme for NAD+ production in mammalian cells and it was suggested that NAMPT and NMNAT3 are responsible for mitochondrial NAD+ production to maintain mitochondrial NAD+ pool. However, subsequent studies suggested mitochondrial may lack the NAMPT-NMANT3 pathway to maintain NAD+ level. Therefore, how NAMPT overexpression rescues mitochondrial NAD+ content to promote cell survival in response to genotoxic stress remains elusive. Here, we show that NAMPT promotes cell survival under oxidative stress via both SIRT1 dependent p53-CD38 pathway and SIRT1 independent NRF2-PPARα/AMPKα pathway, and the NRF2-PPARα/AMPKα pathway plays a more profound role in facilitating cell survival than the SIRT1-p53-CD38 pathway does. Mitochondrial content and membrane potential were significantly reduced in response to H2O2 treatment, whereas activated NRF2-PPARα/AMPKα pathway by NAMPT overexpression rescued the mitochondrial membrane potential and content, suggesting that maintained mitochondrial content and integrity by NAMPT overexpression might be one of the key mechanisms to maintain mitochondrial NAD+ level and subsequently dictate cell survival under oxidative stress. Our results indicated that NRF2 is a novel down-stream target of NAMPT, which mediates anti-apoptosis function of NAMPT via maintaining mitochondrial content and membrane potential.
    Keywords:  Cell apoptosis; Mitochondria content; NAMPT; Oxidative stress
    DOI:  https://doi.org/10.1016/j.cellsig.2019.109496
  20. Br J Cancer. 2019 Dec 10.
    Reprogramming of fatty acid metabolism in cancer.
    Nikos Koundouros, George Poulogiannis.
      A common feature of cancer cells is their ability to rewire their metabolism to sustain the production of ATP and macromolecules needed for cell growth, division and survival. In particular, the importance of altered fatty acid metabolism in cancer has received renewed interest as, aside their principal role as structural components of the membrane matrix, they are important secondary messengers, and can also serve as fuel sources for energy production. In this review, we will examine the mechanisms through which cancer cells rewire their fatty acid metabolism with a focus on four main areas of research. (1) The role of de novo synthesis and exogenous uptake in the cellular pool of fatty acids. (2) The mechanisms through which molecular heterogeneity and oncogenic signal transduction pathways, such as PI3K-AKT-mTOR signalling, regulate fatty acid metabolism. (3) The role of fatty acids as essential mediators of cancer progression and metastasis, through remodelling of the tumour microenvironment. (4) Therapeutic strategies and considerations for successfully targeting fatty acid metabolism in cancer. Further research focusing on the complex interplay between oncogenic signalling and dysregulated fatty acid metabolism holds great promise to uncover novel metabolic vulnerabilities and improve the efficacy of targeted therapies.
    DOI:  https://doi.org/10.1038/s41416-019-0650-z
  21. Nat Commun. 2019 Dec 11. 10(1): 5649
    Mutant p53 drives clonal hematopoiesis through modulating epigenetic pathway.
    Sisi Chen, Qiang Wang, Hao Yu, Maegan L Capitano, Sasidhar Vemula, Sarah C Nabinger, Rui Gao, Chonghua Yao, Michihiro Kobayashi, Zhuangzhuang Geng, Aidan Fahey, Danielle Henley, Stephen Z Liu, Sergio Barajas, Wenjie Cai, Eric R Wolf, Baskar Ramdas, Zhigang Cai, Hongyu Gao, Na Luo, Yang Sun, Terrence N Wong, Daniel C Link, Yunlong Liu, H Scott Boswell, Lindsey D Mayo, Gang Huang, Reuben Kapur, Mervin C Yoder, Hal E Broxmeyer, Zhonghua Gao, Yan Liu.
      Clonal hematopoiesis of indeterminate potential (CHIP) increases with age and is associated with increased risks of hematological malignancies. While TP53 mutations have been identified in CHIP, the molecular mechanisms by which mutant p53 promotes hematopoietic stem and progenitor cell (HSPC) expansion are largely unknown. Here we discover that mutant p53 confers a competitive advantage to HSPCs following transplantation and promotes HSPC expansion after radiation-induced stress. Mechanistically, mutant p53 interacts with EZH2 and enhances its association with the chromatin, thereby increasing the levels of H3K27me3 in genes regulating HSPC self-renewal and differentiation. Furthermore, genetic and pharmacological inhibition of EZH2 decreases the repopulating potential of p53 mutant HSPCs. Thus, we uncover an epigenetic mechanism by which mutant p53 drives clonal hematopoiesis. Our work will likely establish epigenetic regulator EZH2 as a novel therapeutic target for preventing CHIP progression and treating hematological malignancies with TP53 mutations.
    DOI:  https://doi.org/10.1038/s41467-019-13542-2
  22. Cell Death Differ. 2019 Dec 09.
    Mitochondrial 4-HNE derived from MAO-A promotes mitoCa2+ overload in chronic postischemic cardiac remodeling.
    Yohan Santin, Loubina Fazal, Yannis Sainte-Marie, Pierre Sicard, Damien Maggiorani, Florence Tortosa, Yasemin Yücel Yücel, Lise Teyssedre, Jacques Rouquette, Marlene Marcellin, Cécile Vindis, Jean C Shih, Olivier Lairez, Odile Burlet-Schiltz, Angelo Parini, Frank Lezoualc'h, Jeanne Mialet-Perez.
      Chronic remodeling postmyocardial infarction consists in various maladaptive changes including interstitial fibrosis, cardiomyocyte death and mitochondrial dysfunction that lead to heart failure (HF). Reactive aldehydes such as 4-hydroxynonenal (4-HNE) are critical mediators of mitochondrial dysfunction but the sources of mitochondrial 4-HNE in cardiac diseases together with its mechanisms of action remain poorly understood. Here, we evaluated whether the mitochondrial enzyme monoamine oxidase-A (MAO-A), which generates H2O2 as a by-product of catecholamine metabolism, is a source of deleterious 4-HNE in HF. We found that MAO-A activation increased mitochondrial ROS and promoted local 4-HNE production inside the mitochondria through cardiolipin peroxidation in primary cardiomyocytes. Deleterious effects of MAO-A/4-HNE on cardiac dysfunction were prevented by activation of mitochondrial aldehyde dehydrogenase 2 (ALDH2), the main enzyme for 4-HNE metabolism. Mechanistically, MAO-A-derived 4-HNE bound to newly identified targets VDAC and MCU to promote ER-mitochondria contact sites and MCU higher-order complex formation. The resulting mitochondrial Ca2+ accumulation participated in mitochondrial respiratory dysfunction and loss of membrane potential, as shown with the protective effects of the MCU inhibitor, RU360. Most interestingly, these findings were recapitulated in a chronic model of ischemic remodeling where pharmacological or genetic inhibition of MAO-A protected the mice from 4-HNE accumulation, MCU oligomer formation and Ca2+ overload, thus mitigating ventricular dysfunction. To our knowledge, these are the first evidences linking MAO-A activation to mitoCa2+ mishandling through local 4-HNE production, contributing to energetic failure and postischemic remodeling.
    DOI:  https://doi.org/10.1038/s41418-019-0470-y
  23. Sci Rep. 2019 Dec 10. 9(1): 18699
    Glycolytic suppression dramatically changes the intracellular metabolic profile of multiple cancer cell lines in a mitochondrial metabolism-dependent manner.
    Reika Shiratori, Kenta Furuichi, Masashi Yamaguchi, Natsumi Miyazaki, Haruna Aoki, Hiroji Chibana, Kousei Ito, Shigeki Aoki.
      Most cancer cells rely on glycolysis to generate ATP, even when oxygen is available. However, merely inhibiting the glycolysis is insufficient for the eradication of cancer cells. One main reason for this is that cancer cells have the potential to adapt their metabolism to their environmental conditions. In this study, we investigated how cancer cells modify their intracellular metabolism when glycolysis is suppressed, using PANC-1 pancreatic cancer cells and two other solid tumor cell lines, A549 and HeLa. Our study revealed that glycolytically suppressed cells upregulated mitochondrial function and relied on oxidative phosphorylation (OXPHOS) to obtain the ATP necessary for their survival. Dynamic changes in intracellular metabolic profiles were also observed, reflected by the reduced levels of TCA cycle intermediates and elevated levels of most amino acids. Glutamine and glutamate were important for this metabolic reprogramming, as these were largely consumed by influx into the TCA cycle when the glycolytic pathway was suppressed. During the reprogramming process, activated autophagy was involved in modulating mitochondrial function. We conclude that upon glycolytic suppression in multiple types of tumor cells, intracellular energy metabolism is reprogrammed toward mitochondrial OXPHOS in an autophagy-dependent manner to ensure cellular survival.
    DOI:  https://doi.org/10.1038/s41598-019-55296-3
  24. Br J Cancer. 2019 Dec 10.
    Metabolism and cancer: the future is now.
    Christian Frezza.
      In the last decade, the field of cancer metabolism transformed itself from being a description of the metabolic features of cancer cells to become a key component of cellular transformation. Now, the potential role of this field in cancer biology is ready to be unravelled.
    DOI:  https://doi.org/10.1038/s41416-019-0667-3
  25. Cell Death Differ. 2019 Dec 09.
    Prohibitin levels regulate OMA1 activity and turnover in neurons.
    Corey J Anderson, Anja Kahl, Hannah Fruitman, Liping Qian, Ping Zhou, Giovanni Manfredi, Costantino Iadecola.
      The GTPase OPA1 and the AAA-protease OMA1 serve well-established roles in mitochondrial stress responses and mitochondria-initiated cell death. In addition to its role in mitochondrial membrane fusion, cristae structure, and bioenergetic function, OPA1 controls apoptosis by sequestering cytochrome c (cyt c) in mitochondrial cristae. Cleavage of functional long OPA1 (L-OPA1) isoforms by OMA1 inactivates mitochondrial fusion and primes apoptosis. OPA1 cleavage is regulated by the prohibitin (PHB) complex, a heteromeric, ring-shaped mitochondrial inner membrane scaffolding complex composed of PHB1 and PHB2. In neurons, PHB plays a protective role against various stresses, and PHB deletion destabilizes OPA1 causing neurodegeneration. While deletion of OMA1 prevents OPA1 destabilization and attenuates neurodegeneration in PHB2 KO mice, how PHB levels regulate OMA1 is still unknown. Here, we investigate the effects of modulating neuronal PHB levels on OMA1 stability and OPA1 cleavage. We demonstrate that PHB promotes OMA1 turnover, effectively decreasing the pool of OMA1. Further, we show that OMA1 binds to cardiolipin (CL), a major mitochondrial phospholipid. CL binding promotes OMA1 turnover, as we show that deleting the CL-binding domain of OMA1 decreases its turnover rate. Since PHB is known to stabilize CL, these data suggest that PHB modulates OMA1 through CL. Furthermore, we show that PHB decreases cyt c release induced by tBID and attenuates caspase 9 activation in response to hypoxic stress in neurons. Taken together, our results suggest that PHB-mediated CL stabilization regulates stress responses and cell death through OMA1 turnover and cyt c release.
    DOI:  https://doi.org/10.1038/s41418-019-0469-4
  26. Br J Cancer. 2019 Dec 10.
    Kinetic modelling of quantitative proteome data predicts metabolic reprogramming of liver cancer.
    Nikolaus Berndt, Antje Egners, Guido Mastrobuoni, Olga Vvedenskaya, Athanassios Fragoulis, Aurélien Dugourd, Sascha Bulik, Matthias Pietzke, Chris Bielow, Rob van Gassel, Steven W Olde Damink, Merve Erdem, Julio Saez-Rodriguez, Hermann-Georg Holzhütter, Stefan Kempa, Thorsten Cramer.
      BACKGROUND: Metabolic alterations can serve as targets for diagnosis and cancer therapy. Due to the highly complex regulation of cellular metabolism, definite identification of metabolic pathway alterations remains challenging and requires sophisticated experimentation.METHODS: We applied a comprehensive kinetic model of the central carbon metabolism (CCM) to characterise metabolic reprogramming in murine liver cancer.
    RESULTS: We show that relative differences of protein abundances of metabolic enzymes obtained by mass spectrometry can be used to assess their maximal velocity values. Model simulations predicted tumour-specific alterations of various components of the CCM, a selected number of which were subsequently verified by in vitro and in vivo experiments. Furthermore, we demonstrate the ability of the kinetic model to identify metabolic pathways whose inhibition results in selective tumour cell killing.
    CONCLUSIONS: Our systems biology approach establishes that combining cellular experimentation with computer simulations of physiology-based metabolic models enables a comprehensive understanding of deregulated energetics in cancer. We propose that modelling proteomics data from human HCC with our approach will enable an individualised metabolic profiling of tumours and predictions of the efficacy of drug therapies targeting specific metabolic pathways.
    DOI:  https://doi.org/10.1038/s41416-019-0659-3
  27. Trends Cancer. 2019 Dec;pii: S2405-8033(19)30200-6. [Epub ahead of print]5(12): 822-834
    Metabolic Regulation of Macrophage Polarization in Cancer.
    Kamiya Mehla, Pankaj K Singh.
      Macrophages act as scavengers, modulating the immune response against pathogens and maintaining tissue homeostasis. Metabolism governs macrophage differentiation, polarization, mobilization, and the ability to mount an effective antitumor response. However, in cancer, the tumor microenvironment (TME) can actively reprogram macrophage metabolism either by direct exchange of metabolites or through cytokines and other signaling mediators. Thus, metabolic reprogramming holds potential for modulating macrophages and developing new therapeutic approaches. In this review, we provide an overview of macrophage metabolism as it relates to macrophage function and plasticity in cancer.
    Keywords:  M1–M2 macrophage polarization; MUC1; cancer; immunometabolism; metabolic reprogramming; tumor microenvironment; tumor-associated macrophages
    DOI:  https://doi.org/10.1016/j.trecan.2019.10.007
  28. Cell Metab. 2019 Dec 03. pii: S1550-4131(19)30617-5. [Epub ahead of print]
    Greasing the Wheels of the Cancer Machine: The Role of Lipid Metabolism in Cancer.
    Marteinn Thor Snaebjornsson, Sudha Janaki-Raman, Almut Schulze.
      Altered lipid metabolism is among the most prominent metabolic alterations in cancer. Enhanced synthesis or uptake of lipids contributes to rapid cancer cell growth and tumor formation. Lipids are a highly complex group of biomolecules that not only constitute the structural basis of biological membranes but also function as signaling molecules and an energy source. Here, we summarize recent evidence implicating altered lipid metabolism in different aspects of the cancer phenotype and discuss potential strategies by which targeting lipid metabolism could provide a therapeutic window for cancer treatment.
    Keywords:  cancer; fatty acid desaturation; fatty acids; lipid metabolism; lipid remodeling; mevalonate
    DOI:  https://doi.org/10.1016/j.cmet.2019.11.010
  29. Cancer Lett. 2019 Dec 09. pii: S0304-3835(19)30616-0. [Epub ahead of print]
    ATP citrate lyase: a central metabolic enzyme in cancer.
    Philippe Icard, Zherui Wu, Ludovic Fournel, Antoine Coquerel, Hubert Lincet, Marco Alifano.
      ACLY links energy metabolism provided by catabolic pathways to biosynthesis. ACLY, which has been found to be overexpressed in many cancers, converts citrate into acetyl-CoA and OAA. The first of these moleculessupportsprotein acetylation, in particular that of histone, and de novo lipid synthesis, and the last one sustains the production of aspartate (required for nucleotide and polyamine synthesis) and the regeneration of NADPH,H+(consumed in redox reaction and biosynthesis). ACLY transcription is promoted by SREBP1, its activity is stabilized by acetylation and promoted by AKT phosphorylation (stimulated by growth factors and glucose abundance). ACLY plays a pivotal role in cancer metabolism through the potential deprivation of cytosolic citrate, a process promoting glycolysis through the enhancement of the activities of PFK 1 and 2 with concomitant activation of oncogenic drivers such as PI3K/AKT which activate ACLY and the Warburg effect in a feed-back loop. Pending the development of specific inhibitors and tailored methods for identifying which specific metabolism is involved in the development of each tumor, ACLY could be targeted by inhibitors such as hydroxycitrate and bempedoic acid. The administration of citrate at high level mimics a strong inhibition of ACLY and could be tested to strengthen the effects of current therapies.
    Keywords:  ACLY; AKT; acetyl-CoA; citrate; metabolism; oxaloacetate
    DOI:  https://doi.org/10.1016/j.canlet.2019.12.010
  30. EMBO J. 2019 Dec 10. e100875
    LRRK2 regulates endoplasmic reticulum-mitochondrial tethering through the PERK-mediated ubiquitination pathway.
    Toshihiko Toyofuku, Yuki Okamoto, Takako Ishikawa, Shigemi Sasawatari, Atsushi Kumanogoh.
      Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common cause of familial Parkinson's disease (PD). Impaired mitochondrial function is suspected to play a major role in PD. Nonetheless, the underlying mechanism by which impaired LRRK2 activity contributes to PD pathology remains unclear. Here, we identified the role of LRRK2 in endoplasmic reticulum (ER)-mitochondrial tethering, which is essential for mitochondrial bioenergetics. LRRK2 regulated the activities of E3 ubiquitin ligases MARCH5, MULAN, and Parkin via kinase-dependent protein-protein interactions. Kinase-active LRRK2(G2019S) dissociated from these ligases, leading to their PERK-mediated phosphorylation and activation, thereby increasing ubiquitin-mediated degradation of ER-mitochondrial tethering proteins. By contrast, kinase-dead LRRK2(D1994A)-bound ligases blocked PERK-mediated phosphorylation and activation of E3 ligases, thereby increasing the levels of ER-mitochondrial tethering proteins. Thus, the role of LRRK2 in the ER-mitochondrial interaction represents an important control point for cell fate and pathogenesis in PD.
    Keywords:   PERK ; LRRK2; endoplasmic reticulum; mitochondria; ubiquitin ligase
    DOI:  https://doi.org/10.15252/embj.2018100875
  31. Cancer Res. 2019 Dec 15. 79(24): 6074-6075
    Targeting Mitochondrial Fission to Trigger Cancer Cell Death.
    V Ashutosh Rao.
      Carefully orchestrated interactions between mitochondrial proteins that facilitate cell death remain a topic of intense research, however, key steps remain to be elucidated, especially those that drive selective killing in cancer cells. How mitochondrial dysfunction and its regulation in cancer can be robustly leveraged for anticancer cell killing in a heterogeneous population of cells within a tumor also remains a promising but unfulfilled premise. Toward this goal, in this issue of Cancer Research, Seo and colleagues have identified the protein complex between mitochondrial fission factor (MFF1 and MFF2) and voltage-dependent anion channel (VDAC1) as a novel regulator of mitochondrial cell death and a potential target for selective cancer cell killing.See related article by Seo et al., p. 6215.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-19-3276
  32. Br J Cancer. 2019 Dec 10.
    Window of opportunity clinical trial designs to study cancer metabolism.
    Francesca Aroldi, Simon R Lord.
      Window of opportunity trials exploit the 'window' of time after cancer diagnosis, typically prior to initiation of cancer therapy. In recent years this study design has become a more regular feature of drug development, as this 'window' provides an opportunity to carry out a thorough pharmacodynamic assessment of a therapy of interest in tumours that are unperturbed by prior treatment. Many of the first window trials interrogated the bioactivity of drugs being repurposed for cancer treatment, in particular the anti-mitochondrial agent, metformin. In this review, we describe examples of window study designs that have been used to assess drugs that target cancer metabolism with a focus on metformin. In addition, we discuss how window studies may aid the development of molecular metabolic cancer imaging.
    DOI:  https://doi.org/10.1038/s41416-019-0621-4
  33. Proc Natl Acad Sci U S A. 2019 Dec 11. pii: 201911584. [Epub ahead of print]
    FOXA1 upregulation promotes enhancer and transcriptional reprogramming in endocrine-resistant breast cancer.
    Xiaoyong Fu, Resel Pereira, Carmine De Angelis, Jamunarani Veeraraghavan, Sarmistha Nanda, Lanfang Qin, Maria L Cataldo, Vidyalakshmi Sethunath, Sepideh Mehravaran, Carolina Gutierrez, Gary C Chamness, Qin Feng, Bert W O'Malley, Pier Selenica, Britta Weigelt, Jorge S Reis-Filho, Ofir Cohen, Nikhil Wagle, Agostina Nardone, Rinath Jeselsohn, Myles Brown, Mothaffar F Rimawi, C Kent Osborne, Rachel Schiff.
      Forkhead box A1 (FOXA1) is a pioneer factor that facilitates chromatin binding and function of lineage-specific and oncogenic transcription factors. Hyperactive FOXA1 signaling due to gene amplification or overexpression has been reported in estrogen receptor-positive (ER+) endocrine-resistant metastatic breast cancer. However, the molecular mechanisms by which FOXA1 up-regulation promotes these processes and the key downstream targets of the FOXA1 oncogenic network remain elusive. Here, we demonstrate that FOXA1 overexpression in ER+ breast cancer cells drives genome-wide enhancer reprogramming to activate prometastatic transcriptional programs. Up-regulated FOXA1 employs superenhancers (SEs) to synchronize transcriptional reprogramming in endocrine-resistant breast cancer cells, reflecting an early embryonic development process. We identify the hypoxia-inducible transcription factor hypoxia-inducible factor-2α (HIF-2α) as the top high FOXA1-induced SE target, mediating the impact of high FOXA1 in activating prometastatic gene sets and pathways associated with poor clinical outcome. Using clinical ER+/HER2- metastatic breast cancer datasets, we show that the aberrant FOXA1/HIF-2α transcriptional axis is largely nonconcurrent with the ESR1 mutations, suggesting different mechanisms of endocrine resistance and treatment strategies. We further demonstrate the selective efficacy of an HIF-2α antagonist, currently in clinical trials for advanced kidney cancer and recurrent glioblastoma, in reducing the clonogenicity, migration, and invasion of endocrine-resistant breast cancer cells expressing high FOXA1. Our study has uncovered high FOXA1-induced enhancer reprogramming and HIF-2α-dependent transcriptional programs as vulnerable targets for treating endocrine-resistant and metastatic breast cancer.
    Keywords:  FOXA1; breast cancer; endocrine resistance; enhancer/transcriptional reprogramming; metastasis
    DOI:  https://doi.org/10.1073/pnas.1911584116
  34. Cell Chem Biol. 2019 Dec 05. pii: S2451-9456(19)30393-9. [Epub ahead of print]
    A Systems Chemoproteomic Analysis of Acyl-CoA/Protein Interaction Networks.
    Michaella J Levy, David C Montgomery, Mihaela E Sardiu, Jose L Montano, Sarah E Bergholtz, Kellie D Nance, Abigail L Thorpe, Stephen D Fox, Qishan Lin, Thorkell Andresson, Laurence Florens, Michael P Washburn, Jordan L Meier.
      Acyl-coenzyme A (CoA)/protein interactions are essential for life. Despite this importance, their global scope and selectivity remains undefined. Here, we describe CATNIP (CoA/AcetylTraNsferase Interaction Profiling), a chemoproteomic platform for the high-throughput analysis of acyl-CoA/protein interactions in endogenous proteomes. First, we apply CATNIP to identify acetyl-CoA-binding proteins through unbiased clustering of competitive dose-response data. Next, we use this method to profile the selectivity of acyl-CoA/protein interactions, leading to the identification of specific acyl-CoA engagement signatures. Finally, we apply systems-level analyses to assess the features of protein networks that may interact with acyl-CoAs, and use a strategy for high-confidence proteomic annotation of acetyl-CoA-binding proteins to identify a site of non-enzymatic acylation in the NAT10 acetyltransferase domain that is likely driven by acyl-CoA binding. Overall, our studies illustrate how chemoproteomics and systems biology can be integrated to understand the roles of acyl-CoA metabolism in biology and disease.
    Keywords:  acetyl-CoA; acetylation; acetyltransferase; activity-based protein profiling; chemical proteomics; epigenetics; malonylation; metabolism; pharmacology; systems biology
    DOI:  https://doi.org/10.1016/j.chembiol.2019.11.011
  35. Clin Transl Immunology. 2019 ;8(11): e01091
    The clock is ticking: the impact of ageing on T cell metabolism.
    Kylie M Quinn, Riya Palchaudhuri, Clovis S Palmer, Nicole L La Gruta.
      It is now clear that access to specific metabolic programmes controls the survival and function of various immune cell populations, including T cells. Efficient naïve and memory T cell homoeostasis requires the use of specific metabolic pathways and differentiation requires rapid and dramatic metabolic remodelling. While we are beginning to appreciate the crucial role of metabolic programming during normal T cell physiology, many of the potential impacts of ageing on metabolic homoeostasis and remodelling in T cells remain unexplored. This review will outline our current understanding of T cell metabolism and explore age-related metabolic changes that are postulated or have been demonstrated to impact T cell function.
    Keywords:  T cell; ageing; cell signalling; immunosenescence; metabolism
    DOI:  https://doi.org/10.1002/cti2.1091
  36. J Biochem. 2019 Dec 11. pii: mvz111. [Epub ahead of print]
    The "mitochondrial contact site and cristae organising system" (MICOS) in health and human disease.
    Matthew Eramo, Valerie Lisnyak, Luke E Formosa, Michael T Ryan.
      The "Mitochondrial Contact Site and Cristae Organising System" (MICOS) is an essential protein complex that promotes the formation, maintenance and stability of mitochondrial cristae. As such, loss of core MICOS components disrupts cristae structure and impairs mitochondrial function. Aberrant mitochondrial cristae morphology and diminished mitochondrial function is a pathological hallmark observed across many human diseases such as neurodegenerative conditions, obesity and diabetes mellitus, cardiomyopathy, and in muscular dystrophies and myopathies. While mitochondrial abnormalities are often an associated secondary effect to the pathological disease process, a direct role for the MICOS in health and human disease is emerging. This review describes the role of MICOS in the maintenance of mitochondrial architecture, and summarises both the direct and associated roles of the MICOS in human disease.
    Keywords:  MICOS; Mitochondria; cristae; membrane organisation
    DOI:  https://doi.org/10.1093/jb/mvz111
  37. Trends Cancer. 2019 Dec;pii: S2405-8033(19)30219-5. [Epub ahead of print]5(12): 809-821
    The Metabolic Interplay between Cancer and Other Diseases.
    Anne Le, Sunag Udupa, Cissy Zhang.
      Over the past decade, knowledge of cancer metabolism has expanded exponentially and has provided several clinically relevant targets for cancer therapy. Although these current approaches have shown promise, there are very few studies showing how seemingly unrelated metabolic processes in other diseases can readily occur in cancer. Moreover, the striking metabolic overlap between cancer and other diseases such as diabetes, cardiovascular, neurological, obesity, and aging has provided key therapeutic strategies that have even begun to be translated into clinical trials. These promising results necessitate consideration of the interconnected metabolic network while studying the metabolism of cancer. This review article discusses how cancer metabolism is intertwined with systemic metabolism and how knowledge from other diseases can help to broaden therapeutic opportunities for cancer.
    Keywords:  aging; cancer metabolism; cardiovascular diseases; diabetes; neurological diseases; obesity
    DOI:  https://doi.org/10.1016/j.trecan.2019.10.012
  38. Autophagy. 2019 Dec 10. 1-20
    CASP9 (caspase 9) is essential for autophagosome maturation through regulation of mitochondrial homeostasis.
    Hyun-Kyu An, Kyung Min Chung, Hyunhee Park, Jihyun Hong, Ji-Eun Gim, Hyosun Choi, Ye Won Lee, Jieun Choi, Ji Young Mun, Seong-Woon Yu.
      CASP9 (caspase 9) is a well-known initiator caspase which triggers intrinsic apoptosis. Recent studies also suggest various non-apoptotic roles of CASP9, including macroautophagy/autophagy regulation. However, the involvement of CASP9 in autophagy and its molecular mechanisms are not well understood. Here we report the non-apoptotic function of CASP9 in positive regulation of autophagy through maintenance of mitochondrial homeostasis. Growth factor or amino acid deprivation-induced autophagy activated CASP9, but without apoptotic features. Pharmacological inhibition or genetic ablation of CASP9 decreased autophagy flux, while ectopic expression of CASP9 rescued autophagy defects. In CASP9 knockout (KO) cells, initiation and elongation of phagophore membranes were normal, but sealing of the membranes and autophagosome maturation were impaired, and the lifetime of autophagosomes was prolonged. Ablation of CASP9 caused an accumulation of inactive ATG3 and decreased lipidation of the Atg8-family members, most severely that of GABARAPL1. Moreover, it resulted in abnormal mitochondrial morphology with depolarization of the membrane potential, reduced reactive oxygen species production, and aberrant accumulation of mitochondrial fusion-fission proteins. CASP9 expression or exogenously added H2O2 in the CASP9 KO cells corrected the ATG3 level and lipidation status of Atg8-family members, and restored autophagy flux. Of note, only CASP9 expression but not H2O2 rescued mitochondrial defects, revealing regulation of mitochondrial homeostasis by CASP9. Our findings suggest a new regulatory link between mitochondria and autophagy through CASP9 activity, especially for the proper operation of the Atg8-family conjugation system and autophagosome closure and maturation.Abbreviations: AA: amino acid; ACD: autophagic cell death; ACTB: actin beta; ANXA5: annexin A5; APAF1: apoptotic peptidase activating factor 1; Atg: autophagy related; ATG16L1: autophagy related 16 like 1; BafA1: bafilomycin A1; BCL2: BCL2 apoptosis regulator; BECN1: beclin 1; CARD: caspase recruitment domain containing; CASP: caspase; CM-H2DCFDA: chloromethyl-2',7'-dichlorodihydrofluorescein diacetate; Δψm: mitochondrial membrane potential; DN: dominant-negative; DNM1L/DRP1: dynamin 1 like; EBSS: Earle's balanced salt solution; GABARAP: GABA type A receptor-associated protein; GABARAPL1: GABA type A receptor associated protein like 1; GABARAPL2: GABA type A receptor associated protein like 2; HCN: hippocampal neural stem cells; IAM: inner autophagosome membrane; INS: insulin; KO: knockout; LEHD: Z-LEHD-fmk; MAP1LC3: microtubule associated protein 1 light chain 3; MFN1: mitofusin 1; MFN2: mitofusin 2; MTORC1: mechanistic target of rapamycin kinase complex 1; PARP1: poly(ADP-ribose) polymerase 1; PBS: phosphate-buffered saline; PE: phosphatidylethanolamine; ROS: reactive oxygen species; sgRNA: single guide RNA; SR-SIM: super-resolution structured illumination microscopy; SQSTM1: sequestosome 1; STS: staurosporine; STX17: syntaxin 17; TMRE: tetramethylrhodamine ethyl ester; TUBB: tubulin beta class I; ULK1: unc-51 like autophagy activating kinase 1; WT: wild type; ZFYVE1/DFCP1: zinc finger FYVE-type containing 1.
    Keywords:  ATG3; autophagosome maturation; caspase 9; membrane closure; mitochondria; reactive oxygen species
    DOI:  https://doi.org/10.1080/15548627.2019.1695398
  39. BMB Rep. 2019 Dec 10. pii: 4830. [Epub ahead of print]
    Techniques for investigating mitochondrial gene expression.
    Dongkeun Park, Soyeon Lee, Kyung-Tai Min.
      The mitochondrial genome encodes 13 proteins that are components of the oxidative phosphorylation system (OXPHOS), suggesting that precise regulation of these genes is crucial for maintaining OXPHOS functions, including ATP production, calcium buffering, cell signaling, ROS production, and apoptosis. Furthermore, heteroplasmy or mis-regulation of gene expression in mitochondria frequently is associated with human mitochondrial diseases. Thus, various approaches have been developed to investigate the roles of genes encoded by the mitochondrial genome. In this review, we will discuss a wide range of techniques available for investigating the mitochondrial genome, mitochondrial transcription, and mitochondrial translation, which provide a useful guide to understanding mitochondrial gene expression.
  40. Sci Rep. 2019 Dec 11. 9(1): 18907
    Multiphoton NAD(P)H FLIM reveals metabolic changes in individual cell types of the intact cochlea upon sensorineural hearing loss.
    Paromita Majumder, Thomas S Blacker, Lisa S Nolan, Michael R Duchen, Jonathan E Gale.
      An increasing volume of data suggests that changes in cellular metabolism have a major impact on the health of tissues and organs, including in the auditory system where metabolic alterations are implicated in both age-related and noise-induced hearing loss. However, the difficulty of access and the complex cyto-architecture of the organ of Corti has made interrogating the individual metabolic states of the diverse cell types present a major challenge. Multiphoton fluorescence lifetime imaging microscopy (FLIM) allows label-free measurements of the biochemical status of the intrinsically fluorescent metabolic cofactors NADH and NADPH with subcellular spatial resolution. However, the interpretation of NAD(P)H FLIM measurements in terms of the metabolic state of the sample are not completely understood. We have used this technique to explore changes in metabolism associated with hearing onset and with acquired (age-related and noise-induced) hearing loss. We show that these conditions are associated with altered NAD(P)H fluorescence lifetimes, use a simple cell model to confirm an inverse relationship between τbound and oxidative stress, and propose such changes as a potential index of oxidative stress applicable to all mammalian cell types.
    DOI:  https://doi.org/10.1038/s41598-019-55329-x
  41. Cancers (Basel). 2019 Dec 09. pii: E1983. [Epub ahead of print]11(12):
    p53-Mediated Tumor Suppression: DNA-Damage Response and Alternative Mechanisms.
    Consuelo Pitolli, Ying Wang, Eleonora Candi, Yufang Shi, Gerry Melino, Ivano Amelio.
      The tumor suppressor p53 regulates different cellular pathways involved in cell survival, DNA repair, apoptosis, and senescence. However, according to an increasing number of studies, the p53-mediated canonical DNA damage response is dispensable for tumor suppression. p53 is involved in mechanisms regulating many other cellular processes, including metabolism, autophagy, and cell migration and invasion, and these pathways might crucially contribute to its tumor suppressor function. In this review we summarize the canonical and non-canonical functions of p53 in an attempt to provide an overview of the potentially crucial aspects related to its tumor suppressor activity.
    Keywords:  cancer; cell death; epigenetics; metabolism
    DOI:  https://doi.org/10.3390/cancers11121983
  42. Br J Cancer. 2019 Dec 10.
    MFN1-dependent alteration of mitochondrial dynamics drives hepatocellular carcinoma metastasis by glucose metabolic reprogramming.
    Ze Zhang, Tian-En Li, Mo Chen, Da Xu, Ying Zhu, Bei-Yuan Hu, Zhi-Fei Lin, Jun-Jie Pan, Xuan Wang, Chao Wu, Yan Zheng, Lu Lu, Hu-Liang Jia, Song Gao, Qiong-Zhu Dong, Lun-Xiu Qin.
      BACKGROUND: Mitochondrial dynamics plays an important role in tumour progression. However, how these dynamics integrate tumour metabolism in hepatocellular carcinoma (HCC) metastasis is still unclear.METHODS: The mitochondrial fusion protein mitofusin-1 (MFN1) expression and its prognostic value are detected in HCC. The effects and underlying mechanisms of MFN1 on HCC metastasis and metabolic reprogramming are analysed both in vitro and in vivo.
    RESULTS: Mitochondrial dynamics, represented by constant fission and fusion, are found to be associated with HCC metastasis. High metastatic HCC displays excessive mitochondrial fission. Among genes involved in mitochondrial dynamics, MFN1 is identified as a leading downregulated candidate that is closely associated with HCC metastasis and poor prognosis. While promoting mitochondrial fusion, MFN1 inhibits cell proliferation, invasion and migration capacity both in vitro and in vivo. Mechanistically, disruption of mitochondrial dynamics by depletion of MFN1 triggers the epithelial-to-mesenchymal transition (EMT) of HCC. Moreover, MFN1 modulates HCC metastasis by metabolic shift from aerobic glycolysis to oxidative phosphorylation. Treatment with glycolytic inhibitor 2-Deoxy-D-glucose (2-DG) significantly suppresses the effects induced by depletion of MFN1.
    CONCLUSIONS: Our results reveal a critical involvement of mitochondrial dynamics in HCC metastasis via modulating glucose metabolic reprogramming. MFN1 may serve as a novel potential therapeutic target for HCC.
    DOI:  https://doi.org/10.1038/s41416-019-0658-4
  43. Circulation. 2019 Dec 10. 140(24): 1968-1970
    Targeting Succinate Metabolism in Ischemia/Reperfusion Injury.
    Duvaraka Kula-Alwar, Hiran A Prag, Thomas Krieg.
      
    Keywords:  malonic acid; mitochondria; reactive oxygen species; succinic acid
    DOI:  https://doi.org/10.1161/CIRCULATIONAHA.119.042791
  44. Cell Stress. 2019 Nov 04. 3(12): 361-368
    Metabolism remodeling in pancreatic ductal adenocarcinoma.
    Jin-Tao Li, Yi-Ping Wang, Miao Yin, Qun-Ying Lei.
      Pancreatic ductal adenocarcinoma (PDAC) is predicted to become the second leading cause of death of patients with malignant cancers by 2030. Current options of PDAC treatment are limited and the five-year survival rate is less than 8%, leading to an urgent need to explore innovatively therapeutic strategies. PDAC cells exhibit extensively reprogrammed metabolism to meet their energetic and biomass demands under extremely harsh conditions. The metabolic changes are closely linked to signaling triggered by activation of oncogenes like KRAS as well as inactivation of tumor suppressors. Furthermore, tumor microenvironmental factors including extensive desmoplastic stroma reaction result in series of metabolism remodeling to facilitate PDAC development. In this review, we focus on the dysregulation of metabolism in PDAC and its surrounding microenvironment to explore potential metabolic targets in PDAC therapy.
    Keywords:  KRAS; PDAC; metabolism; tumor microenvironment
    DOI:  https://doi.org/10.15698/cst2019.12.205
  45. Nature. 2019 Dec 11.
    Plasma membrane V-ATPase controls oncogenic RAS-induced macropinocytosis.
    Craig Ramirez, Andrew D Hauser, Emily A Vucic, Dafna Bar-Sagi.
      Oncogenic activation of RAS is associated with the acquisition of a unique set of metabolic dependencies that contribute to tumour cell fitness. Cells that express oncogenic RAS are able to internalize and degrade extracellular protein via a fluid-phase uptake mechanism termed macropinocytosis1. There is increasing recognition of the role of this RAS-dependent process in the generation of free amino acids that can be used to support tumour cell growth under nutrient-limiting conditions2. However, little is known about the molecular steps that mediate the induction of macropinocytosis by oncogenic RAS. Here we identify vacuolar ATPase (V-ATPase) as an essential regulator of RAS-induced macropinocytosis. Oncogenic RAS promotes the translocation of V-ATPase from intracellular membranes to the plasma membrane via a pathway that requires the activation of protein kinase A by a bicarbonate-dependent soluble adenylate cyclase. Accumulation of V-ATPase at the plasma membrane is necessary for the cholesterol-dependent plasma-membrane association of RAC1, a prerequisite for the stimulation of membrane ruffling and macropinocytosis. These observations establish a link between V-ATPase trafficking and nutrient supply by macropinocytosis that could be exploited to curtail the metabolic adaptation capacity of RAS-mutant tumour cells.
    DOI:  https://doi.org/10.1038/s41586-019-1831-x
  46. Front Mol Biosci. 2019 ;6 116
    The Role of Iron Regulation in Immunometabolism and Immune-Related Disease.
    Shane J F Cronin, Clifford J Woolf, Guenter Weiss, Josef M Penninger.
      Immunometabolism explores how the intracellular metabolic pathways in immune cells can regulate their function under different micro-environmental and (patho-)-physiological conditions (Pearce, 2010; Buck et al., 2015; O'Neill and Pearce, 2016). In the last decade great advances have been made in studying and manipulating metabolic programs in immune cells. Immunometabolism has primarily focused on glycolysis, the TCA cycle and oxidative phosphorylation (OXPHOS) as well as free fatty acid synthesis and oxidation. These pathways are important for providing the energy needs of cell growth, membrane rigidity, cytokine production and proliferation. In this review, we will however, highlight the specific role of iron metabolism at the cellular and organismal level, as well as how the bioavailability of this metal orchestrates complex metabolic programs in immune cell homeostasis and inflammation. We will also discuss how dysregulation of iron metabolism contributes to alterations in the immune system and how these novel insights into iron regulation can be targeted to metabolically manipulate immune cell function under pathophysiological conditions, providing new therapeutic opportunities for autoimmunity and cancer.
    Keywords:  BH4; anemia; infection; iron; mitochondria
    DOI:  https://doi.org/10.3389/fmolb.2019.00116
  47. Cell Metab. 2019 Dec 02. pii: S1550-4131(19)30611-4. [Epub ahead of print]
    Ten-Hour Time-Restricted Eating Reduces Weight, Blood Pressure, and Atherogenic Lipids in Patients with Metabolic Syndrome.
    Michael J Wilkinson, Emily N C Manoogian, Adena Zadourian, Hannah Lo, Savannah Fakhouri, Azarin Shoghi, Xinran Wang, Jason G Fleischer, Saket Navlakha, Satchidananda Panda, Pam R Taub.
      In animal models, time-restricted feeding (TRF) can prevent and reverse aspects of metabolic diseases. Time-restricted eating (TRE) in human pilot studies reduces the risks of metabolic diseases in otherwise healthy individuals. However, patients with diagnosed metabolic syndrome often undergo pharmacotherapy, and it has never been tested whether TRE can act synergistically with pharmacotherapy in animal models or humans. In a single-arm, paired-sample trial, 19 participants with metabolic syndrome and a baseline mean daily eating window of ≥14 h, the majority of whom were on a statin and/or antihypertensive therapy, underwent 10 h of TRE (all dietary intake within a consistent self-selected 10 h window) for 12 weeks. We found this TRE intervention improves cardiometabolic health for patients with metabolic syndrome receiving standard medical care including high rates of statin and anti-hypertensive use. TRE is a potentially powerful lifestyle intervention that can be added to standard medical practice to treat metabolic syndrome. VIDEO ABSTRACT.
    Keywords:  TRE; TRF; circadian rhythm; dyslipidemia; hypertension; impaired glucose tolerance; metabolic syndrome; obesity; time-restricted eating
    DOI:  https://doi.org/10.1016/j.cmet.2019.11.004
  48. Int J Mol Sci. 2019 Dec 11. pii: E6239. [Epub ahead of print]20(24):
    LDHA Suppression Altering Metabolism Inhibits Tumor Progress by an Organic Arsenical.
    Yu-Jiao Liu, Xiao-Yang Fan, An-Dong Wang, Yin-Zheng Xia, Wen-Rong Fu, Jun-Yi Liu, Feng-Lei Jiang, Yi Liu.
      Based on the potential therapeutic value in targeting metabolism for the treatment of cancer, an organic arsenical PDT-BIPA was fabricated, which exerted selective anti-cancer activity in vitro and in vivo via targeting lactate dehydrogenase A (LDHA) to remodel the metabolic pathway. In details, the precursor PDT-BIPA directly inhibited the function of LDHA and converted the glycolysis to oxidative phosphorylation causing ROS burst and mitochondrial dysfunction. PDT-BIPA also altered several gene expression, such as HIF-1α and C-myc, to support the metabolic remodeling. All these changes lead to caspase family-dependent cell apoptosis in vivo and in vitro without obvious side effect. Our results provided this organic arsenical precursor as a promising anticancer candidate and suggested metabolism as a target for cancer therapies.
    Keywords:  ROS; apoptosis; lactate dehydrogenase A; metabolism; mitochondria; organic arsenicals
    DOI:  https://doi.org/10.3390/ijms20246239
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