- News & ViewsHow much does a disrupted mitochondrial network influence neuronal dysfunction?
Mitochondria are organelles that are present in all nucleated cells in the body. They have manifold functions but famously generate ATP efficiently through the process of oxidative phosphorylation. This ensures all tissues have an adequate energy supply and underlines the need for a fully functional mitochondrial network. Since mitochondrial biogenesis and maintenance require components from two genetic sources, mitochondrial diseases can result from mutations in either the nuclear or the mitochondrial genome (mtDNA). Enigmatically, mitochondrial disease can affect individuals at any age and in any tissue (Lightowlers et al, 2015). For a subset of mutations, the genotype can be ascribed to a clinical phenotype and a number of mutations are associated with remarkable tissue selectivity (Boczonadi et al, 2018). However, the gene expression pathways governing this tissue‐specific presentation are far from clear. In this issue of EMBO Molecular Medicine, Sprenger et al (2018) use mouse models to investigate the consequences of deleting a mitochondrial protease, YME1L, in neuronal/glial precursors. The loss causes multiple defects at both cell and tissue level, including a marked fragmentation of the mitochondrial network. Tandem depletion of a second mitochondrial protease, Oma1, successfully restored the mitochondrial connectivity, but did not rescue the ocular defects and caused an earlier onset of neurological dysfunction. Thus, in addition to other findings, the authors conclude that a fragmented mitochondrial network contributes less to the disease phenotype than the disruption of mitochondrial proteostasis.
See also: HG Sprenger et al
Chrzanowska‐Lightowlers and Lightowlers discuss the work of Sprenger et al who examined in mice the consequences of deleting a mitochondrial protease, YME1L, in neuronal/glial precursors and how a fragmented mitochondrial network contributes to the disruption of mitochondrial proteostasis.
EMBO Mol Med (2018) e9899
- © 2018 The Authors. Published under the terms of the CC BY 4.0 license
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.
- Research ArticleAPOPT1/COA8 assists COX assembly and is oppositely regulated by UPS and ROS
- Alba Signes1,
- Raffaele Cerutti1,
- Anna S Dickson2,
- Cristiane Benincá1,
- Elizabeth C Hinchy1,
- Daniele Ghezzi3,4,
- Rosalba Carrozzo5,
- Enrico Bertini5,
- Michael P Murphy1,
- James A Nathan2,
- Carlo Viscomi1,
- Erika Fernandez‐Vizarra (emfvb2{at}mrc-mbu.cam.ac.uk)*,1 and
- Massimo Zeviani (mdz21{at}mrc-mbu.cam.ac.uk)*,1
- 1MRC‐Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK
- 2Department of Medicine, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK
- 3Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico “Carlo Besta”, Milan, Italy
- 4Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
- 5Unit of Neuromuscular and Neurodegenerative Disorders, Bambino Gesù Children's Research Hospital, IRCCS, Rome, Italy
- ↵*
Corresponding author. Tel: +44 1223 252846; E‐mail: emfvb2{at}mrc-mbu.cam.ac.uk
Corresponding author. Tel: +44 1223 252704; E‐mail: mdz21{at}mrc-mbu.cam.ac.uk
APOPT1 loss‐of‐function causes a leukoencephalopathy associated with mitochondrial cytochrome c oxidase (COX) deficiency in patients. APOPT1 does not play a role in apoptosis, but contributes to the biogenesis of COX, which is part of the mitochondrial respiratory chain.
Synopsis
APOPT1 loss‐of‐function causes a leukoencephalopathy associated with mitochondrial cytochrome c oxidase (COX) deficiency in patients. APOPT1 does not play a role in apoptosis, but contributes to the biogenesis of cytochrome c oxidase (COX), which is part of the mitochondrial respiratory chain.
Isolated COX deficiency in multiple tissues was caused by ablation of Apopt1 in mice.
Mature APOPT1 is localized in the inner compartment of mitochondria participating in the intermediate stages of COX assembly.
APOPT1 precursor is degraded by the Ubiquitin‐Proteasome System in non‐stress conditions.
Under oxidative stress, the amount of intra‐mitochondrial APOPT1 was found to increase and to protect assembly COX intermediates from oxidative‐induced degradation.
A new term for APOPT1 is proposed: COA8, for COX assembly 8th factor.
EMBO Mol Med (2018) e9582
- Received July 20, 2018.
- Revision received November 20, 2018.
- Accepted November 21, 2018.
- © 2018 The Authors. Published under the terms of the CC BY 4.0 license
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.
- Research ArticleRGS9‐2 rescues dopamine D2 receptor levels and signaling in DYT1 dystonia mouse models
- Paola Bonsi (p.bonsi{at}hsantalucia.it)*,1,
- Giulia Ponterio1,2,
- Valentina Vanni1,2,
- Annalisa Tassone1,2,
- Giuseppe Sciamanna1,2,
- Sara Migliarini3,
- Giuseppina Martella1,2,
- Maria Meringolo1,2,
- Benjamin Dehay4,5,
- Evelyne Doudnikoff4,5,
- Venetia Zachariou6,
- Rose E Goodchild7,
- Nicola B Mercuri1,2,
- Marcello D'Amelio8,9,
- Massimo Pasqualetti3,10,
- Erwan Bezard4,5 and
- Antonio Pisani (pisani{at}uniroma2.it)*,1,2
- 1Laboratory of Neurophysiology and Plasticity, IRCCS Fondazione Santa Lucia, Rome, Italy
- 2Department of Systems Medicine, University Tor Vergata, Rome, Italy
- 3Unit of Cell and Developmental Biology, Department of Biology, University of Pisa, Pisa, Italy
- 4Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France
- 5CNRS, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France
- 6Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- 7Department of Neurosciences, VIB‐KU Leuven Center for Brain and Disease Research, KU Leuven, Leuven, Belgium
- 8Laboratory Molecular Neurosciences, IRCCS Fondazione Santa Lucia, Rome, Italy
- 9Unit of Molecular Neurosciences, Department of Medicine, University Campus‐Biomedico, Rome, Italy
- 10Center for Neuroscience and Cognitive Systems @UniTn, Istituto Italiano di Tecnologia, Rovereto, Italy
- ↵*
Corresponding author. Tel: +39‐06501703211; E‐mail: p.bonsi{at}hsantalucia.it
Corresponding author. Tel: +39‐06501703153; E‐mail: pisani{at}uniroma2.it
Striatal dopamine D2 receptor (DRD2) dysfunction in DYT1 dystonia mouse models was uncovered and shown to be mediated by an abnormal and selective trafficking to lysosomal degradation. The regulatory protein RGS9‐2 over‐expression can restore both the striatal level and the function of DRD2.
Synopsis
Striatal dopamine D2 receptor (DRD2) dysfunction in DYT1 dystonia mouse models was uncovered and shown to be mediated by an abnormal and selective trafficking to lysosomal degradation. The regulatory protein RGS9‐2 over‐expression can restore both the striatal level and the function of DRD2.
Correlated developmental changes in the expression level of DRD2 and its regulatory protein RGS9‐2 are observed in wild‐type mouse striatum.
A simultaneous reduction in striatal DRD2 and RGS9‐2 protein expression levels is observed in adult Dyt1 mouse models.
DRD2 downregulation is mediated by its selective trafficking to lysosomal degradation.
Viral‐induced expression of RGS9‐2 is able to restore both the expression level and function of striatal DRD2.
EMBO Mol Med (2018) e9283
- Received May 2, 2018.
- Revision received November 21, 2018.
- Accepted November 23, 2018.
- © 2018 The Authors. Published under the terms of the CC BY 4.0 license
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.
- Research ArticleAlternative oxidase‐mediated respiration prevents lethal mitochondrial cardiomyopathy
- Jayasimman Rajendran1,2,
- Janne Purhonen1,2,
- Saara Tegelberg1,3,4,
- Olli‐Pekka Smolander5,
- Matthias Mörgelin6,
- Jan Rozman7,8,
- Valerie Gailus‐Durner7,
- Helmut Fuchs7,
- Martin Hrabe de Angelis7,8,9,
- Petri Auvinen5,
- Eero Mervaala10,
- Howard T Jacobs5,11,
- Marten Szibor5,11,
- Vineta Fellman1,3,12 and
- Jukka Kallijärvi (jukka.kallijarvi{at}helsinki.fi)*,1,2
- 1Folkhälsan Research Center, Helsinki, Finland
- 2Clinicum, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- 3Department of Clinical Sciences, Lund, Pediatrics, Lund University, Lund, Sweden
- 4Molecular Neurology Research Program and Neuroscience Center, University of Helsinki, Helsinki, Finland
- 5Institute of Biotechnology, University of Helsinki, Helsinki, Finland
- 6Division of Infection Medicine, Clinical Sciences, Lund University, Lund, Sweden
- 7German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
- 8German Center for Diabetes Research (DZD), Neuherberg, Germany
- 9Chair of Experimental Genetics, Center of Life and Food Sciences Weihenstephan, TU Munich, Freising‐Weihenstephan, Germany
- 10Department of Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- 11Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland
- 12Children's Hospital, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
- ↵*Corresponding author. Tel: +358 504487006; E‐mail: jukka.kallijarvi{at}helsinki.fi
Bcs1l mutant mice show respiratory chain cIII dysfunction resulting in poor electron and proton transfer, and quinol oxidation. This study makes use of alternative oxidase (AOX), an enzyme that shunts electrons from quinols directly to oxygen, thus restoring electron flow upstream of cIII.
Synopsis
Bcs1l mutant mice show respiratory chain cIII dysfunction resulting in poor electron and proton transfer, and quinol oxidation. This study makes use of alternative oxidase (AOX), an enzyme that shunts electrons from quinols directly to oxygen, thus restoring electron flow upstream of cIII.
Broadly expressed transgenic AOX prevents lethal cardiomyopathy in Bcs1lp.S78G knock‐in mice and extends their median survival from 210 to 590 days.
Restoration of electron flow upstream of cIII by AOX is sufficient to prevent the cardiac decompensation.
AOX prevents pathological changes in the expression of central transcriptional regulators of substrate utilization and metabolic stress in the heart.
Analyses of reactive oxygen species (ROS) production and damage suggest that ROS are not instrumental in the rescue.
EMBO Mol Med (2018) e9456
- Received August 8, 2018.
- Revision received November 8, 2018.
- Accepted November 12, 2018.
- © 2018 The Authors. Published under the terms of the CC BY 4.0 license
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.
- News & ViewsSea squirt alternative oxidase bypasses fatal mitochondrial heart disease
Mitochondrial diseases are a diverse group of inborn disorders affecting cellular energy production by oxidative phosphorylation (OXPHOS) via the five (CI‐CV) mitochondrial respiratory chain (MRC) complexes. The sea squirt alternative oxidase (AOX) is able to bypass the distal part of the MRC and was shown to alleviate the consequences of CIII and CIV defects in several cellular and Drosophila models. In this issue of EMBO Molecular Medicine, Rajendran et al (2018) demonstrate the first proof of concept in mammals, by showing that AOX is capable to extend lifespan and prevent heart failure in a CIII deficient mouse model, raising the possibility of future human AOX bypass treatment.
See also: J Rajendran et al (2018)
A. Saada discusses the proof‐of‐concept study by Rajendran et al (in this issue of EMBO Molecular Medicine) that indicates that AOX bypass expands lifespan in a relevant genetic mouse model of a human mitochondrial disorder.
EMBO Mol Med (2018) e9962
- © 2018 The Author. Published under the terms of the CC BY 4.0 license
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.
- Research ArticleMurine MPDZ‐linked hydrocephalus is caused by hyperpermeability of the choroid plexus
- Junning Yang1,
- Claire Simonneau1,
- Robert Kilker1,
- Laura Oakley2,
- Matthew D Byrne2,
- Zuzana Nichtova3,
- Ioana Stefanescu1,
- Fnu Pardeep‐Kumar4,
- Sushil Tripathi4,
- Eric Londin5,
- Pascale Saugier‐Veber6,
- Belinda Willard7,
- Mathew Thakur4,
- Stephen Pickup8,
- Hiroshi Ishikawa9,
- Horst Schroten10,
- Richard Smeyne2 and
- Arie Horowitz (arie.horowitz{at}jefferson.edu)*,1,11
- 1Cardeza Center for Vascular Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA
- 2Department of Neuroscience, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA
- 3Department of Pathology, Anatomy and Cell Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA
- 4Department of Radiology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA
- 5Computational Medicine Center, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA
- 6Department of Genetics, University of Rouen, Rouen, France
- 7Proteomics Core Facility, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA
- 8Department of Radiology, University of Pennsylvania Medical School, Philadelphia, PA, USA
- 9Department of NDU Life Sciences, School of Life Dentistry, Nippon Dental University, Chiyoda‐ku, Tokyo, Japan
- 10Pediatric Infectious Diseases, University Children's Hospital Mannheim, Heidelberg University, Mannheim, Germany
- 11Department of Cancer Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA
- ↵*Corresponding author. Tel: +1 215 955 8017; E‐mail: arie.horowitz{at}jefferson.edu
Dysfunction of the choroid plexus (CP) is a likely cause of hydrocephalus, but the underlying pathophysiological and molecular mechanisms remain unclear. Depletion of Mpdz, a cell junction protein, is shown here to induce paracellular and transcellular hyperpermeability of the CP in mice.
Synopsis
Dysfunction of the choroid plexus (CP) is a likely cause of hydrocephalus, but the underlying pathophysiological and molecular mechanisms remain unclear. Depletion of Mpdz, a cell junction protein, is shown here to induce paracellular and transcellular hyperpermeability of the CP in mice.
Contrast medium leaks from the choroid plexus into the lateral ventricles of Mpdz−/− mice.
Transmitted electron microscopy (TEM) of the CP of Mpdz−/− mice shows that intercellular junctions between the CP epithelial cells (CPECs) are structurally defective.
The receptor to low‐density lipoprotein is overabundant in CPECs of Mpdz−/− mice by approximately 40%, and its constitutive transcytosis higher by more than 50% compared to CPECs of Mpdz+/+ mice.
Fluid‐phase uptake is approximately two‐fold higher than Mpdz+/+ mice.
Comparative proteomic analysis of the cerebrospinal fluid of Mpdz+/+ and Mpdz−/− mice finds protein overabundance in the latter, including more than 50‐fold abundance of ApoE.
EMBO Mol Med (2018) e9540
- Received July 11, 2018.
- Revision received November 6, 2018.
- Accepted November 9, 2018.
- © 2018 The Authors. Published under the terms of the CC BY 4.0 license
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.
- ReportA dual‐AAV approach restores fast exocytosis and partially rescues auditory function in deaf otoferlin knock‐out mice
- Hanan Al‐Moyed1,2,
- Andreia P Cepeda1,2,
- SangYong Jung3,4,
- Tobias Moser2,3,4,
- Sebastian Kügler (sebastian.kuegler{at}med.uni-goettingen.de)*,5 and
- Ellen Reisinger (ellen.reisinger{at}med.uni-goettingen.de)*,1
- 1Molecular Biology of Cochlear Neurotransmission Group, Department of Otorhinolaryngology, University Medical Center Göttingen, and Collaborative Research Center 889, University of Göttingen, Göttingen, Germany
- 2Göttingen Graduate School for Neurosciences, Biophysics, and Molecular Biosciences, University of Göttingen, Göttingen, Germany
- 3Institute for Auditory Neurosciences and InnerEarLab, University Medical Center Göttingen, Göttingen, Germany
- 4Synaptic Nanophysiology Group, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany
- 5Center Nanoscale Microscopy and Physiology of the Brain (CNMPB), Department of Neurology, University Medical Center Göttingen, Göttingen, Germany
- ↵*
Corresponding author. Tel: +49 551 39 8351; E‐mail: sebastian.kuegler{at}med.uni-goettingen.de
Corresponding author. Tel: +49 551 39 9688; E‐mail: ellen.reisinger{at}med.uni-goettingen.de
Gene delivery of large genes exceeding the packing capacity of a single adeno‐associated virus (AAV) is challenging. Split‐AAV vectors can bypass this problem. This work offers the first application of split‐AAV gene therapy to the inner ear to restore hearing in a genetically deaf mouse model.
Synopsis
Gene delivery of large genes exceeding the packing capacity of a single adeno‐associated virus (AAV) is challenging. Split‐AAV vectors can bypass this problem. This work offers the first application of split‐AAV gene therapy to the inner ear to restore hearing in a genetically deaf mouse model.
The 6 kb‐long otoferlin coding sequence was split into two fragments and packaged into two separate AAV2/6 viruses which were co‐injected into cochleae of otoferlin knock‐out mice.
Both the dual‐AAV trans‐splicing and the hybrid strategy led to re‐assembly of the two otoferlin cDNA fragments and expression of full‐length otoferlin.
Otoferlin expression from dual‐AAVs was restricted to hair cells and reached ˜30% of wild type otoferlin protein levels in inner hair cells.
In inner hair cells, fast exocytosis of the readily releasable pool of vesicles was fully recovered, and vesicle replenishment was restored to 35–50% of wild‐type controls.
Auditory brainstem responses were present albeit with reduced wave amplitudes in dual‐AAV transduced otoferlin knock‐out mice and indicated hearing thresholds of 40–60 dB.
EMBO Mol Med (2018) e9396
- Received June 3, 2018.
- Revision received November 9, 2018.
- Accepted November 12, 2018.
- © 2018 The Authors. Published under the terms of the CC BY 4.0 license
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.
