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  • News & Views
    Amyloid‐β in mitochondrial disease: mutation in a human metallopeptidase links amyloidotic neurodegeneration with mitochondrial processing
    Amyloid‐β in mitochondrial disease: mutation in a human metallopeptidase links amyloidotic neurodegeneration with mitochondrial processing
    1. Veronika Boczonadi1 and
    2. Rita Horvath (rita.horvath{at}ncl.ac.uk)1
    1. 1Institute of Genetic Medicine, Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, UK

    There is increasing evidence that common molecular pathways in neurons are closely linked with mitochondrial function and that mitochondrial dysfunction is connected to various forms of neurodegenerative diseases. For instance, mitochondria are involved in amyloid‐β (Aβ) deposition in Alzheimer's disease, although the exact molecular pathways remain largely unknown. Brunetti et al (2015) in this issue of EMBO Molecular Medicine provide a novel link between Aβ accumulation and mitochondria. A pathogenic mutation in a Norwegian family in the mitochondrial metallopeptidase PITRM1 is found to underlie a novel mitochondrial neurodegenerative phenotype associated with Aβ accumulation.

    See also: D Brunetti et al

    Boczonadi and Horvath comment on the Brunetti et al's paper in this issue describing a mitochondrial metallopeptidase PITRM1 pathogenic mutation in a Norwegian family, underlying a novel mitochondrial neurodegenerative phenotype with Aβ accumulation.

    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.

    Veronika Boczonadi, Rita Horvath
  • Research Article
    mTORC2 sustains thermogenesis via Akt‐induced glucose uptake and glycolysis in brown adipose tissue
    mTORC2 sustains thermogenesis via Akt‐induced glucose uptake and glycolysis in brown adipose tissue
    1. Verena Albert1,
    2. Kristoffer Svensson1,
    3. Mitsugu Shimobayashi1,
    4. Marco Colombi1,
    5. Sergio Muñoz2,3,
    6. Veronica Jimenez2,3,
    7. Christoph Handschin1,
    8. Fatima Bosch2,3 and
    9. Michael N Hall*,1
    1. 1Biozentrum, University of Basel, Basel, Switzerland
    2. 2Center of Animal Biotechnology and Gene Therapy and Department of Biochemistry and Molecular Biology, School of Veterinary Medicine, Universitat Autònoma de Barcelona, Bellaterra, Spain
    3. 3Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain
    1. *Corresponding author. Tel: +41 61 267 21 50; E‐mail: m.hall{at}unibas.ch

    Albert et al show that β‐adrenergic stimulation activates mTORC2 in brown adipocytes. Active mTORC2 signaling in BAT is required for cold‐induced stimulation of glucose uptake and glycolysis to maintain temperature homeostasis upon cold stress.

    Synopsis

    Albert et al show that β‐adrenergic stimulation activates mTORC2 in brown adipocytes. Active mTORC2 signaling in BAT is required for cold‐induced stimulation of glucose uptake and glycolysis to maintain temperature homeostasis upon cold stress.

    • β‐adrenergic stimulation activates mTORC2 in brown adipocytes.

    • Mice deficient for mTORC2 in adipose tissue are hypothermic and sensitive to cold.

    • mTORC2 in BAT stimulates cold‐induced glucose uptake and glycolysis via Akt.

    • Restoration of glucose uptake in BAT of AdRiKO mice restores temperature homeostasis.

    • brown adipose tissue
    • glucose uptake
    • mTORC2
    • thermogenesis
    • Received July 9, 2015.
    • Revision received December 10, 2015.
    • Accepted December 14, 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.

    Verena Albert, Kristoffer Svensson, Mitsugu Shimobayashi, Marco Colombi, Sergio Muñoz, Veronica Jimenez, Christoph Handschin, Fatima Bosch, Michael N Hall
  • Research Article
    Defective PITRM1 mitochondrial peptidase is associated with Aβ amyloidotic neurodegeneration
    Defective PITRM1 mitochondrial peptidase is associated with Aβ amyloidotic neurodegeneration
    1. Dario Brunetti1,,
    2. Janniche Torsvik2,,
    3. Cristina Dallabona3,
    4. Pedro Teixeira4,
    5. Pawel Sztromwasser5,6,
    6. Erika Fernandez‐Vizarra1,
    7. Raffaele Cerutti1,
    8. Aurelio Reyes1,
    9. Carmela Preziuso7,
    10. Giulia D'Amati7,
    11. Enrico Baruffini3,
    12. Paola Goffrini3,
    13. Carlo Viscomi1,
    14. Ileana Ferrero3,
    15. Helge Boman8,
    16. Wenche Telstad9,
    17. Stefan Johansson5,8,
    18. Elzbieta Glaser4,
    19. Per M Knappskog5,8,
    20. Massimo Zeviani*,1 and
    21. Laurence A Bindoff*,2,10
    1. 1MRC Mitochondrial Biology Unit, Wellcome Trust, Cambridge, UK
    2. 2Department of Neurology, Haukeland University Hospital, Bergen, Norway
    3. 3Department of Life Sciences, University of Parma, Parma, Italy
    4. 4Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden
    5. 5Department of Clinical Science, University of Bergen, Bergen, Norway
    6. 6Computational Biology Unit, Department of Informatics, University of Bergen, Bergen, Norway
    7. 7Department of Radiological, Oncological and Pathological Sciences Sapienza University of Rome, Rome, Italy
    8. 8Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway
    9. 9Department of Neurology, Førde Hospital, Førde, Norway
    10. 10Department of Clinical Medicine (K1), University of Bergen, Bergen, Norway
    1. * Corresponding author. Tel: +44 1223 252704; Fax: +44 1223 252715; E‐mail: mdz21{at}mrc-mbu.cam.ac.uk
      Corresponding author. Tel: +47 55975096; Fax: +47 55975164; E‐mail: laurence.bindoff{at}nevro.uib.no
    1. These authors contributed equally to this work

    A clinically peculiar neurodegenerative disorder in humans was indentified and shown to be caused by a pathogenic homozygous mutation in PITRM1, encoding an oligopeptidase of the mitochondrial inner compartment. The neuropathology of a PITRM1−/+ mouse provides genetic evidence that Aβ is present within mitochondria, and demonstrates a link between impaired PITRM1 activity and Aβ amyloidotic neurodegeneration in mammals.

    Synopsis

    A clinically peculiar neurodegenerative disorder in humans was indentified and shown to be caused by a pathogenic homozygous mutation in PITRM1, encoding an oligopeptidase of the mitochondrial inner compartment. The neuropathology of a PITRM1−/+ mouse provides genetic evidence that Aβ is present within mitochondria, and demonstrates a link between impaired PITRM1 activity and Aβ amyloidotic neurodegeneration in mammals.

    • A homozygous disease segregating missense mutation was found in the PITRM1 gene in two siblings of a consanguineous family.

    • The pathogenic role of the mutation, causing PITRM1 instability, was validated by in vitro assay, characterization of mutant fibroblasts from patients and in PITRM1 knocked‐down human fibroblasts, and in a mutant yeast model.

    • A hemizygous PITRM1 knockout mouse displayed reduced amount of PITRM1, associated with slowly progressive neurodegeneration, hallmarked by accumulation of Aβ amyloid in the brain.

    • amyloid beta
    • mitochondrial targeting sequence
    • mitochondrial disease
    • neurodegeneration
    • pitrilysin 1
    • Received September 26, 2015.
    • Revision received November 19, 2015.
    • Accepted November 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.

    Dario Brunetti, Janniche Torsvik, Cristina Dallabona, Pedro Teixeira, Pawel Sztromwasser, Erika Fernandez‐Vizarra, Raffaele Cerutti, Aurelio Reyes, Carmela Preziuso, Giulia D'Amati, Enrico Baruffini, Paola Goffrini, Carlo Viscomi, Ileana Ferrero, Helge Boman, Wenche Telstad, Stefan Johansson, Elzbieta Glaser, Per M Knappskog, Massimo Zeviani, Laurence A Bindoff