bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2019‒06‒02
forty-four papers selected by
Christian Frezza,

  1. CDK9 Inhibition Induces a Metabolic Switch that Renders Prostate Cancer Cells Dependent on Fatty Acid Oxidation.
  2. Malignant manipulaTORs of metabolism: suppressing BCAA catabolism to enhance mTORC1 activity.
  3. Polyamines and eIF5A Hypusination Modulate Mitochondrial Respiration and Macrophage Activation.
  4. Metabolic control of BRISC-SHMT2 assembly regulates immune signalling.
  5. Adipocyte ACLY Facilitates Dietary Carbohydrate Handling to Maintain Metabolic Homeostasis in Females.
  6. NF-κB and mitochondria cross paths in cancer: Mitochondrial metabolism and beyond.
  7. Pyruvate Dehydrogenase Kinase Is a Metabolic Checkpoint for Polarization of Macrophages to the M1 Phenotype.
  8. Metabolic pathways regulating colorectal cancer initiation and progression.
  9. CerS6-Derived Sphingolipids Interact with Mff and Promote Mitochondrial Fragmentation in Obesity.
  10. Epigenetic Control of Mitochondrial Fission Enables Self-Renewal of Stem-like Tumor Cells in Human Prostate Cancer.
  11. Regulation of Mitochondrial Biogenesis as a Way for Active Longevity: Interaction Between the Nrf2 and PGC-1α Signaling Pathways.
  12. The Antioxidant Moiety of MitoQ Imparts Minimal Metabolic Effects in Adipose Tissue of High Fat Fed Mice.
  13. Mitochondrial (Dys)function and Insulin Resistance: From Pathophysiological Molecular Mechanisms to the Impact of Diet.
  14. Isocitrate dehydrogenase 1-mutated cancers are sensitive to the green tea polyphenol epigallocatechin-3-gallate.
  15. Preserving Mitochondrial Structure and Motility Promotes Recovery of White Matter After Ischemia.
  16. Autophagy Exacerbates Muscle Wasting in Cancer Cachexia and Impairs Mitochondrial Function.
  17. Slc12a8 is a nicotinamide mononucleotide transporter.
  18. Rsp5 and Mdm30 reshape the mitochondrial network in response to age-induced vacuole stress.
  19. Metabolic analysis reveals evidence for branched chain amino acid catabolism crosstalk and the potential for improved treatment of organic acidurias.
  20. MTHFD1 interaction with BRD4 links folate metabolism to transcriptional regulation.
  21. Nutrient Sensing in CD11c Cells Alters the Gut Microbiota to Regulate Food Intake and Body Mass.
  22. PKM2 Knockdown Induces Autophagic Cell Death via AKT/mTOR Pathway in Human Prostate Cancer Cells.
  23. Functional wiring of proteostatic and mitostatic modules ensures transient organismal survival during imbalanced mitochondrial dynamics.
  24. 3D gastrointestinal models and organoids to study metabolism in human colon cancer.
  25. The metabolites NADP+ and NADPH are the targets of the circadian protein Nocturnin (Curled).
  26. Loss of GCN5L1 in cardiac cells disrupts glucose metabolism and promotes cell death via reduced Akt/mTORC2 signaling.
  27. Metformin inhibits PPARδ agonist-mediated tumor growth by reducing Glut1 and SLC1A5 expressions of cancer cells.
  28. Mitochondrial metabolism promotes adaptation to proteotoxic stress.
  29. BMAL1-Driven Tissue Clocks Respond Independently to Light to Maintain Homeostasis.
  30. Defining the Independence of the Liver Circadian Clock.
  31. Inhibition of nucleotide synthesis promotes replicative senescence of human mammary epithelial cells.
  32. Epigenetic dysregulation by aberrant metabolism in renal cell carcinoma can be reversed with Ascorbic acid.
  33. Cancer cell lipid class homeostasis is altered under nutrient-deprivation but stable under hypoxia.
  34. NAD+-capped RNAs are widespread in the Arabidopsis transcriptome and can probably be translated.
  35. Two human patient mitochondrial pyruvate carrier mutations reveal distinct molecular mechanisms of dysfunction.
  36. Neuron-Astrocyte Metabolic Coupling Protects against Activity-Induced Fatty Acid Toxicity.
  37. AIF-regulated oxidative phosphorylation supports lung cancer development.
  38. Too close not to encyst: Polycystic kidney disease and interorganellar contact sites.
  39. Transcriptional and metabolic rewiring of colorectal cancer cells expressing the oncogenic KRASG13D mutation.
  40. Right place, right time: localisation and assembly of the NLRP3 inflammasome.
  41. NRG1 is a critical regulator of differentiation in TP63-driven squamous cell carcinoma.
  42. Guarding the gate for mitochondrial entry.
  43. Surviving starvation simply without TFEB.
  44. Role of Mitochondria in the Mechanism(s) of Action of Metformin.
  1. Neoplasia. 2019 May 28. pii: S1476-5586(19)30108-3. [Epub ahead of print]21(7): 713-720
    CDK9 Inhibition Induces a Metabolic Switch that Renders Prostate Cancer Cells Dependent on Fatty Acid Oxidation.
    Harri M Itkonen, Ninu Poulose, Suzanne Walker, Ian G Mills.
      Cyclin-dependent kinase 9 (CDK9), a key regulator of RNA-polymeraseII, is a candidate drug target for cancers driven by transcriptional deregulation. Here we report a multi-omics-profiling of prostate cancer cell responses to CDK9 inhibition to identify synthetic lethal interactions. These interactions were validated using live-cell imaging, mitochondrial flux-, viability- and cell death activation assays. We show that CDK9 inhibition induces acute metabolic stress in prostate cancer cells. This is manifested by a drastic down-regulation of mitochondrial oxidative phosphorylation, ATP depletion and induction of a rapid and sustained phosphorylation of AMP-activated protein kinase (AMPK), the key sensor of cellular energy homeostasis. We used metabolomics to demonstrate that inhibition of CDK9 leads to accumulation of acyl-carnitines, metabolic intermediates in fatty acid oxidation (FAO). Acyl-carnitines are produced by carnitine palmitoyltransferase enzymes 1 and 2 (CPT), and we used both genetic and pharmacological tools to show that inhibition of CPT-activity is synthetically lethal with CDK9 inhibition. To our knowledge this is the first report to show that CDK9 inhibition dramatically alters cancer cell metabolism.
    DOI:  https://doi.org/10.1016/j.neo.2019.05.001
  2. Mol Cell Oncol. 2019 ;6(3): 1585171
    Malignant manipulaTORs of metabolism: suppressing BCAA catabolism to enhance mTORC1 activity.
    Russell E Ericksen, Weiping Han.
      The mammalian target of rapamycin complex 1 (mTORC1) plays an important role in the development and progression of multiple cancers. Its activity is regulated by both growth factor and nutrient signals, and the branched-chain amino acid (BCAA) leucine plays an important and unique role in this process. Recently we found that cancers of the liver and multiple other tissues suppress the catabolism of BCAAs, thereby facilitating the chronic activation of mTORC1. Our results unveil how mTORC1's nutrient-sensing arm can be manipulated by tumors, and suggest that restoring BCAA catabolism may help control mTORC1 activity in cancer cells.
    Keywords:  branched-chain amino acids; cancer metabolism; dietary intake; liver cancer; mTOR
    DOI:  https://doi.org/10.1080/23723556.2019.1585171
  3. Cell Metab. 2019 May 17. pii: S1550-4131(19)30243-8. [Epub ahead of print]
    Polyamines and eIF5A Hypusination Modulate Mitochondrial Respiration and Macrophage Activation.
    Daniel J Puleston, Michael D Buck, Ramon I Klein Geltink, Ryan L Kyle, George Caputa, David O'Sullivan, Alanna M Cameron, Angela Castoldi, Yaarub Musa, Agnieszka M Kabat, Ying Zhang, Lea J Flachsmann, Cameron S Field, Annette E Patterson, Stefanie Scherer, Francesca Alfei, Francesc Baixauli, S Kyle Austin, Beth Kelly, Mai Matsushita, Jonathan D Curtis, Katarzyna M Grzes, Matteo Villa, Mauro Corrado, David E Sanin, Jing Qiu, Nora Pällman, Katelyn Paz, Maria Elena Maccari, Bruce R Blazar, Gerhard Mittler, Joerg M Buescher, Dietmar Zehn, Sabine Rospert, Edward J Pearce, Stefan Balabanov, Erika L Pearce.
      How cells adapt metabolism to meet demands is an active area of interest across biology. Among a broad range of functions, the polyamine spermidine is needed to hypusinate the translation factor eukaryotic initiation factor 5A (eIF5A). We show here that hypusinated eIF5A (eIF5AH) promotes the efficient expression of a subset of mitochondrial proteins involved in the TCA cycle and oxidative phosphorylation (OXPHOS). Several of these proteins have mitochondrial targeting sequences (MTSs) that in part confer an increased dependency on eIF5AH. In macrophages, metabolic switching between OXPHOS and glycolysis supports divergent functional fates stimulated by activation signals. In these cells, hypusination of eIF5A appears to be dynamically regulated after activation. Using in vivo and in vitro models, we show that acute inhibition of this pathway blunts OXPHOS-dependent alternative activation, while leaving aerobic glycolysis-dependent classical activation intact. These results might have implications for therapeutically controlling macrophage activation by targeting the polyamine-eIF5A-hypusine axis.
    Keywords:  deoxyhypusine hydroxylase; deoxyhypusine synthase; eIF5A; hypusination; immunometabolism; macrophage activation; metabolism; polyamines
    DOI:  https://doi.org/10.1016/j.cmet.2019.05.003
  4. Nature. 2019 May 29.
    Metabolic control of BRISC-SHMT2 assembly regulates immune signalling.
    Miriam Walden, Lei Tian, Rebecca L Ross, Upasana M Sykora, Dominic P Byrne, Emma L Hesketh, Safi K Masandi, Joel Cassel, Rachel George, James R Ault, Farid El Oualid, Krzysztof Pawłowski, Joseph M Salvino, Patrick A Eyers, Neil A Ranson, Francesco Del Galdo, Roger A Greenberg, Elton Zeqiraj.
      Serine hydroxymethyltransferase 2 (SHMT2) regulates one-carbon transfer reactions that are essential for amino acid and nucleotide metabolism, and uses pyridoxal-5'-phosphate (PLP) as a cofactor. Apo SHMT2 exists as a dimer with unknown functions, whereas PLP binding stabilizes the active tetrameric state. SHMT2 also promotes inflammatory cytokine signalling by interacting with the deubiquitylating BRCC36 isopeptidase complex (BRISC), although it is unclear whether this function relates to metabolism. Here we present the cryo-electron microscopy structure of the human BRISC-SHMT2 complex at a resolution of 3.8 Å. BRISC is a U-shaped dimer of four subunits, and SHMT2 sterically blocks the BRCC36 active site and inhibits deubiquitylase activity. Only the inactive SHMT2 dimer-and not the active PLP-bound tetramer-binds and inhibits BRISC. Mutations in BRISC that disrupt SHMT2 binding impair type I interferon signalling in response to inflammatory stimuli. Intracellular levels of PLP regulate the interaction between BRISC and SHMT2, as well as inflammatory cytokine responses. These data reveal a mechanism in which metabolites regulate deubiquitylase activity and inflammatory signalling.
    DOI:  https://doi.org/10.1038/s41586-019-1232-1
  5. Cell Rep. 2019 May 28. pii: S2211-1247(19)30602-3. [Epub ahead of print]27(9): 2772-2784.e6
    Adipocyte ACLY Facilitates Dietary Carbohydrate Handling to Maintain Metabolic Homeostasis in Females.
    Sully Fernandez, John M Viola, AnnMarie Torres, Martina Wallace, Sophie Trefely, Steven Zhao, Hayley C Affronti, Jivani M Gengatharan, David A Guertin, Nathaniel W Snyder, Christian M Metallo, Kathryn E Wellen.
      Sugars and refined carbohydrates are major components of the modern diet. ATP-citrate lyase (ACLY) is upregulated in adipocytes in response to carbohydrate consumption and generates acetyl-coenzyme A (CoA) for both lipid synthesis and acetylation reactions. Here, we investigate the role of ACLY in the metabolic and transcriptional responses to carbohydrates in adipocytes and unexpectedly uncover a sexually dimorphic function in maintaining systemic metabolic homeostasis. When fed a high-sucrose diet, AclyFAT-/- females exhibit a lipodystrophy-like phenotype, with minimal fat accumulation, insulin resistance, and hepatic lipid accumulation, whereas AclyFAT-/- males have only mild metabolic phenotypes. We find that ACLY is crucial for nutrient-dependent carbohydrate response element-binding protein (ChREBP) activation in adipocytes and plays a key role, particularly in females, in the storage of newly synthesized fatty acids in adipose tissue. The data indicate that adipocyte ACLY is important in females for the systemic handling of dietary carbohydrates and for the preservation of metabolic homeostasis.
    Keywords:  ATP-citrate lyase; ChREBP; acetyl-CoA; adipocyte; adipose tissue; carbohydrate; fatty acid synthesis; glucose; liver; sexual dimorphism
    DOI:  https://doi.org/10.1016/j.celrep.2019.04.112
  6. Semin Cell Dev Biol. 2019 May 24. pii: S1084-9521(18)30183-6. [Epub ahead of print]
    NF-κB and mitochondria cross paths in cancer: Mitochondrial metabolism and beyond.
    Daria Capece, Daniela Verzella, Barbara Di Francesco, Edoardo Alesse, Guido Franzoso, Francesca Zazzeroni.
      NF-κB plays a pivotal role in oncogenesis. This transcription factor is best known for promoting cancer cell survival and tumour-driving inflammation. However, several lines of evidence support a crucial role for NF-κB in governing energy homeostasis and mediating cancer metabolic reprogramming. Mitochondria are central players in many metabolic processes altered in cancer. Beyond their bioenergetic activity, several facets of mitochondria biology, including mitochondrial dynamics and oxidative stress, promote and sustain malignant transformation. Recent reports revealed an intimate connection between NF-κB pathway and the oncogenic mitochondrial functions. NF-κB can impact mitochondrial respiration and mitochondrial dynamics, and, reciprocally, mitochondria can sense stress signals and convert them into cell biological responses leading to NF-κB activation. In this review we discuss their emerging reciprocal regulation and the significance of this interplay for anticancer therapy.
    Keywords:  Mitochondria; NF-κB; OXPHOS; ROS; Revers Warburg effect
    DOI:  https://doi.org/10.1016/j.semcdb.2019.05.021
  7. Front Immunol. 2019 ;10 944
    Pyruvate Dehydrogenase Kinase Is a Metabolic Checkpoint for Polarization of Macrophages to the M1 Phenotype.
    Byong-Keol Min, Sungmi Park, Hyeon-Ji Kang, Dong Wook Kim, Hye Jin Ham, Chae-Myeong Ha, Byung-Jun Choi, Jung Yi Lee, Chang Joo Oh, Eun Kyung Yoo, Hui Eon Kim, Byung-Gyu Kim, Jae-Han Jeon, Do Young Hyeon, Daehee Hwang, Yong-Hoon Kim, Chul-Ho Lee, Taeho Lee, Jung-Whan Kim, Yeon-Kyung Choi, Keun-Gyu Park, Ajay Chawla, Jongsoon Lee, Robert A Harris, In-Kyu Lee.
      Metabolic reprogramming during macrophage polarization supports the effector functions of these cells in health and disease. Here, we demonstrate that pyruvate dehydrogenase kinase (PDK), which inhibits the pyruvate dehydrogenase-mediated conversion of cytosolic pyruvate to mitochondrial acetyl-CoA, functions as a metabolic checkpoint in M1 macrophages. Polarization was not prevented by PDK2 or PDK4 deletion but was fully prevented by the combined deletion of PDK2 and PDK4; this lack of polarization was correlated with improved mitochondrial respiration and rewiring of metabolic breaks that are characterized by increased glycolytic intermediates and reduced metabolites in the TCA cycle. Genetic deletion or pharmacological inhibition of PDK2/4 prevents polarization of macrophages to the M1 phenotype in response to inflammatory stimuli (lipopolysaccharide plus IFN-γ). Transplantation of PDK2/4-deficient bone marrow into irradiated wild-type mice to produce mice with PDK2/4-deficient myeloid cells prevented M1 polarization, reduced obesity-associated insulin resistance, and ameliorated adipose tissue inflammation. A novel, pharmacological PDK inhibitor, KPLH1130, improved high-fat diet-induced insulin resistance; this was correlated with a reduction in the levels of pro-inflammatory markers and improved mitochondrial function. These studies identify PDK2/4 as a metabolic checkpoint for M1 phenotype polarization of macrophages, which could potentially be exploited as a novel therapeutic target for obesity-associated metabolic disorders and other inflammatory conditions.
    Keywords:  dichloroacetate; high-fat diet; inflammation; insulin resistance; macrophage polarization; metabolic reprogramming; pyruvate dehydrogenase kinase
    DOI:  https://doi.org/10.3389/fimmu.2019.00944
  8. Semin Cell Dev Biol. 2019 May 27. pii: S1084-9521(18)30168-X. [Epub ahead of print]
    Metabolic pathways regulating colorectal cancer initiation and progression.
    Sofia La Vecchia, Carlos Sebastián.
      Colorectal cancer (CRC) is one of the most common types of cancer worldwide. Despite recent advances in the molecular genetics of CRC, poor treatment outcomes highlight the need for a better understanding of the underlying mechanisms accounting for tumor initiation and progression. Recently, deregulation of cellular metabolism has emerged as a key hallmark of cancer. Reprogramming of core cellular metabolic pathways by cancer cells provides energy, anaplerotic precursors and reducing equivalents required to support tumor growth. Here, we review key findings implicating cancer metabolism as a major contributor of tumor initiation, growth and metastatic dissemination in CRC. We summarize the metabolic pathways governing stem cell fate in the intestine, the metabolic adaptations of proliferating colon cancer cells and their crosstalk with oncogenic signaling, and how they fulfill the energetic demands imposed by the metastatic cascade. Lastly, we discuss how some of these metabolic pathways could represent new vulnerabilities of CRC cells with the potential to be targeted.
    Keywords:  Colorectal cancer; Intestinal stem cells; Metabolic therapies; Metabolism; Metastasis
    DOI:  https://doi.org/10.1016/j.semcdb.2019.05.018
  9. Cell. 2019 May 30. pii: S0092-8674(19)30506-9. [Epub ahead of print]177(6): 1536-1552.e23
    CerS6-Derived Sphingolipids Interact with Mff and Promote Mitochondrial Fragmentation in Obesity.
    Philipp Hammerschmidt, Daniela Ostkotte, Hendrik Nolte, Mathias J Gerl, Alexander Jais, Hanna L Brunner, Hans-Georg Sprenger, Motoharu Awazawa, Hayley T Nicholls, Sarah M Turpin-Nolan, Thomas Langer, Marcus Krüger, Britta Brügger, Jens C Brüning.
      Ectopic lipid deposition and altered mitochondrial dynamics contribute to the development of obesity and insulin resistance. However, the mechanistic link between these processes remained unclear. Here we demonstrate that the C16:0 sphingolipid synthesizing ceramide synthases, CerS5 and CerS6, affect distinct sphingolipid pools and that abrogation of CerS6 but not of CerS5 protects from obesity and insulin resistance. We identify proteins that specifically interact with C16:0 sphingolipids derived from CerS5 or CerS6. Here, only CerS6-derived C16:0 sphingolipids bind the mitochondrial fission factor (Mff). CerS6 and Mff deficiency protect from fatty acid-induced mitochondrial fragmentation in vitro, and the two proteins genetically interact in vivo in obesity-induced mitochondrial fragmentation and development of insulin resistance. Our experiments reveal an unprecedented specificity of sphingolipid signaling depending on specific synthesizing enzymes, provide a mechanistic link between hepatic lipid deposition and mitochondrial fragmentation in obesity, and define the CerS6-derived sphingolipid/Mff interaction as a therapeutic target for metabolic diseases.
    DOI:  https://doi.org/10.1016/j.cell.2019.05.008
  10. Cell Metab. 2019 May 20. pii: S1550-4131(19)30244-X. [Epub ahead of print]
    Epigenetic Control of Mitochondrial Fission Enables Self-Renewal of Stem-like Tumor Cells in Human Prostate Cancer.
    Gianluca Civenni, Roberto Bosotti, Andrea Timpanaro, Ramiro Vàzquez, Jessica Merulla, Shusil Pandit, Simona Rossi, Domenico Albino, Sara Allegrini, Abhishek Mitra, Sarah N Mapelli, Luca Vierling, Martina Giurdanella, Martina Marchetti, Alyssa Paganoni, Andrea Rinaldi, Marco Losa, Enrica Mira-Catò, Rocco D'Antuono, Diego Morone, Keyvan Rezai, Gioacchino D'Ambrosio, L'Houcine Ouafik, Sarah Mackenzie, Maria E Riveiro, Esteban Cvitkovic, Giuseppina M Carbone, Carlo V Catapano.
      Cancer stem cells (CSCs) contribute to disease progression and treatment failure in human cancers. The balance among self-renewal, differentiation, and senescence determines the expansion or progressive exhaustion of CSCs. Targeting these processes might lead to novel anticancer therapies. Here, we uncover a novel link between BRD4, mitochondrial dynamics, and self-renewal of prostate CSCs. Targeting BRD4 by genetic knockdown or chemical inhibitors blocked mitochondrial fission and caused CSC exhaustion and loss of tumorigenic capability. Depletion of CSCs occurred in multiple prostate cancer models, indicating a common vulnerability and dependency on mitochondrial dynamics. These effects depended on rewiring of the BRD4-driven transcription and repression of mitochondrial fission factor (Mff). Knockdown of Mff reproduced the effects of BRD4 inhibition, whereas ectopic Mff expression rescued prostate CSCs from exhaustion. This novel concept of targeting mitochondrial plasticity in CSCs through BRD4 inhibition provides a new paradigm for developing more effective treatment strategies for prostate cancer.
    Keywords:  BET inhibitors; BRD4; MFF; OTX015/MK-8628; bromodomain and extra-terminal domain proteins; cancer stem cells; mitochondrial dynamics; mitochondrial fission; mitochondrial fission factor; prostate cancer
    DOI:  https://doi.org/10.1016/j.cmet.2019.05.004
  11. Front Genet. 2019 ;10 435
    Regulation of Mitochondrial Biogenesis as a Way for Active Longevity: Interaction Between the Nrf2 and PGC-1α Signaling Pathways.
    Artem P Gureev, Ekaterina A Shaforostova, Vasily N Popov.
      Aging is a general degenerative process related to deterioration of cell functions in the entire organism. Mitochondria, which play a key role in energy homeostasis and metabolism of reactive oxygen species (ROS), require lifetime control and constant renewal. This explains recently peaked interest in the processes of mitochondrial biogenesis and mitophagy. The principal event of mitochondrial metabolism is regulation of mitochondrial DNA (mtDNA) transcription and translation, which is a complex coordinated process that involves at least two systems of transcription factors. It is commonly believed that its major regulatory proteins are PGC-1α and PGC-1β, which act as key factors connecting several regulator cascades involved in the control of mitochondrial metabolism. In recent years, the number of publications on the essential role of Nrf2/ARE signaling in the regulation of mitochondrial biogenesis has grown exponentially. Nrf2 is induced by various xenobiotics and oxidants that oxidize some Nrf2 negative regulators. Thus, ROS, in particular H2O2, were found to be strong Nrf2 activators. At present, there are two major concepts of mitochondrial biogenesis. Some authors suggest direct involvement of Nrf2 in the regulation of this process. Others believe that Nrf2 regulates expression of the antioxidant genes, while the major and only regulator of mitochondrial biogenesis is PGC-1α. Several studies have demonstrated the existence of the regulatory loop involving both PGC-1α and Nrf2. In this review, we summarized recent data on the Nrf2 role in mitochondrial biogenesis and its interaction with PGC-1α in the context of extending longevity.
    Keywords:  Nrf2; PGC-1α; active longevity; aging; mitochondrial biogenesis
    DOI:  https://doi.org/10.3389/fgene.2019.00435
  12. Front Physiol. 2019 ;10 543
    The Antioxidant Moiety of MitoQ Imparts Minimal Metabolic Effects in Adipose Tissue of High Fat Fed Mice.
    Simon T Bond, Jisu Kim, Anna C Calkin, Brian G Drew.
      Mitochondrial dysfunction is associated with a diverse array of diseases ranging from dystrophy and heart failure to obesity and hepatosteatosis. One of the major biochemical consequences of impaired mitochondrial function is an accumulation of mitochondrial superoxide, or reactive oxygen species (ROS). Excessive ROS can be detrimental to cellular health and is proposed to underpin many mitochondrial diseases. Accordingly, much research has been committed to understanding ways to therapeutically prevent and reduce ROS accumulation. In white adipose tissue (WAT), ROS is associated with obesity and its subsequent complications, and thus reducing mitochondrial ROS may represent a novel strategy for treating obesity related disorders. One therapeutic approach employed to reduce ROS abundance is the mitochondrial-targeted coenzyme Q (MitoQ), which enables mitochondrial specific delivery of a CoQ10 antioxidant via its triphenylphosphonium bromide (TPP+) cation. Indeed, MitoQ has been successfully shown to accumulate at the outer mitochondrial membrane and prevent ROS accumulation in several tissues in vivo; however, the specific effects of MitoQ on adipose tissue metabolism in vivo have not been studied. Here we demonstrate that mice fed high-fat diet with concomitant administration of MitoQ, exhibit minimal metabolic benefit in adipose tissue. We also demonstrate that both MitoQ and its control agent dTPP+ had significant and equivalent effects on whole-body metabolism, suggesting that the dTPP+ cation rather than the antioxidant moiety, was responsible for these changes. These findings have important implications for future studies using MitoQ and other TPP+ compounds.
    Keywords:  ROS; adipose tissue; antioxidant; mitochondria; mitoquinone; obesity
    DOI:  https://doi.org/10.3389/fphys.2019.00543
  13. Front Physiol. 2019 ;10 532
    Mitochondrial (Dys)function and Insulin Resistance: From Pathophysiological Molecular Mechanisms to the Impact of Diet.
    Domenico Sergi, Nenad Naumovski, Leonie Kaye Heilbronn, Mahinda Abeywardena, Nathan O'Callaghan, Lillà Lionetti, Natalie Luscombe-Marsh.
      Mitochondrial dysfunction has been implicated in the pathogenesis of insulin resistance, the hallmark of type 2 diabetes mellitus (T2DM). However, the cause-effect relationship remains to be fully elucidated. Compelling evidence suggests that boosting mitochondrial function may represent a valuable therapeutic tool to improve insulin sensitivity. Mitochondria are highly dynamic organelles, which adapt to short- and long-term metabolic perturbations by undergoing fusion and fission cycles, spatial rearrangement of the electron transport chain complexes into supercomplexes and biogenesis governed by peroxisome proliferator-activated receptor γ co-activator 1α (PGC 1α). However, these processes appear to be dysregulated in type 2 diabetic individuals. Herein, we describe the mechanistic link between mitochondrial dysfunction and insulin resistance in skeletal muscle alongside the intracellular pathways orchestrating mitochondrial bioenergetics. We then review current evidence on nutritional tools, including fatty acids, amino acids, caloric restriction and food bioactive derivatives, which may enhance insulin sensitivity by therapeutically targeting mitochondrial function and biogenesis.
    Keywords:  insulin resistance; lipotoxicity; mitochondrial function; oxidative metabolism; skeletal muscle
    DOI:  https://doi.org/10.3389/fphys.2019.00532
  14. Cancer Metab. 2019 ;7 4
    Isocitrate dehydrogenase 1-mutated cancers are sensitive to the green tea polyphenol epigallocatechin-3-gallate.
    Tom H Peeters, Krissie Lenting, Vincent Breukels, Sanne A M van Lith, Corina N A M van den Heuvel, Remco Molenaar, Arno van Rooij, Ron Wevers, Paul N Span, Arend Heerschap, William P J Leenders.
      Background: Mutations in isocitrate dehydrogenase 1 (IDH1) occur in various types of cancer and induce metabolic alterations resulting from the neomorphic activity that causes production of D-2-hydroxyglutarate (D-2-HG) at the expense of α-ketoglutarate (α-KG) and NADPH. To overcome metabolic stress induced by these alterations, IDH-mutated (IDH mut ) cancers utilize rescue mechanisms comprising pathways in which glutaminase and glutamate dehydrogenase (GLUD) are involved. We hypothesized that inhibition of glutamate processing with the pleiotropic GLUD-inhibitor epigallocatechin-3-gallate (EGCG) would not only hamper D-2-HG production, but also decrease NAD(P)H and α-KG synthesis in IDH mut cancers, resulting in increased metabolic stress and increased sensitivity to radiotherapy.Methods: We performed 13C-tracing studies to show that HCT116 colorectal cancer cells with an IDH1 R132H knock-in allele depend more on glutaminolysis than on glycolysis for the production of D-2-HG. We treated HCT116 cells, HCT116-IDH1 R132H cells, and HT1080 cells (carrying an IDH1 R132C mutation) with EGCG and evaluated D-2-HG production, cell proliferation rates, and sensitivity to radiotherapy.
    Results: Significant amounts of 13C from glutamate accumulate in D-2-HG in HCT116-IDH1 wt/R132H but not in HCT116-IDH1 wt/wt . Preventing glutamate processing in HCT116-IDH1 wt/R132H cells with EGCG resulted in reduction of D-2-HG production. In addition, EGCG treatment decreased proliferation rates of IDH1 mut cells and at high doses sensitized cancer cells to ionizing radiation. Effects of EGCG in IDH-mutated cell lines were diminished by treatment with the IDH1mut inhibitor AGI-5198.
    Conclusions: This work shows that glutamate can be directly processed into D-2-HG and that reduction of glutamatolysis may be an effective and promising new treatment option for IDH mut cancers.
    Keywords:  EGCG; Glutamate; IDH mutations; Metabolism; Radiotherapy
    DOI:  https://doi.org/10.1186/s40170-019-0198-7
  15. Neuromolecular Med. 2019 May 31.
    Preserving Mitochondrial Structure and Motility Promotes Recovery of White Matter After Ischemia.
    Chinthasagar Bastian, Jerica Day, Stephen Politano, John Quinn, Sylvain Brunet, Selva Baltan.
      Stroke significantly affects white matter in the brain by impairing axon function, which results in clinical deficits. Axonal mitochondria are highly dynamic and are transported via microtubules in the anterograde or retrograde direction, depending upon axonal energy demands. Recently, we reported that mitochondrial division inhibitor 1 (Mdivi-1) promotes axon function recovery by preventing mitochondrial fission only when applied during ischemia. Application of Mdivi-1 after injury failed to protect axon function. Interestingly, L-NIO, which is a NOS3 inhibitor, confers post-ischemic protection to axon function by attenuating mitochondrial fission and preserving mitochondrial motility via conserving levels of the microtubular adaptor protein Miro-2. We propose that preventing mitochondrial fission protects axon function during injury, but that restoration of mitochondrial motility is more important to promote axon function recovery after injury. Thus, Miro-2 may be a therapeutic molecular target for recovery following a stroke.
    Keywords:  Ischemia; Miro-2; Mitochondria; Mitochondrial dynamics; NOS3; Stroke
    DOI:  https://doi.org/10.1007/s12017-019-08550-w
  16. J Mol Biol. 2019 May 28. pii: S0022-2836(19)30316-X. [Epub ahead of print]
    Autophagy Exacerbates Muscle Wasting in Cancer Cachexia and Impairs Mitochondrial Function.
    Fabio Penna, Riccardo Ballarò, Paula Martinez-Cristobal, David Sala, David Sebastian, Silvia Busquets, Maurizio Muscaritoli, Josep M Argilés, Paola Costelli, Antonio Zorzano.
      Cancer cachexia is a multifactorial syndrome characterized by anorexia, weight loss and muscle wasting that impairs patients' quality of life and survival. Aim of this work was to evaluate the impact of either autophagy inhibition (knocking-down beclin-1) or promotion (overexpressing TP53INP2/DOR) on cancer-induced muscle wasting. In C26 tumor-bearing mice, stress-induced autophagy inhibition was unable to rescue the loss of muscle mass and worsened muscle morphology. Treating C26-bearing mice with formoterol, a selective β2-agonist, muscle sparing was paralleled by reduced static autophagy markers although the flux was maintained. Conversely, the stimulation of muscle autophagy exacerbated muscle atrophy in tumor-bearing mice. TP53INP2 further promoted atrogene expression and suppressed mitochondrial dynamics-related genes. Excessive autophagy might impair mitochondrial function through mitophagy. Consistently, tumor-induced mitochondrial dysfunction was detected by reduced ex vivo muscle fiber respiration. Overall, the results evoke a central role for muscle autophagy in cancer-induced muscle wasting.
    Keywords:  Autophagy; Cancer cachexia; Mitochondria; Mitophagy; Muscle wasting; TP53INP2
    DOI:  https://doi.org/10.1016/j.jmb.2019.05.032
  17. Nat Metab. 2019 Jan;1(1): 47-57
    Slc12a8 is a nicotinamide mononucleotide transporter.
    Alessia Grozio, Kathryn F Mills, Jun Yoshino, Santina Bruzzone, Giovanna Sociali, Kyohei Tokizane, Hanyue Cecilia Lei, Richard Cunningham, Yo Sasaki, Marie E Migaud, Shin-Ichiro Imai.
      Nicotinamide mononucleotide (NMN) is a biosynthetic precursor of NAD+ known to promote cellular NAD+ production and counteract age-associated pathologies associated with a decline in tissue NAD+ levels. How NMN is taken up into cells has not been entirely clear. Here we show that the Slc12a8 gene encodes a specific NMN transporter. We find that Slc12a8 is highly expressed and regulated by NAD+ in the murine small intestine. Slc12a8 knockdown abrogates the uptake of NMN in vitro and in vivo. We further show that Slc12a8 specifically transports NMN, but not nicotinamide riboside, and that NMN transport depends on the presence of sodium ion. Slc12a8 deficiency significantly decreases NAD+ levels in the jejunum and ileum, which is associated with reduced NMN uptake as traced by doubly labeled isotopic NMN. Finally, we observe that Slc12a8 expression is upregulated in the aged murine ileum, which contributes to the maintenance of ileal NAD+ levels. Our work identifies the first NMN transporter and demonstrates that Slc12a8 has a critical role in regulating intestinal NAD+ metabolism.
    DOI:  https://doi.org/10.1038/s42255-018-0009-4
  18. Mol Biol Cell. 2019 May 29. mbcE19020094
    Rsp5 and Mdm30 reshape the mitochondrial network in response to age-induced vacuole stress.
    Jenna M Goodrum, Austin R Lever, Troy K Coody, Daniel E Gottschling, Adam L Hughes.
      Mitochondrial decline is a hallmark of aging, and cells are equipped with many systems to regulate mitochondrial structure and function in response to stress and metabolic alterations. Here, using budding yeast, we identify a proteolytic pathway that contributes to alterations in mitochondrial structure in aged cells through control of the mitochondrial fusion GTPase Fzo1. We show that mitochondrial fragmentation in old cells correlates with reduced abundance of Fzo1, which is triggered by functional alterations in the vacuole, a known early event in aging. Fzo1 degradation is mediated by a proteolytic cascade consisting of the E3 ubiquitin ligases SCFMdm30 and Rsp5, and the Cdc48 cofactor Doa1. Fzo1 proteolysis is activated by metabolic stress that arises from vacuole impairment, and loss of Fzo1 degradation severely impairs mitochondrial structure and function. Together, these studies identify a new mechanism for stress-responsive regulation of mitochondrial structure that is activated during cellular aging.
    DOI:  https://doi.org/10.1091/mbc.E19-02-0094
  19. Mol Genet Metab. 2019 May 21. pii: S1096-7192(19)30270-7. [Epub ahead of print]
    Metabolic analysis reveals evidence for branched chain amino acid catabolism crosstalk and the potential for improved treatment of organic acidurias.
    Stephen McCalley, David Pirman, Michelle Clasquin, Kendall Johnson, Shengfang Jin, Jerry Vockley.
      Branched chain amino acid (BCAA) metabolism occurs within the mitochondrial matrix and is comprised of multiple enzymes, some shared, organized into three pathways for the catabolism of leucine, isoleucine, and valine (LEU, ILE, and VAL respectively). Three different acyl-CoA dehydrogenases (ACADs) are active in each catabolic pathway and genetic deficiencies in each have been identified. While characteristic metabolites related to the enzymatic block accumulate in each deficiency, for reasons that are not clear, clinical symptoms are only seen in the context of deficiency of isovaleryl-CoA dehydrogenase (IVDH) in the leucine pathway. Metabolism of fibroblasts derived from patients with mutations in each of the BCAA ACADs were characterized using metabolomics to better understand the flux of BCAA through their respective pathways. Stable isotope labeled LEU, ILE, and VAL in patient and control cell lines revealed that mutations in isobutyryl-CoA dehydrogenase (IBDH in the valine pathway) lead to a significant increase in isobutyrylcarnitine (a surrogate for the enzyme substrate isobutyryl-CoA) leading to metabolism by short-branched chain acyl-CoA dehydrogenase (SBCADH in the isoleucine pathway) and production of the pathway end product propionylcarnitine (a surrogate for propionyl-CoA). Similar cross activity was observed for SBCADH deficient patient cells, leading to a significant increase in propionylcarnitine, presumably by metabolism of 2 methylbutyryl-CoA via IBDH activity. Labeled BCAA studies identified that the majority of the intracellular propionyl-CoA pool in fibroblasts is generated from isoleucine, but heptanoic acid (a surrogate for odd-chain fatty acids) is also efficiently converted to propionate.
    DOI:  https://doi.org/10.1016/j.ymgme.2019.05.008
  20. Nat Genet. 2019 Jun;51(6): 990-998
    MTHFD1 interaction with BRD4 links folate metabolism to transcriptional regulation.
    Sara Sdelci, André F Rendeiro, Philipp Rathert, Wanhui You, Jung-Ming G Lin, Anna Ringler, Gerald Hofstätter, Herwig P Moll, Bettina Gürtl, Matthias Farlik, Sandra Schick, Freya Klepsch, Matthew Oldach, Pisanu Buphamalai, Fiorella Schischlik, Peter Májek, Katja Parapatics, Christian Schmidl, Michael Schuster, Thomas Penz, Dennis L Buckley, Otto Hudecz, Richard Imre, Shuang-Yan Wang, Hans Michael Maric, Robert Kralovics, Keiryn L Bennett, Andre C Müller, Karl Mechtler, Jörg Menche, James E Bradner, Georg E Winter, Kristaps Klavins, Emilio Casanova, Christoph Bock, Johannes Zuber, Stefan Kubicek.
      The histone acetyl reader bromodomain-containing protein 4 (BRD4) is an important regulator of chromatin structure and transcription, yet factors modulating its activity have remained elusive. Here we describe two complementary screens for genetic and physical interactors of BRD4, which converge on the folate pathway enzyme MTHFD1 (methylenetetrahydrofolate dehydrogenase, cyclohydrolase and formyltetrahydrofolate synthetase 1). We show that a fraction of MTHFD1 resides in the nucleus, where it is recruited to distinct genomic loci by direct interaction with BRD4. Inhibition of either BRD4 or MTHFD1 results in similar changes in nuclear metabolite composition and gene expression; pharmacological inhibitors of the two pathways synergize to impair cancer cell viability in vitro and in vivo. Our finding that MTHFD1 and other metabolic enzymes are chromatin associated suggests a direct role for nuclear metabolism in the control of gene expression.
    DOI:  https://doi.org/10.1038/s41588-019-0413-z
  21. Cell Metab. 2019 May 21. pii: S1550-4131(19)30242-6. [Epub ahead of print]
    Nutrient Sensing in CD11c Cells Alters the Gut Microbiota to Regulate Food Intake and Body Mass.
    D Nyasha Chagwedera, Qi Yan Ang, Jordan E Bisanz, Yew Ann Leong, Kirthana Ganeshan, Jingwei Cai, Andrew D Patterson, Peter J Turnbaugh, Ajay Chawla.
      Microbial dysbiosis and inflammation are implicated in diet-induced obesity and insulin resistance. However, it is not known whether crosstalk between immunity and microbiota also regulates metabolic homeostasis in healthy animals. Here, we report that genetic deletion of tuberous sclerosis 1 (Tsc1) in CD11c+ myeloid cells (Tsc1f/fCD11cCre mice) reduced food intake and body mass in the absence of metabolic disease. Co-housing and fecal transplant experiments revealed a dominant role for the healthy gut microbiota in regulation of body weight. 16S rRNA sequencing, selective culture, and reconstitution experiments further confirmed that selective deficiency of Lactobacillus johnsonii Q1-7 contributed to decreased food intake and body mass in Tsc1f/fCD11cCre mice. Mechanistically, activation of mTORC1 signaling in CD11c cells regulated production of L. johnsonii Q1-7-specific IgA, allowing for its stable colonization in the gut. Together, our findings reveal an unexpected transkingdom immune-microbiota feedback loop for homeostatic regulation of food intake and body mass in mammals.
    Keywords:  IgA; Lactobacillus; cohousing; comparative genomics; coprophagia; energy balance; immunometabolism; innate immunity; phylogenetics
    DOI:  https://doi.org/10.1016/j.cmet.2019.05.002
  22. Cell Physiol Biochem. 2019 ;52(6): 1535-1552
    PKM2 Knockdown Induces Autophagic Cell Death via AKT/mTOR Pathway in Human Prostate Cancer Cells.
    Prasanta Dey, Amit Kundu, Richa Sachan, Jae Hyeon Park, Mee Young Ahn, Kyungsil Yoon, Jaewon Lee, Nam Deuk Kim, In Su Kim, Byung Mu Lee, Hyung Sik Kim.
      BACKGROUND/AIMS: Pyruvate kinase M2 (PKM2) is essential for aerobic glycolysis. Although high PKM2 expression is observed in various cancer tissues, its functional role in cancer metabolism is unclear. Here, we investigated the role of PKM2 in regulating autophagy and its associated pathways in prostate cancer cells.METHODS: Immunohistochemistry was performed to compare the expression level of PKM2 in prostate cancer patients and normal human, whereas expression of PKM2 in several cell lines was also examined by using western blot. PKM2 expression was silenced using various small interfering RNAs (siRNAs). Cell viability was examined using IncuCyte ZOOM™ live cell imaging system. Western blotting and immunofluorescence were performed to investigate the PKM2 knockdown on other cellular signaling molecules. Acridine orange and Monodansylcadaverine staining was performed to check effect of PKM2 knockdown on autophagy induction. High performance thin layer chromatography was carried out to quantify the level of different cellular metabolites (pyruvate and lactate). Colony formation assay was performed to determine the ability of a cells to form large colonies.
    RESULTS: PKM2 was highly expressed in prostate cancer patients as compared to normal human. PKM2 siRNA-transfected prostate cancer cells showed significantly reduced viability. Acridine orange, Monodansylcadaverine staining and western blotting analysis showed that PKM2 downregulation markedly increased autophagic cell death. Results of western blotting analysis showed that PKM2 knockdown affected protein kinase B/mechanistic target of rapamycin 1 pathway, which consequently downregulated the expression of glycolytic enzymes lactate dehydrogenase A and glucose transporter 1. Knockdown of PKM2 also reduced the colony formation ability of human prostate cancer cell DU145.
    CONCLUSION: To the best of our knowledge, this is the first study to show that PKM2 inhibition alters prostate cancer cell metabolism and induces autophagy, thus providing new perspectives for developing PKM2-targeting anticancer therapies for treating prostate cancer.
    Keywords:  Autophagy; Cancer metabolism; Prostate cancer; Pyruvate kinase M2; mTOR
    DOI:  https://doi.org/10.33594/000000107
  23. Redox Biol. 2019 May 17. pii: S2213-2317(19)30412-4. [Epub ahead of print]24 101219
    Functional wiring of proteostatic and mitostatic modules ensures transient organismal survival during imbalanced mitochondrial dynamics.
    Sentiljana Gumeni, Zoi Evangelakou, Eleni N Tsakiri, Luca Scorrano, Ioannis P Trougakos.
      Being an assembly of protein machines, cells depend on adequate supply of energetic molecules for retaining their homeodynamics. Consequently, mitochondria functionality is ensured by quality control systems and mitochondrial dynamics (fusion/fission). Similarly, proteome stability is maintained by the machineries of the proteostasis network. We report here that reduced mitochondrial fusion rates in Drosophila caused developmental lethality or if induced in the adult accelerated aging. Imbalanced mitochondrial dynamics were tolerable for various periods in young flies, where they caused oxidative stress and proteome instability that mobilized Nrf2 and foxo to upregulate cytoprotective antioxidant/proteostatic modules. Consistently, proteasome inhibition or Nrf2, foxo knock down in young flies exaggerated perturbed mitochondrial dynamics toxicity. Neither Nrf2 overexpression (with concomitant proteasome activation) nor Atg8a upregulation suppressed the deregulated mitochondrial dynamics toxicity, which was mildly mitigated by antioxidants. Thus, despite extensive functional wiring of mitostatic and antioxidant/proteostatic modules, sustained loss-of mitostasis exhausts adaptation responses triggering premature aging.
    Keywords:  Aging; Drp1; Mitofusins; Mitostasis; Opa1; Proteostasis
    DOI:  https://doi.org/10.1016/j.redox.2019.101219
  24. Semin Cell Dev Biol. 2019 May 25. pii: S1084-9521(19)30079-5. [Epub ahead of print]
    3D gastrointestinal models and organoids to study metabolism in human colon cancer.
    Catarina Silva-Almeida, Marie-Ann Ewart, Colin Wilde.
      Recent advances in the field of cancer metabolism raised awareness for the importance of the tumour microenvironment in tumour growth and progression. The initial theory by Heinrich Warburg was that cancer cells had a deficient oxidative respiration and thus had to perform aerobic glycolysis to produce energy. However, further research suggested that there is a metabolic reprogramming within the tumour microenvironment, controlled by communication between tumour and stromal cells. The importance of this communication exposes the need to use complex models in cancer research. Until recently, classic cell models included immortalized 2D cell lines or patient-derived tumour xenografts. Despite having contributed to many discoveries, these models present many limitations. Improved models are now being developed using 3D cell culture technology. These models are more physiologically relevant allowing the co-culture of different cells types and establishing a gradient concentration of solutes. Recent developments in organoid technology contributed largely to the expansion of 3D cell technology. Organoids can be developed from different tissues including tumours, representing the cell population and spatial organization of the tissue of origin. In the field of cancer metabolism, the interaction of different cell types, the stroma, and the different solutes and oxygen concentrations are crucial parameters. Current models to study metabolism either include only one cell population or are unable to represent solute/oxygen gradients or to collect samples in a proficient manner. The characteristics of organoid culture thus makes them a potent model to use in metabolic studies, drug development, disease model or even personalized medicine.
    Keywords:  3D models; Cancer; Colorectal; Metabolism; Organoids
    DOI:  https://doi.org/10.1016/j.semcdb.2019.05.019
  25. Nat Commun. 2019 May 30. 10(1): 2367
    The metabolites NADP+ and NADPH are the targets of the circadian protein Nocturnin (Curled).
    Michael A Estrella, Jin Du, Li Chen, Sneha Rath, Eliza Prangley, Alisha Chitrakar, Tsutomu Aoki, Paul Schedl, Joshua Rabinowitz, Alexei Korennykh.
      Nocturnin (NOCT) is a rhythmically expressed protein that regulates metabolism under the control of circadian clock. It has been proposed that NOCT deadenylates and regulates metabolic enzyme mRNAs. However, in contrast to other deadenylases, purified NOCT lacks the deadenylase activity. To identify the substrate of NOCT, we conducted a mass spectrometry screen and report that NOCT specifically and directly converts the dinucleotide NADP+ into NAD+ and NADPH into NADH. Further, we demonstrate that the Drosophila NOCT ortholog, Curled, has the same enzymatic activity. We obtained the 2.7 Å crystal structure of the human NOCT•NADPH complex, which revealed that NOCT recognizes the chemically unique ribose-phosphate backbone of the metabolite, placing the 2'-terminal phosphate productively for removal. We provide evidence for NOCT targeting to mitochondria and propose that NADP(H) regulation, which takes place at least in part in mitochondria, establishes the molecular link between circadian clock and metabolism.
    DOI:  https://doi.org/10.1038/s41467-019-10125-z
  26. Biochem J. 2019 May 28. pii: BCJ20190302. [Epub ahead of print]
    Loss of GCN5L1 in cardiac cells disrupts glucose metabolism and promotes cell death via reduced Akt/mTORC2 signaling.
    Janet R Manning, Dharendra Thapa, Manling Zhang, Michael W Stoner, Javier Traba, Catherine Corey, Sruti Shiva, Michael N Sack, Iain Scott.
      GCN5L1 regulates protein acetylation and mitochondrial energy metabolism in diverse cell types. In the heart, loss of GCN5L1 sensitizes the myocardium to injury from exposure to nutritional excess and ischemia/reperfusion injury. This phenotype is associated with the reduced acetylation of metabolic enzymes and elevated mitochondrial reactive oxygen species (ROS) generation, although the direct molecular targets of GCN5L1 remain largely unknown. In this study, we sought to determine the mechanism by which GCN5L1 impacts energy substrate utilization and mitochondrial health. We find that hypoxia and reoxygenation (H/R) leads to a reduction in cell viability and Akt phosphorylation in GCN5L1 knockdown AC16 cardiomyocytes, in parallel with elevated glucose utilization and impaired fatty acid use. We demonstrate that glycolysis is uncoupled from glucose oxidation under normoxic conditions in GCN5L1 depleted cells. We show that GCN5L1 directly binds to the Akt-activating mTORC2 component Rictor, and that loss of Rictor acetylation is evident in GCN5L1 knockdown cells. Finally, we show that restoring Rictor acetylation in GCN5L1 depleted cells reduces mitochondrial ROS generation and increases cell survival in response to H/R. These studies suggest that GCN5L1 may play a central role in energy substrate metabolism and cell survival via regulation of Akt/mTORC2 signaling.
    Keywords:  Akt; GCN5L1; Rictor; glycolysis; heart; hypoxia
    DOI:  https://doi.org/10.1042/BCJ20190302
  27. Eur J Pharmacol. 2019 May 28. pii: S0014-2999(19)30376-0. [Epub ahead of print] 172425
    Metformin inhibits PPARδ agonist-mediated tumor growth by reducing Glut1 and SLC1A5 expressions of cancer cells.
    Jiajun Ding, Qian Gou, Jianhua Jin, Juanjuan Shi, Qian Liu, Yongzhong Hou.
      As a nuclear receptor, ligand binding and activated PPARδ (peroxisome-proliferator-activated receptor δ) plays an important role in regulation of inflammation, metabolism and cancer, while it is unclear the effect of metformin on PPARδ-mediated cancer cell metabolism. Here we found that PPARδ agonist GW501516 significantly increased Glut1 (Glucose transporter 1) and SLC1A5 (solutecarrier family 1 member 5) gene and protein expressions in HCT-116, SW480, HeLa, and MCF-7 cancer cell lines, while metformin inhibited this event, which was associated with metformin-mediated inhibition of PPARδ activity in response to GW501516. Importantly, GW501516 inhibited the binding of PPARδ to AMPK, while metformin reversed this process. Metformin inhibited Glut1 and SLC1A5 expressions leading to reduced influx of glucose and glutamine in cancer cells, which is associated with reduced tumor growth. These findings suggest that metformin inhibited PPARδ agonist GW501516-induced cancer cell metabolism and tumor growth.
    Keywords:  AMPK; GW501516; Glut1; Metformin; PPARδ; SLC1A5; Transcriptional activity
    DOI:  https://doi.org/10.1016/j.ejphar.2019.172425
  28. Nat Chem Biol. 2019 May 27.
    Mitochondrial metabolism promotes adaptation to proteotoxic stress.
    Peter Tsvetkov, Alexandre Detappe, Kai Cai, Heather R Keys, Zarina Brune, Weiwen Ying, Prathapan Thiru, Mairead Reidy, Guillaume Kugener, Jordan Rossen, Mustafa Kocak, Nora Kory, Aviad Tsherniak, Sandro Santagata, Luke Whitesell, Irene M Ghobrial, John L Markley, Susan Lindquist, Todd R Golub.
      The mechanisms by which cells adapt to proteotoxic stress are largely unknown, but are key to understanding how tumor cells, particularly in vivo, are largely resistant to proteasome inhibitors. Analysis of cancer cell lines, mouse xenografts and patient-derived tumor samples all showed an association between mitochondrial metabolism and proteasome inhibitor sensitivity. When cells were forced to use oxidative phosphorylation rather than glycolysis, they became proteasome-inhibitor resistant. This mitochondrial state, however, creates a unique vulnerability: sensitivity to the small molecule compound elesclomol. Genome-wide CRISPR-Cas9 screening showed that a single gene, encoding the mitochondrial reductase FDX1, could rescue elesclomol-induced cell death. Enzymatic function and nuclear-magnetic-resonance-based analyses further showed that FDX1 is the direct target of elesclomol, which promotes a unique form of copper-dependent cell death. These studies explain a fundamental mechanism by which cells adapt to proteotoxic stress and suggest strategies to mitigate proteasome inhibitor resistance.
    DOI:  https://doi.org/10.1038/s41589-019-0291-9
  29. Cell. 2019 May 30. pii: S0092-8674(19)30507-0. [Epub ahead of print]177(6): 1436-1447.e12
    BMAL1-Driven Tissue Clocks Respond Independently to Light to Maintain Homeostasis.
    Patrick-Simon Welz, Valentina M Zinna, Aikaterini Symeonidi, Kevin B Koronowski, Kenichiro Kinouchi, Jacob G Smith, Inés Marín Guillén, Andrés Castellanos, Georgiana Crainiciuc, Neus Prats, Juan Martín Caballero, Andrés Hidalgo, Paolo Sassone-Corsi, Salvador Aznar Benitah.
      Circadian rhythms control organismal physiology throughout the day. At the cellular level, clock regulation is established by a self-sustained Bmal1-dependent transcriptional oscillator network. However, it is still unclear how different tissues achieve a synchronized rhythmic physiology. That is, do they respond independently to environmental signals, or require interactions with each other to do so? We show that unexpectedly, light synchronizes the Bmal1-dependent circadian machinery in single tissues in the absence of Bmal1 in all other tissues. Strikingly, light-driven tissue autonomous clocks occur without rhythmic feeding behavior and are lost in constant darkness. Importantly, tissue-autonomous Bmal1 partially sustains homeostasis in otherwise arrhythmic and prematurely aging animals. Our results therefore support a two-branched model for the daily synchronization of tissues: an autonomous response branch, whereby light entrains circadian clocks without any commitment of other Bmal1-dependent clocks, and a memory branch using other Bmal1-dependent clocks to "remember" time in the absence of external cues.
    DOI:  https://doi.org/10.1016/j.cell.2019.05.009
  30. Cell. 2019 May 30. pii: S0092-8674(19)30444-1. [Epub ahead of print]177(6): 1448-1462.e14
    Defining the Independence of the Liver Circadian Clock.
    Kevin B Koronowski, Kenichiro Kinouchi, Patrick-Simon Welz, Jacob G Smith, Valentina M Zinna, Jiejun Shi, Muntaha Samad, Siwei Chen, Christophe N Magnan, Jason M Kinchen, Wei Li, Pierre Baldi, Salvador Aznar Benitah, Paolo Sassone-Corsi.
      Mammals rely on a network of circadian clocks to control daily systemic metabolism and physiology. The central pacemaker in the suprachiasmatic nucleus (SCN) is considered hierarchically dominant over peripheral clocks, whose degree of independence, or tissue-level autonomy, has never been ascertained in vivo. Using arrhythmic Bmal1-null mice, we generated animals with reconstituted circadian expression of BMAL1 exclusively in the liver (Liver-RE). High-throughput transcriptomics and metabolomics show that the liver has independent circadian functions specific for metabolic processes such as the NAD+ salvage pathway and glycogen turnover. However, although BMAL1 occupies chromatin at most genomic targets in Liver-RE mice, circadian expression is restricted to ∼10% of normally rhythmic transcripts. Finally, rhythmic clock gene expression is lost in Liver-RE mice under constant darkness. Hence, full circadian function in the liver depends on signals emanating from other clocks, and light contributes to tissue-autonomous clock function.
    Keywords:  autonomous; bmal1; chromatin; circadian; clock; diurnal physiology; epigenetics; light; metabolism; systemic signaling
    DOI:  https://doi.org/10.1016/j.cell.2019.04.025
  31. J Biol Chem. 2019 May 28. pii: jbc.RA118.005806. [Epub ahead of print]
    Inhibition of nucleotide synthesis promotes replicative senescence of human mammary epithelial cells.
    Alireza Delfarah, Sydney Parrish, Jason A Junge, Jesse Yang, Frances Seo, Si Li, John Mac, Pin Wang, Scott E Fraser, Nicholas A Graham.
      Cellular senescence is a mechanism by which cells permanently withdraw from the cell cycle in response to stresses including telomere shortening, DNA damage, or oncogenic signaling. Senescent cells contribute to both age-related degeneration and hyperplastic pathologies, including cancer. In culture, normal human epithelial cells enter senescence after a limited number of cell divisions, known as replicative senescence. Here, to investigate how metabolic pathways regulate replicative senescence, we used LC-MS-based metabolomics to analyze senescent primary human mammary epithelial cells (HMECs). We did not observe significant changes in glucose uptake or lactate secretion in senescent HMECs. However, analysis of intracellular metabolite pool sizes indicated that senescent cells exhibit depletion of metabolites from nucleotide synthesis pathways. Furthermore, stable isotope tracing with 13C-labeled glucose or glutamine revealed a dramatic blockage of flux of these two metabolites into nucleotide synthesis pathways in senescent HMECs. To test whether cellular immortalization would reverse these observations, we expressed telomerase in HMECs. In addition to preventing senescence, telomerase expression maintained metabolic flux from glucose into nucleotide synthesis pathways. Finally, we investigated whether inhibition of nucleotide synthesis in proliferating HMECs is sufficient to induce senescence. In proliferating HMECs, both pharmacological and genetic inhibition of ribonucleotide reductase regulatory subunit M2 (RRM2), a rate-limiting enzyme in dNTP synthesis, induced premature senescence with concomitantly decreased metabolic flux from glucose into nucleotide synthesis. Taken together, our results suggest that nucleotide synthesis inhibition plays a causative role in the establishment of replicative senescence in HMECs.
    Keywords:  aging; cell stress; cellular senescence; epithelial cell; growth arrest; metabolomics; nucleoside/nucleotide biosynthesis; ribonucleotide reductase regulatory subunit M2 (RRM2); systems biology
    DOI:  https://doi.org/10.1074/jbc.RA118.005806
  32. Mol Cell Oncol. 2019 ;6(3): 1595309
    Epigenetic dysregulation by aberrant metabolism in renal cell carcinoma can be reversed with Ascorbic acid.
    Niraj Shenoy.
      Our recently published study uncovered mechanisms and prognostic impact of aberrant DNA methylation/hydroxymethylation in clear cell renal cell carcinoma, and comprehensively explored the potential of Ascorbic acid in reversing the epigenetic aberrancy. This article provides a summary of the findings and their translational significance, and important considerations while testing Ascorbic acid as an anti-cancer agent. Abbreviations- ccRCC: clear cell renal cell carcinoma; TET: Ten-Eleven Translocation; 5mC: 5-methylcytosine; 5hmC: 5-hydroxymethylcytosine; L2HG: l-2-hydroxyglutarate; L2HGDH: l-2-hydroxyglutarate dehydrogenase; 2-OG: 2-Oxoglutarate; AA: Ascorbic acid.
    Keywords:  Ascorbic acid; cancer; epigenetics; hydroxymethylcytosine; kidney cancer
    DOI:  https://doi.org/10.1080/23723556.2019.1595309
  33. BMC Cancer. 2019 May 28. 19(1): 501
    Cancer cell lipid class homeostasis is altered under nutrient-deprivation but stable under hypoxia.
    Jan Lisec, Carsten Jaeger, Rida Rashid, Rimsha Munir, Nousheen Zaidi.
      BACKGROUND: Cancer cells modify the balance between fatty acid (FA) synthesis and uptake under metabolic stress, induced by oxygen/nutrient deprivation. These modifications were shown to alter the levels of individual triglyceride (TG) or phospholipid sub-species. To attain a holistic overview of the lipidomic profiles of cancer cells under stress we performed a broad lipidomic assay, comprising 244 lipids from six major classes. This assay allowed us to perform robust analyses and assess the changes in averages of broader lipid-classes, stratified on the basis of saturation index of their fatty-acyl side chains.METHODS: Global lipidomic profiling using Liquid Chromatography-Mass Spectrometry was performed to assess lipidomic profiles of biologically diverse cancer cell lines cultivated under metabolically stressed conditions.
    RESULTS: Neutral lipid compositions were markedly modified under serum-deprived conditions and, strikingly, the cellular level of triglyceride subspecies decreased with increasing number of double bonds in their fatty acyl chains. In contrast and unexpectedly, no robust changes were observed in lipidomic profiles of hypoxic (2% O2) cancer cells despite concurrent changes in proliferation rates and metabolic gene expression.
    CONCLUSIONS: Serum-deprivation significantly affects lipidomic profiles of cancer cells. Although, the levels of individual lipid moieties alter under hypoxia (2% O2), the robust averages of broader lipid classes remain unchanged.
    Keywords:  Fatty acid metabolism; Lipidomic profile; Metabolic stress; Tumor metabolism
    DOI:  https://doi.org/10.1186/s12885-019-5733-y
  34. Proc Natl Acad Sci U S A. 2019 May 29. pii: 201903682. [Epub ahead of print]
    NAD+-capped RNAs are widespread in the Arabidopsis transcriptome and can probably be translated.
    Yuan Wang, Shaofang Li, Yonghui Zhao, Chenjiang You, Brandon Le, Zhizhong Gong, Beixin Mo, Yiji Xia, Xuemei Chen.
      As the most common RNA cap in eukaryotes, the 7-methylguanosine (m7G) cap impacts nearly all processes that a messenger RNA undergoes, such as splicing, polyadenylation, nuclear export, translation, and degradation. The metabolite and redox agent, nicotinamide adenine diphosphate (NAD+), can be used as an initiating nucleotide in RNA synthesis to result in NAD+-capped RNAs. Such RNAs have been identified in bacteria, yeast, and human cells, but it is not known whether they exist in plant transcriptomes. The functions of the NAD+ cap in RNA metabolism or translation are still poorly understood. Here, through NAD captureSeq, we show that NAD+-capped RNAs are widespread in Arabidopsis thaliana NAD+-capped RNAs are predominantly messenger RNAs encoded by the nuclear and mitochondrial genomes, but not the chloroplast genome. NAD+-capped transcripts from the nuclear genome appear to be spliced and polyadenylated. Furthermore, although NAD+-capped transcripts constitute a small proportion of the total transcript pool from any gene, they are enriched in the polysomal fraction and associate with translating ribosomes. Our findings implicate the existence of as yet unknown mechanisms whereby the RNA NAD+ cap interfaces with RNA metabolic processes as well as translation initiation. More importantly, our findings suggest that cellular metabolic and/or redox states may influence, or be regulated by, mRNA NAD+ capping.
    Keywords:  NAD captureSeq; NAD+ cap; m7G cap; polysome; translation
    DOI:  https://doi.org/10.1073/pnas.1903682116
  35. JCI Insight. 2019 May 30. pii: 126132. [Epub ahead of print]5
    Two human patient mitochondrial pyruvate carrier mutations reveal distinct molecular mechanisms of dysfunction.
    Lalita Oonthonpan, Adam J Rauckhorst, Lawrence R Gray, Audrey C Boutron, Eric B Taylor.
      The Mitochondrial Pyruvate Carrier (MPC) occupies a central metabolic node by transporting cytosolic pyruvate into the mitochondrial matrix and linking glycolysis with mitochondrial metabolism. Two reported human MPC1 mutations cause developmental abnormalities, neurological problems, metabolic deficits, and for one patient, early death. We aimed to understand biochemical mechanisms by which the human patient C289T and T236A MPC1 alleles disrupt MPC function. MPC1 C289T encodes two protein variants, a mis-spliced, truncation mutant (A58G) and a full length point mutant (R97W). MPC1 T236A encodes a full length point mutant (L79H). Using human patient fibroblasts and complementation of CRISPR-deleted, MPC1 null mouse C2C12 cells, we investigated how MPC1 mutations cause MPC deficiency. Truncated MPC1 A58G protein was intrinsically unstable and failed to form MPC complexes. The MPC1 R97W protein was less stable but when overexpressed formed complexes with MPC2 that retained pyruvate transport activity. Conversely, MPC1 L79H protein formed stable complexes with MPC2, but these complexes failed to transport pyruvate. These findings inform MPC structure-function relationships and delineate three distinct biochemical pathologies resulting from two human patient MPC1 mutations. They also illustrate an efficient gene pass-through system for mechanistically investigating human inborn errors in pyruvate metabolism.
    Keywords:  Carbohydrate metabolism; Cell Biology; Metabolism; Mitochondria; Transport
    DOI:  https://doi.org/10.1172/jci.insight.126132
  36. Cell. 2019 May 30. pii: S0092-8674(19)30387-3. [Epub ahead of print]177(6): 1522-1535.e14
    Neuron-Astrocyte Metabolic Coupling Protects against Activity-Induced Fatty Acid Toxicity.
    Maria S Ioannou, Jesse Jackson, Shu-Hsien Sheu, Chi-Lun Chang, Aubrey V Weigel, Hui Liu, H Amalia Pasolli, C Shan Xu, Song Pang, Doreen Matthies, Harald F Hess, Jennifer Lippincott-Schwartz, Zhe Liu.
      Metabolic coordination between neurons and astrocytes is critical for the health of the brain. However, neuron-astrocyte coupling of lipid metabolism, particularly in response to neural activity, remains largely uncharacterized. Here, we demonstrate that toxic fatty acids (FAs) produced in hyperactive neurons are transferred to astrocytic lipid droplets by ApoE-positive lipid particles. Astrocytes consume the FAs stored in lipid droplets via mitochondrial β-oxidation in response to neuronal activity and turn on a detoxification gene expression program. Our findings reveal that FA metabolism is coupled in neurons and astrocytes to protect neurons from FA toxicity during periods of enhanced activity. This coordinated mechanism for metabolizing FAs could underlie both homeostasis and a variety of disease states of the brain.
    Keywords:  ApoE; NMDA; astrocyte; fatty acid; lipid droplet; lipid peroxidation; lipoprotein particle; lipotoxicity; neuron; neuronal activity
    DOI:  https://doi.org/10.1016/j.cell.2019.04.001
  37. Cell Res. 2019 May 27.
    AIF-regulated oxidative phosphorylation supports lung cancer development.
    Shuan Rao, Laura Mondragón, Blanka Pranjic, Toshikatsu Hanada, Gautier Stoll, Thomas Köcher, Peng Zhang, Alexander Jais, Alexander Lercher, Andreas Bergthaler, Daniel Schramek, Katharina Haigh, Valentina Sica, Marion Leduc, Nazanine Modjtahedi, Tsung-Pin Pai, Masahiro Onji, Iris Uribesalgo, Reiko Hanada, Ivona Kozieradzki, Rubina Koglgruber, Shane J Cronin, Zhigang She, Franz Quehenberger, Helmut Popper, Lukas Kenner, Jody J Haigh, Oliver Kepp, Malgorzata Rak, Kaican Cai, Guido Kroemer, Josef M Penninger.
      Cancer is a major and still increasing cause of death in humans. Most cancer cells have a fundamentally different metabolic profile from that of normal tissue. This shift away from mitochondrial ATP synthesis via oxidative phosphorylation towards a high rate of glycolysis, termed Warburg effect, has long been recognized as a paradigmatic hallmark of cancer, supporting the increased biosynthetic demands of tumor cells. Here we show that deletion of apoptosis-inducing factor (AIF) in a KrasG12D-driven mouse lung cancer model resulted in a marked survival advantage, with delayed tumor onset and decreased malignant progression. Mechanistically, Aif deletion leads to oxidative phosphorylation (OXPHOS) deficiency and a switch in cellular metabolism towards glycolysis in non-transformed pneumocytes and at early stages of tumor development. Paradoxically, although Aif-deficient cells exhibited a metabolic Warburg profile, this bioenergetic change resulted in a growth disadvantage of KrasG12D-driven as well as Kras wild-type lung cancer cells. Cell-autonomous re-expression of both wild-type and mutant AIF (displaying an intact mitochondrial, but abrogated apoptotic function) in Aif-knockout KrasG12D mice restored OXPHOS and reduced animal survival to the same level as AIF wild-type mice. In patients with non-small cell lung cancer, high AIF expression was associated with poor prognosis. These data show that AIF-regulated mitochondrial respiration and OXPHOS drive the progression of lung cancer.
    DOI:  https://doi.org/10.1038/s41422-019-0181-4
  38. Sci Signal. 2019 May 28. pii: eaaw6996. [Epub ahead of print]12(583):
    Too close not to encyst: Polycystic kidney disease and interorganellar contact sites.
    Isotta Lorenzi, Luca Scorrano.
      Mitofusin 2 (MFN2) tethers mitochondria to the endoplasmic reticulum (ER). In the 7 May 2019 issue of Science Signaling, Kuo et al. report that polycystin 2 (PC2), encoded by a gene mutated in type 2 autosomal dominant polycystic kidney disease (ADPKD), contributes to cystogenesis by affecting MFN2, thus extending the role of mitochondria-ER contact sites to a common genetic disorder.
    DOI:  https://doi.org/10.1126/scisignal.aaw6996
  39. Br J Cancer. 2019 May 28.
    Transcriptional and metabolic rewiring of colorectal cancer cells expressing the oncogenic KRASG13D mutation.
    Theodosia Charitou, Sriganesh Srihari, Miriam A Lynn, Mohamed-Ali Jarboui, Erik Fasterius, Max Moldovan, Senji Shirasawa, Toshiyuki Tsunoda, Marius Ueffing, Jianling Xie, Jin Xin, Xuemin Wang, Christopher G Proud, Karsten Boldt, Cristina Al-Khalili Szigyarto, Walter Kolch, David J Lynn.
      BACKGROUND: Activating mutations in KRAS frequently occur in colorectal cancer (CRC) patients, leading to resistance to EGFR-targeted therapies.METHODS: To better understand the cellular reprogramming which occurs in mutant KRAS cells, we have undertaken a systems-level analysis of four CRC cell lines which express either wild type (wt) KRAS or the oncogenic KRASG13D allele (mtKRAS).
    RESULTS: RNAseq revealed that genes involved in ribosome biogenesis, mRNA translation and metabolism were significantly upregulated in mtKRAS cells. Consistent with the transcriptional data, protein synthesis and cell proliferation were significantly higher in the mtKRAS cells. Targeted metabolomics analysis also confirmed the metabolic reprogramming in mtKRAS cells. Interestingly, mtKRAS cells were highly transcriptionally responsive to EGFR activation by TGFα stimulation, which was associated with an unexpected downregulation of genes involved in a range of anabolic processes. While TGFα treatment strongly activated protein synthesis in wtKRAS cells, protein synthesis was not activated above basal levels in the TGFα-treated mtKRAS cells. This was likely due to the defective activation of the mTORC1 and other pathways by TGFα in mtKRAS cells, which was associated with impaired activation of PKB signalling and a transient induction of AMPK signalling.
    CONCLUSIONS: We have found that mtKRAS cells are substantially rewired at the transcriptional, translational and metabolic levels and that this rewiring may reveal new vulnerabilities in oncogenic KRAS CRC cells that could be exploited in future.
    DOI:  https://doi.org/10.1038/s41416-019-0477-7
  40. F1000Res. 2019 ;pii: F1000 Faculty Rev-676. [Epub ahead of print]8
    Right place, right time: localisation and assembly of the NLRP3 inflammasome.
    Claire Hamilton, Paras K Anand.
      The NLRP3 inflammasome is a multimeric protein complex that cleaves caspase-1 and the pro-inflammatory cytokines interleukin 1 beta (IL-1β) and IL-18. Dysregulated NLRP3 inflammasome signalling is linked to several chronic inflammatory and autoimmune conditions; thus, understanding the activation mechanisms of the NLRP3 inflammasome is essential. Studies over the past few years have implicated vital roles for distinct intracellular organelles in both the localisation and assembly of the NLRP3 inflammasome. However, conflicting reports exist. Prior to its activation, NLRP3 has been shown to be resident in the endoplasmic reticulum (ER) and cytosol, although, upon activation, the NLRP3 inflammasome has been shown to assemble in the cytosol, mitochondria, and mitochondria-associated ER membranes by different reports. Finally, very recent work has suggested that NLRP3 may be localised on or adjacent to the Golgi apparatus and that release of mediators from this organelle may contribute to inflammasome assembly. Therefore, NLRP3 may be strategically placed on or in close proximity to these subcellular compartments to both sense danger signals originating from these organelles and use the compartment as a scaffold to assemble the complex. Understanding where and when NLRP3 inflammasome assembly occurs may help identify potential targets for treatment of NLRP3-related disorders.
    Keywords:  Golgi; IL-18; IL-1β; NLRP3; SREBP2; caspase-1; cholesterol; endoplasmic reticulum; inflammasome; mitochondria
    DOI:  https://doi.org/10.12688/f1000research.18557.1
  41. Elife. 2019 May 30. pii: e46551. [Epub ahead of print]8
    NRG1 is a critical regulator of differentiation in TP63-driven squamous cell carcinoma.
    Ganapati V Hegde, Cecile de la Cruz, Jennifer M Giltnane, Lisa Crocker, Avinashnarayan Venkatanarayan, Gabriele Schaefer, Debra Dunlap, Joerg D Hoeck, Robert Piskol, Florian Gnad, Zora Modrusan, Frederic J de Sauvage, Christian W Siebel, Erica L Jackson.
      Squamous cell carcinomas (SCCs) account for the majority of cancer mortalities. Although TP63 is an established lineage-survival oncogene in SCCs, therapeutic strategies have not been developed to target TP63 or it's downstream effectors. In this study we demonstrate that TP63 directly regulates NRG1 expression in human SCC cell lines and that NRG1 is a critical component of the TP63 transcriptional program. Notably, we show that squamous tumors are dependent NRG1 signaling in vivo, in both genetically engineered mouse models and human xenograft models, and demonstrate that inhibition of NRG1 induces keratinization and terminal squamous differentiation of tumor cells, blocking proliferation and inhibiting tumor growth. Together, our findings identify a lineage-specific function of NRG1 in SCCs of diverse anatomic origin.
    Keywords:  cancer biology; human; mouse
    DOI:  https://doi.org/10.7554/eLife.46551
  42. Nature. 2019 May;569(7758): 635-637
    Guarding the gate for mitochondrial entry.
    Sylvie Callegari, Peter Rehling.
      
    Keywords:  Cell biology
    DOI:  https://doi.org/10.1038/d41586-019-01588-7
  43. PLoS Biol. 2019 May 28. 17(5): e3000285
    Surviving starvation simply without TFEB.
    Alexander A Soukas, Ben Zhou.
      Starvation is among the most ancient of selection pressures, driving evolution of a robust arsenal of starvation survival defenses. In order to survive starvation stress, organisms must be able to curtail anabolic processes during starvation and judiciously activate catabolic pathways. Although the activation of metabolic defenses in response to nutrient deprivation is an obvious component of starvation survival, less appreciated is the importance of the ability to recover from starvation upon re-exposure to nutrients. In order for organisms to successfully recover from starvation, cells must be kept in a state of ready so that upon the return of nutrients, activities such as growth and reproduction can be resumed. Critical to this state of ready is the lysosome, an organelle that provides essential signals of nutrient sufficiency to cell growth-activating pathways in the fed state. In this issue, Murphy and colleagues provide evidence that exposure of Caenorhabditis elegans roundworms to 2 simple nutrients, glucose and the polyunsaturated fatty acid linoleate, is able to render lysosomal function competent to activate key downstream starvation recovery pathways, bypassing the need for a master transcriptional regulator of lysosomes. These findings provide a quantum leap forward in our understanding of the cellular determinants that permit organisms to survive cycles of feast and famine.
    DOI:  https://doi.org/10.1371/journal.pbio.3000285
  44. Front Endocrinol (Lausanne). 2019 ;10 294
    Role of Mitochondria in the Mechanism(s) of Action of Metformin.
    Guillaume Vial, Dominique Detaille, Bruno Guigas.
      Metformin is a drug from the biguanide family that is used for decades as the first-line therapeutic choice for the treatment of type 2 diabetes. Despite its worldwide democratization, owing to its clinical efficacy, high safety profile and cheap cost, the exact mechanism(s) of action of this anti-hyperglycemic molecule with pleiotropic properties still remains to be fully elucidated. The concept that metformin would exert some of its actions though modulation of the mitochondrial bioenergetics was initially forged in the 50s but undeniably revived at the beginning of the twenty-first century when it was shown to induce a weak but specific inhibition of the mitochondrial respiratory-chain complex 1. Furthermore, metformin has been reported to reduce generation of reactive oxygen species at the complex 1 and to prevent mitochondrial-mediated apoptosis, suggesting that it can protect against oxidative stress-induced cell death. Nevertheless, despite some recent progress and the demonstration of its key role in the inhibition of hepatic gluconeogenesis, the exact nature of the mitochondrial interaction between the drug and the complex 1 is still poorly characterized. Recent studies reported that metformin may also have anti-neoplastic properties by inhibiting cancer cell growth and proliferation, at least partly through its mitochondrial action. As such, many trials are currently conducted for exploring the repositioning of metformin as a potential drug for cancer therapy. In this mini-review, we discuss both historical and more recent findings on the central role played by the interaction between metformin and the mitochondria in its cellular mechanism of action.
    Keywords:  AMPK; biguanides; bioenergetics; cancer; respiratory-chain complex 1
    DOI:  https://doi.org/10.3389/fendo.2019.00294
This page is being maintained by Thomas Krichel. It was last updated on 2024‒03‒10 at 13:08.