Journal article
Dynein mutations associated with hereditary motor neuropathies impair mitochondrial morphology and function with age
Neurobiology of disease, Vol.58, pp.220-230
10/2013
DOI: 10.1016/j.nbd.2013.05.015
PMID: 23742762
Abstract
Mutations in the DYNC1H1 gene encoding for dynein heavy chain cause two closely related human motor neuropathies, dominant spinal muscular atrophy with lower extremity predominance (SMA–LED) and axonal Charcot–Marie–Tooth (CMT) disease, and lead to sensory neuropathy and striatal atrophy in mutant mice. Dynein is the molecular motor carrying mitochondria retrogradely on microtubules, yet the consequences of dynein mutations on mitochondrial physiology have not been explored. Here, we show that mouse fibroblasts bearing heterozygous or homozygous point mutation in Dync1h1, similar to human mutations, show profoundly abnormal mitochondrial morphology associated with the loss of mitofusin 1. Furthermore, heterozygous Dync1h1 mutant mice display progressive mitochondrial dysfunction in muscle and mitochondria progressively increase in size and invade sarcomeres. As a likely consequence of systemic mitochondrial dysfunction, Dync1h1 mutant mice develop hyperinsulinemia and hyperglycemia and progress to glucose intolerance with age. Similar defects in mitochondrial morphology and mitofusin levels are observed in fibroblasts from patients with SMA–LED. Last, we show that Dync1h1 mutant fibroblasts show impaired perinuclear clustering of mitochondria in response to mitochondrial uncoupling. Our results show that dynein function is required for the maintenance of mitochondrial morphology and function with aging and suggest that mitochondrial dysfunction contributes to dynein-dependent neurological diseases, such as SMA–LED.
[Display omitted]
•Human and murine dynein mutations lead to mitochondrial fragmentation in cultured fibroblasts.•Human and murine dynein mutant fibroblasts display decreased levels of mitofusin 1.•Murine dynein mutant fibroblasts display impaired mitochondrial clustering in response to mitochondrial uncoupling.•Mouse Cramping dynein mutation leads to widespread mitochondrial dysfunction and glucose intolerance in vivo.
Details
- Title: Subtitle
- Dynein mutations associated with hereditary motor neuropathies impair mitochondrial morphology and function with age
- Creators
- Judith Eschbach - Inserm U1118, Strasbourg F-67085, FranceJérôme Sinniger - Inserm U1118, Strasbourg F-67085, FranceJamal Bouitbir - Faculté de Médecine, Université de Strasbourg, EA 3072, Strasbourg 67085, FranceAnissa Fergani - Inserm U1118, Strasbourg F-67085, FranceAnna-Isabel Schlagowski - Faculté de Médecine, Université de Strasbourg, EA 3072, Strasbourg 67085, FranceJoffrey Zoll - Faculté de Médecine, Université de Strasbourg, EA 3072, Strasbourg 67085, FranceBernard Geny - Faculté de Médecine, Université de Strasbourg, EA 3072, Strasbourg 67085, FranceFrédérique René - Inserm U1118, Strasbourg F-67085, FranceYves Larmet - Inserm U1118, Strasbourg F-67085, FranceVincent Marion - Laboratoire de Physiopathologie des syndromes rares héréditaires, AVENIR-Inserm, EA3949, Université de Strasbourg, 11 Rue Humann, 67085 Strasbourg, FranceRobert H Baloh - Cedars-Sinai Medical Center, 8730 Alden Drive, Los Angeles, CA 90048, USAMatthew B Harms - Washington University, 660 S. Euclid Avenue, St. Louis, MO 63110, USAMichael E Shy - Department of Neurology, University of Iowa, 200 Hawkins Drive, Iowa City, IA 52242, USANadia Messadeq - Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM) U964, Centre National de la Recherche Scientifique (CNRS) UMR7104, University of Strasbourg, 67500 Illkirch, FrancePatrick Weydt - Department of Neurology, Ulm University, Ulm 89081, GermanyJean-Philippe Loeffler - Inserm U1118, Strasbourg F-67085, FranceAlbert C Ludolph - Department of Neurology, Ulm University, Ulm 89081, GermanyLuc Dupuis - Inserm U1118, Strasbourg F-67085, France
- Resource Type
- Journal article
- Publication Details
- Neurobiology of disease, Vol.58, pp.220-230
- DOI
- 10.1016/j.nbd.2013.05.015
- PMID
- 23742762
- NLM abbreviation
- Neurobiol Dis
- ISSN
- 0969-9961
- eISSN
- 1095-953X
- Publisher
- Elsevier Inc
- Grant note
- DOI: 10.13039/501100001665, name: Agence Nationale de la Recherche; name: Association pour la recherche sur la SLA et les autres maladies du motoneurone (ARSla); name: Thierry Latran Foundation; name: Association pour la recherche et le développement de moyens de lutte contre les maladies neurodégénératives (AREMANE); name: European Community's Health Seventh Framework Programme, award: FP7/2007–2013, 259867; name: Association française de lutte contre les myopathies (AFM); name: Helmholtz Institute; DOI: 10.13039/100005202, name: Muscular Dystrophy Association; DOI: 10.13039/100002721, name: Charcot Marie Tooth Association; name: National Institute of Health (NIH), award: U54NS065712, NS055980, NS069669; name: Mercator Professorship; name: contrat d'interface INSERM/AP-HP
- Language
- English
- Date published
- 10/2013
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Stead Family Department of Pediatrics; Iowa Neuroscience Institute
- Record Identifier
- 9984020655402771
Metrics
29 Record Views