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  • Defects in mitophagy promote redox‐driven metabolic syndrome in the absence of TP53INP1
    Defects in mitophagy promote redox‐driven metabolic syndrome in the absence of TP53INP1
    1. Marion Seillier1,2,3,4,
    2. Laurent Pouyet1,2,3,4,
    3. Prudence N'Guessan1,2,3,4,
    4. Marie Nollet1,2,3,4,
    5. Florence Capo1,2,3,4,
    6. Fabienne Guillaumond1,2,3,4,
    7. Laure Peyta5,
    8. Jean‐François Dumas5,
    9. Annie Varrault6,
    10. Gyslaine Bertrand6,
    11. Stéphanie Bonnafous7,8,9,
    12. Albert Tran7,8,9,
    13. Gargi Meur10,
    14. Piero Marchetti11,
    15. Magalie A Ravier6,
    16. Stéphane Dalle6,
    17. Philippe Gual7,8,9,
    18. Dany Muller6,
    19. Guy A Rutter10,
    20. Stéphane Servais5,
    21. Juan L Iovanna1,2,3,4 and
    22. Alice Carrier*,1,2,3,4
    1. 1Inserm, U1068, CRCM, Marseille, France
    2. 2Institut Paoli‐Calmettes, Marseille, France
    3. 3Aix‐Marseille Université, Marseille, France
    4. 4CNRS, UMR7258, CRCM, Marseille, France
    5. 5Inserm, U1069 Nutrition, Croissance et Cancer (N2C), Tours, France
    6. 6CNRS, UMR5203, Inserm, U661 Universités de Montpellier 1 & 2, IGF, Montpellier, France
    7. 7Inserm, U1065, C3M Team 8 “Hepatic Complications in Obesity”, Nice, France
    8. 8Université de Nice‐Sophia‐Antipolis, Nice, France
    9. 9Centre Hospitalier Universitaire de Nice, Pôle Digestif Hôpital L'Archet, Nice, France
    10. 10Cell Biology, Department of Medicine, Imperial College, London, UK
    11. 11Islet Cell Laboratory, University of Pisa – Cisanello Hospital, Pisa, Italy
    1. *Corresponding author. Tel: +33 4 91 82 88 29; Fax: +33 4 91 82 60 83; E‐mail: alice.carrier{at}inserm.fr

    TP53INP1, a p53‐regulated protein with antioxidant and tumor suppressive functions, is shown to prevent redox‐driven obesity, which leads to insulin resistance and type 2 diabetes, likely by impacting on mitochondria homeostasis and mitophagy.

    Synopsis

    TP53INP1, a p53‐regulated protein with antioxidant and tumor suppressive functions, is shown to prevent redox‐driven obesity, which leads to insulin resistance and type 2 diabetes (T2D), likely by impacting on mitochondria homeostasis and mitophagy.

    • TP53INP1 is known for its tumor suppressive activity due to its implication in redox control.

    • TP53INP1 also plays a role in T2D prevention by regulating redox‐associated lipid metabolism.

    • Excess of ROS in TP53INP1‐deficient mice stems from accumulation of defective mitochondria producing ROS.

    • Accumulation of mitochondria in TP53INP1‐deficient mice is due in part from defective autophagy, and in particular mitophagy.

    • autophagy
    • diabetes
    • mitochondria
    • obesity
    • oxidative stress
    • Received June 3, 2014.
    • Revision received March 4, 2015.
    • Accepted March 9, 2015.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Marion Seillier, Laurent Pouyet, Prudence N'Guessan, Marie Nollet, Florence Capo, Fabienne Guillaumond, Laure Peyta, Jean‐François Dumas, Annie Varrault, Gyslaine Bertrand, Stéphanie Bonnafous, Albert Tran, Gargi Meur, Piero Marchetti, Magalie A Ravier, Stéphane Dalle, Philippe Gual, Dany Muller, Guy A Rutter, Stéphane Servais, Juan L Iovanna, Alice Carrier
  • Genetic and hypoxic alterations of the microRNA‐210‐ISCU1/2 axis promote iron–sulfur deficiency and pulmonary hypertension
    Genetic and hypoxic alterations of the microRNA‐210‐ISCU1/2 axis promote iron–sulfur deficiency and pulmonary hypertension
    1. Kevin White121,
    2. Yu Lu1,,
    3. Sofia Annis1,
    4. Andrew E Hale1,
    5. B Nelson Chau222,
    6. James E Dahlman3,4,5,6,
    7. Craig Hemann7,
    8. Alexander R Opotowsky1,8,
    9. Sara O Vargas9,
    10. Ivan Rosas10,
    11. Mark A Perrella10,11,
    12. Juan C Osorio10,
    13. Kathleen J Haley10,
    14. Brian B Graham12,
    15. Rahul Kumar12,
    16. Rajan Saggar13,
    17. Rajeev Saggar14,
    18. W Dean Wallace13,
    19. David J Ross13,
    20. Omar F Khan5,6,
    21. Andrew Bader3,4,
    22. Bernadette R Gochuico15,
    23. Majed Matar16,
    24. Kevin Polach16,
    25. Nicolai M Johannessen17,
    26. Haydn M Prosser18,
    27. Daniel G Anderson3,4,5,6,
    28. Robert Langer3,4,5,6,
    29. Jay L Zweier7,
    30. Laurence A Bindoff19,20,
    31. David Systrom10,
    32. Aaron B Waxman10,
    33. Richard C Jin1 and
    34. Stephen Y Chan*,1
    1. 1Divisions of Cardiovascular Medicine and Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
    2. 2Regulus Therapeutics, San Diego, CA, USA
    3. 3Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA
    4. 4Harvard‐MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA, USA
    5. 5Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA
    6. 6David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
    7. 7The Davis Heart and Lung Research Institute, Division of Cardiovascular Medicine, Department of Internal Medicine, Wexner Medical Center, The Ohio State University, Columbus, OH, USA
    8. 8Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
    9. 9Department of Pathology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
    10. 10Division of Pulmonary/Critical Care Medicine, Department of Medicine, Harvard Medical School, Boston, MA, USA
    11. 11Department of Pediatric Newborn Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
    12. 12Program in Translational Lung Research, University of Colorado, Denver, Aurora, CO, USA
    13. 13Departments of Medicine and Pathology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
    14. 14Department of Cardiothoracic Surgery, University of Arizona College of Medicine, Phoenix, AZ, USA
    15. 15Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
    16. 16Celsion‐EGEN, Inc., Huntsville, AL, USA
    17. 17Department of Cardiology, University of Bergen, Bergen, Norway
    18. 18The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK
    19. 19Department of Clinical Medicine, University of Bergen, Bergen, Norway
    20. 20Department of Neurology, Haukeland University Hospital, Bergen, Norway
    21. 21Novartis, Cambridge, MA, USA
    22. 22 RaNA Therapeutics, Cambridge, MA, USA
    1. *Corresponding author. Tel: +1 617 525 4844; Fax: +1 617 525 4830; E‐mail: sychan{at}partners.org
    1. These authors contributed equally to this work

    Hypoxia‐inducible miR‐210 down‐regulates its targets ISCU1/2 to regulate pulmonary vascular and endothelial levels of Fe‐S clusters upon acquired injury or mutations. A patient with ISCU loss‐of‐function mutation presents with pulmonary vasculopathy.

    Synopsis

    Hypoxia‐inducible miR‐210 down‐regulates its targets ISCU1/2 to regulate pulmonary vascular and endothelial levels of Fe‐S clusters upon acquired injury or mutations. A patient with ISCU loss‐of‐function mutation presents with pulmonary vasculopathy.

    • In mouse and human pulmonary vascular and endothelial tissue affected by PH, hypoxic induction of miR‐210 and repression of its targets ISCU1/2, down‐regulates iron‐sulfur levels.

    • Using genetic and pharmacologic methods to perform gain‐of‐function and loss‐of‐function analyses of miR‐210 and ISCU1/2 in the pulmonary vasculature of mice, the miR‐210‐ISCU1/2 axis is shown to be necessary and sufficient for induction of hypoxic PH.

    • Cardiopulmonary exercise testing of a woman with ISCU mutations revealed exercise‐induced pulmonary vascular dysfunction.

    • endothelial
    • iron–sulfur
    • metabolism
    • microRNA
    • mitochondria
    • Received August 23, 2014.
    • Revision received February 20, 2015.
    • Accepted February 23, 2015.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Kevin White, Yu Lu, Sofia Annis, Andrew E Hale, B Nelson Chau, James E Dahlman, Craig Hemann, Alexander R Opotowsky, Sara O Vargas, Ivan Rosas, Mark A Perrella, Juan C Osorio, Kathleen J Haley, Brian B Graham, Rahul Kumar, Rajan Saggar, Rajeev Saggar, W Dean Wallace, David J Ross, Omar F Khan, Andrew Bader, Bernadette R Gochuico, Majed Matar, Kevin Polach, Nicolai M Johannessen, Haydn M Prosser, Daniel G Anderson, Robert Langer, Jay L Zweier, Laurence A Bindoff, David Systrom, Aaron B Waxman, Richard C Jin, Stephen Y Chan
  • Targeting DDX3 with a small molecule inhibitor for lung cancer therapy
    Targeting DDX3 with a small molecule inhibitor for lung cancer therapy
    1. Guus M Bol1,2,
    2. Farhad Vesuna1,
    3. Min Xie1,
    4. Jing Zeng3,
    5. Khaled Aziz3,
    6. Nishant Gandhi3,
    7. Anne Levine1,
    8. Ashley Irving1,
    9. Dorian Korz1,
    10. Saritha Tantravedi1,
    11. Marise R Heerma van Voss1,2,
    12. Kathleen Gabrielson4,
    13. Evan A Bordt5,
    14. Brian M Polster5,
    15. Leslie Cope6,
    16. Petra van der Groep2,
    17. Atul Kondaskar7,
    18. Michelle A Rudek6,
    19. Ramachandra S Hosmane7,
    20. Elsken van der Wall8,
    21. Paul J van Diest2,6,
    22. Phuoc T Tran3,6 and
    23. Venu Raman*,1,2,6
    1. 1Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA
    2. 2Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
    3. 3Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
    4. 4Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
    5. 5Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, MD, USA
    6. 6Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
    7. 7Department of Chemistry & Biochemistry, University of Maryland, Baltimore County, MD, USA
    8. 8Department of Internal Medicine, University Medical Center Utrecht, Utrecht, The Netherlands
    1. *Corresponding author. Tel: +1 410 955 7492; E‐mail: vraman2{at}jhmi.edu

    The RNA helicase DDX3 is a new independent marker of lung cancer and targeted chemotherapy option. The novel inhibitor RK‐33, combined with radiation therapy, induces tumor regression in lung cancer models, with no toxicity at the therapeutic dose.

    Synopsis

    The RNA helicase DDX3 is a new independent marker of lung cancer and targeted chemotherapy option. The novel inhibitor RK‐33, combined with radiation therapy, induces tumor regression in lung cancer models, with no toxicity at the therapeutic dose.

    • The RNA helicase DDX3 is overexpressed in lung cancer and is associated with lower survival in lung cancer patients.

    • Knockdown of DDX3 in highly aggressive lung cancer cell lines (H1299 and A549) curbed their colony‐forming abilities.

    • A small molecule inhibitor of DDX3, RK‐33, designed to bind to the nucleotide‐binding site within the DDX3 protein was synthesized.

    • RK‐33 was able to induce cell cycle arrest causing apoptosis in aggressive lung cancer, but not in normal cells, and promoted sensitization to radiation in DDX3‐overexpressing cells. Mechanistically, RK‐33 inhibited non‐homologous end joining and impaired Wnt signaling by disrupting the DDX3–β‐catenin axis.

    • RK‐33 in combination with radiation, induced tumor regression in multiple mouse models of lung cancer, while showing no toxicity at the therapeutic dose.

    • DDX3
    • DNA repair
    • lung cancer
    • radiation‐sensitizing agent
    • small molecule inhibitor
    • Received June 25, 2014.
    • Revision received February 9, 2015.
    • Accepted February 12, 2015.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Guus M Bol, Farhad Vesuna, Min Xie, Jing Zeng, Khaled Aziz, Nishant Gandhi, Anne Levine, Ashley Irving, Dorian Korz, Saritha Tantravedi, Marise R Heerma van Voss, Kathleen Gabrielson, Evan A Bordt, Brian M Polster, Leslie Cope, Petra van der Groep, Atul Kondaskar, Michelle A Rudek, Ramachandra S Hosmane, Elsken van der Wall, Paul J van Diest, Phuoc T Tran, Venu Raman
  • A metabolic switch toward lipid use in glycolytic muscle is an early pathologic event in a mouse model of amyotrophic lateral sclerosis
    A metabolic switch toward lipid use in glycolytic muscle is an early pathologic event in a mouse model of amyotrophic lateral sclerosis
    1. Lavinia Palamiuc1,2,
    2. Anna Schlagowski3,4,
    3. Shyuan T Ngo5,6,
    4. Aurelia Vernay1,2,
    5. Sylvie Dirrig‐Grosch1,2,
    6. Alexandre Henriques1,2,
    7. Anne‐Laurence Boutillier7,
    8. Joffrey Zoll3,4,
    9. Andoni Echaniz‐Laguna1,2,8,
    10. Jean‐Philippe Loeffler*,1,2 and
    11. Frédérique René*,1,2
    1. 1INSERM, U1118 Mécanismes Centraux et Périphériques de la Neurodégénérescence, Strasbourg, France
    2. 2Université de Strasbourg UMRS1118, Strasbourg, France
    3. 3Equipe d'Accueil 3072, Mitochondrie, Stress oxydant et Protection Musculaire, Fédération de Médecine Translationelle de Strasbourg, Université de Strasbourg, Strasbourg, France
    4. 4Service de Physiologie et d'Explorations Fonctionnelles, Pôle de Pathologie Thoracique Hôpitaux Universitaires, CHRU de Strasbourg, Strasbourg, France
    5. 5School of Biomedical Sciences, The University of Queensland, St Lucia, Qld, Australia
    6. 6University of Queensland Centre for Clinical Research, The University of Queensland, Herston, Qld, Australia
    7. 7UMR7364 Laboratoire de Neurosciences Cognitives et Adaptatives, Faculté de Psychologie, Université de Strasbourg‐CNRS, GDR CNRS 2905, Strasbourg, France
    8. 8Département de Neurologie, Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
    1. * Corresponding author. Tel: +33 368 853 081; Fax: +33 368 853 065; E‐mail: loeffler{at}unistra.fr

      Corresponding author. Tel: +33 368 853 086; Fax: +33 368 853 065; E‐mail: frederique.rene{at}unistra.fr

    Altered metabolic homeostasis is an early event in amyotrophic lateral sclerosis (ALS) manifestation. This study reveals that skeletal muscles stop using glucose as a source of energy but use lipids instead and this chronic pathologic alteration in muscles is exacerbated with disease progression.

    Synopsis

    Altered metabolic homeostasis is an early event in amyotrophic lateral sclerosis (ALS) manifestation. This study reveals that skeletal muscles stop using glucose as a source of energy but use lipids instead and this chronic pathologic alteration in muscles is exacerbated with disease progression.

    • The early alteration of muscle metabolic equilibrium between glucose and lipid use impacts on the capacity for muscle to efficiently adapt to increased energetic demands in the SOD1G86R ALS mouse model.

    • PDK4 is central to these metabolic changes, being upregulated at early asymptomatic stages and increasing throughout disease progression in the SOD1G86R model, as well as in ALS patients.

    • The metabolic alterations described are specific to glycolytic muscle (TA) in the SOD1G86R model.

    • Regulation of the glycolytic pathway presents as a potential therapeutic strategy as a drug targeting of PDK4 improves muscle function and overall metabolic status in the SOD1G86R model.

    • amyotrophic lateral sclerosis
    • exercise
    • glucose
    • lipids
    • muscle
    • Received July 14, 2014.
    • Revision received February 17, 2015.
    • Accepted February 20, 2015.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Lavinia Palamiuc, Anna Schlagowski, Shyuan T Ngo, Aurelia Vernay, Sylvie Dirrig‐Grosch, Alexandre Henriques, Anne‐Laurence Boutillier, Joffrey Zoll, Andoni Echaniz‐Laguna, Jean‐Philippe Loeffler, Frédérique René
  • Comprehensive establishment and characterization of orthoxenograft mouse models of malignant peripheral nerve sheath tumors for personalized medicine
    Comprehensive establishment and characterization of orthoxenograft mouse models of malignant peripheral nerve sheath tumors for personalized medicine
    1. Joan Castellsagué1,2,,
    2. Bernat Gel3,,
    3. Juana Fernández‐Rodríguez1,2,,
    4. Roger Llatjós4,
    5. Ignacio Blanco1,
    6. Yolanda Benavente5,
    7. Diana Pérez‐Sidelnikova6,
    8. Javier García‐del Muro7,
    9. Joan Maria Viñals6,
    10. August Vidal4,
    11. Rafael Valdés‐Mas8,
    12. Ernest Terribas3,
    13. Adriana López‐Doriga1,2,
    14. Miguel Angel Pujana2,
    15. Gabriel Capellá1,2,
    16. Xose S Puente8,
    17. Eduard Serra*,3,
    18. Alberto Villanueva*,2 and
    19. Conxi Lázaro*,1,2
    1. 1Hereditary Cancer Program, Catalan Institute of Oncology (ICO‐IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain
    2. 2Translational Research Laboratory ICO‐IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain
    3. 3Institut de Medicina Predictiva i Personalitzada del Càncer (IMPPC), Badalona, Barcelona, Spain
    4. 4Pathology Service, HUB‐IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain
    5. 5Unit of Infections and Cancer (UNIC), Cancer Epidemiology Research Program ICO‐IDIBELL and CIBER Epidemiología y Salud Pública (CIBERESP), L'Hospitalet de Llobregat, Barcelona, Spain
    6. 6Plastic Surgery Service HUB‐IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain
    7. 7Medical Oncology Service ICO‐IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain
    8. 8Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo, Oviedo, Spain
    1. * Corresponding author. Tel: +34 93 2607342; Fax: +34 93 2607466; E‐mail: clazaro{at}iconcologia.net

      Corresponding author. Tel: +34 93 2607952; Fax: +34 93 2607466; E‐mail: avillanueva{at}iconcologia.net

      Corresponding author. Tel: +34 93 5543067; Fax: +34 93 4651472; E‐mail: eserra{at}imppc.org

    1. These authors contributed equally to this work

    The first patient‐derived MPNST orthoxenograft models are presented together with a preclinical proof‐of‐concept experimentation that supports the use of sorafenib‐based combination therapy to curb MPNST growth.

    Synopsis

    The first patient‐derived MPNST orthoxenograft models are presented together with a preclinical proof‐of‐concept experimentation that supports the use of sorafenib‐based combination therapy to curb MPNST growth.

    • Five malignant peripheral nerve sheath tumor (MPNST) orthoxenograft models—both sporadic and NF1‐associated—are presented.

    • A comprehensive histological, genomic and transcriptomic characterization shows that the models reliably mimic the respective primary tumors, validating these models for pre‐clinical personalized treatments.

    • A first preclinical drug experimentation performed as a proof of concept shows that combined therapy with sorafenib is the most effective in reducing MPNST growth.

    • MPNST
    • NF1
    • patient‐derived tumor xenograft
    • preclinical mouse models
    • sorafenib
    • Received August 13, 2014.
    • Revision received February 24, 2015.
    • Accepted February 25, 2015.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Joan Castellsagué, Bernat Gel, Juana Fernández‐Rodríguez, Roger Llatjós, Ignacio Blanco, Yolanda Benavente, Diana Pérez‐Sidelnikova, Javier García‐del Muro, Joan Maria Viñals, August Vidal, Rafael Valdés‐Mas, Ernest Terribas, Adriana López‐Doriga, Miguel Angel Pujana, Gabriel Capellá, Xose S Puente, Eduard Serra, Alberto Villanueva, Conxi Lázaro
  • The clinical heterogeneity of coenzyme Q10 deficiency results from genotypic differences in the Coq9 gene
    <div xmlns="http://www.w3.org/1999/xhtml">The clinical heterogeneity of coenzyme Q<sub>10</sub> deficiency results from genotypic differences in the <em>Coq9</em> gene</div>
    1. Marta Luna‐Sánchez1,2,
    2. Elena Díaz‐Casado1,2,
    3. Emanuele Barca3,
    4. Miguel Ángel Tejada4,5,
    5. Ángeles Montilla‐García4,5,
    6. Enrique Javier Cobos4,5,
    7. Germaine Escames1,2,
    8. Dario Acuña‐Castroviejo1,2,
    9. Catarina M Quinzii3 and
    10. Luis Carlos López*,1,2
    1. 1Departamento de Fisiología, Facultad de Medicina, Universidad de Granada, Granada, Spain
    2. 2Centro de Investigación Biomédica, Instituto de Biotecnología, Parque Tecnológico de Ciencias de la Salud, Granada, Spain
    3. 3Department of Neurology, Columbia University Medical Center, New York, NY, USA
    4. 4Departamento de Farmacología, Facultad de Medicina, Universidad de Granada, Granada, Spain
    5. 5Centro de Investigación Biomédica, Instituto de Neurociencias, Parque Tecnológico de Ciencias de la Salud, Granada, Spain
    1. *Corresponding author. Tel: +34 9582 41000, ext 20197; E‐mail: luisca{at}ugr.es

    Two different premature terminations in the COQ9 protein uniquely affect the expression levels of components of the multiprotein complex for CoQ biosynthesis, establishing for the first time a genotype/clinical phenotype relationship with therapeutic consequences.

    Synopsis

    Two different premature terminations in the COQ9 protein uniquely affect the expression levels of components of the multiprotein complex for CoQ biosynthesis, establishing for the first time a genotype/clinical phenotype relationship with therapeutic consequences.

    • The first mouse model of mild mitochondrial myopathy due to CoQ deficiency was generated and characterized (Coq9Q95X).

    • The clinical phenotypes of CoQ deficiency observed in two mouse models (Coq9Q95X and Coq9R239X) are caused by genotypic difference in the Coq9 gene and were influenced by the efficiency of nonsense‐mediated mRNA decay.

    • CoQ multiprotein complex for CoQ biosynthesis was destabilized by the presence of a truncated protein in Coq9R239X mice, leading to a severe CoQ deficiency and clinical phenotype.

    • Whether a bypass therapy aimed at increasing CoQ biosynthesis is successful depends on CoQ biosynthetic proteins levels.

    • CoQ multiprotein complex
    • Coq9
    • mitochondrial myopathy
    • mouse model
    • nonsense‐mediated mRNA decay
    • Received October 31, 2014.
    • Revision received February 24, 2015.
    • Accepted February 26, 2015.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Marta Luna‐Sánchez, Elena Díaz‐Casado, Emanuele Barca, Miguel Ángel Tejada, Ángeles Montilla‐García, Enrique Javier Cobos, Germaine Escames, Dario Acuña‐Castroviejo, Catarina M Quinzii, Luis Carlos López
  • CRISPR‐Cas9: how research on a bacterial RNA‐guided mechanism opened new perspectives in biotechnology and biomedicine
    CRISPR‐Cas9: how research on a bacterial RNA‐guided mechanism opened new perspectives in biotechnology and biomedicine
    1. Emmanuelle Charpentier (emmanuelle.charpentier{at}mims.umu.se) 1,2,3
    1. 1Department of Regulation in Infection Biology, Helmholtz Centre for Infection Research, Braunschweig, Germany
    2. 2Department of Molecular Biology, The Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå Centre for Microbial Research (UCMR), Umeå University, Umeå, Sweden
    3. 3Hannover Medical School, Hannover, Germany

    The 2015 Louis‐Jeantet Prize for Medicine winner Emmanuelle Charpentier describes the CRISPR‐Cas9 unique mechanism. The system was harnessed into a new tool that makes genome editing within the cell a simple and straightforward system.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Emmanuelle Charpentier