Dynein mutations associated with hereditary motor neuropathies impair mitochondrial morphology and function with age
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 m...
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Elsevier
2013-10-01
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Series: | Neurobiology of Disease |
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Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996113001575 |
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doaj-7d3226828a914e8f87d56033c9cb35bf |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Judith Eschbach Jérôme Sinniger Jamal Bouitbir Anissa Fergani Anna-Isabel Schlagowski Joffrey Zoll Bernard Geny Frédérique René Yves Larmet Vincent Marion Robert H. Baloh Matthew B. Harms Michael E. Shy Nadia Messadeq Patrick Weydt Jean-Philippe Loeffler Albert C. Ludolph Luc Dupuis |
spellingShingle |
Judith Eschbach Jérôme Sinniger Jamal Bouitbir Anissa Fergani Anna-Isabel Schlagowski Joffrey Zoll Bernard Geny Frédérique René Yves Larmet Vincent Marion Robert H. Baloh Matthew B. Harms Michael E. Shy Nadia Messadeq Patrick Weydt Jean-Philippe Loeffler Albert C. Ludolph Luc Dupuis Dynein mutations associated with hereditary motor neuropathies impair mitochondrial morphology and function with age Neurobiology of Disease Dynein Spinal muscular atrophy Motor neuron disease Charcot–Marie–Tooth disease Mitochondria Diabetes |
author_facet |
Judith Eschbach Jérôme Sinniger Jamal Bouitbir Anissa Fergani Anna-Isabel Schlagowski Joffrey Zoll Bernard Geny Frédérique René Yves Larmet Vincent Marion Robert H. Baloh Matthew B. Harms Michael E. Shy Nadia Messadeq Patrick Weydt Jean-Philippe Loeffler Albert C. Ludolph Luc Dupuis |
author_sort |
Judith Eschbach |
title |
Dynein mutations associated with hereditary motor neuropathies impair mitochondrial morphology and function with age |
title_short |
Dynein mutations associated with hereditary motor neuropathies impair mitochondrial morphology and function with age |
title_full |
Dynein mutations associated with hereditary motor neuropathies impair mitochondrial morphology and function with age |
title_fullStr |
Dynein mutations associated with hereditary motor neuropathies impair mitochondrial morphology and function with age |
title_full_unstemmed |
Dynein mutations associated with hereditary motor neuropathies impair mitochondrial morphology and function with age |
title_sort |
dynein mutations associated with hereditary motor neuropathies impair mitochondrial morphology and function with age |
publisher |
Elsevier |
series |
Neurobiology of Disease |
issn |
1095-953X |
publishDate |
2013-10-01 |
description |
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. |
topic |
Dynein Spinal muscular atrophy Motor neuron disease Charcot–Marie–Tooth disease Mitochondria Diabetes |
url |
http://www.sciencedirect.com/science/article/pii/S0969996113001575 |
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doaj-7d3226828a914e8f87d56033c9cb35bf2021-03-22T12:40:02ZengElsevierNeurobiology of Disease1095-953X2013-10-0158220230Dynein mutations associated with hereditary motor neuropathies impair mitochondrial morphology and function with ageJudith Eschbach0Jérôme Sinniger1Jamal Bouitbir2Anissa Fergani3Anna-Isabel Schlagowski4Joffrey Zoll5Bernard Geny6Frédérique René7Yves Larmet8Vincent Marion9Robert H. Baloh10Matthew B. Harms11Michael E. Shy12Nadia Messadeq13Patrick Weydt14Jean-Philippe Loeffler15Albert C. Ludolph16Luc Dupuis17Inserm U1118, Strasbourg F-67085, France; Université de Strasbourg, Faculté de Médecine, UMRS1118, Strasbourg F-67085, France; Department of Neurology, Ulm University, Ulm 89081, GermanyInserm U1118, Strasbourg F-67085, France; Université de Strasbourg, Faculté de Médecine, UMRS1118, Strasbourg F-67085, FranceFaculté de Médecine, Université de Strasbourg, EA 3072, Strasbourg 67085, France; CHRU of Strasbourg, Physiology and Functional Explorations Department, New Civil Hospital, B.P. 426, Strasbourg 67091, FranceInserm U1118, Strasbourg F-67085, France; Université de Strasbourg, Faculté de Médecine, UMRS1118, Strasbourg F-67085, FranceFaculté de Médecine, Université de Strasbourg, EA 3072, Strasbourg 67085, France; CHRU of Strasbourg, Physiology and Functional Explorations Department, New Civil Hospital, B.P. 426, Strasbourg 67091, FranceFaculté de Médecine, Université de Strasbourg, EA 3072, Strasbourg 67085, France; CHRU of Strasbourg, Physiology and Functional Explorations Department, New Civil Hospital, B.P. 426, Strasbourg 67091, FranceFaculté de Médecine, Université de Strasbourg, EA 3072, Strasbourg 67085, France; CHRU of Strasbourg, Physiology and Functional Explorations Department, New Civil Hospital, B.P. 426, Strasbourg 67091, FranceInserm U1118, Strasbourg F-67085, France; Université de Strasbourg, Faculté de Médecine, UMRS1118, Strasbourg F-67085, FranceInserm U1118, Strasbourg F-67085, France; Université de Strasbourg, Faculté de Médecine, UMRS1118, Strasbourg F-67085, FranceLaboratoire de Physiopathologie des syndromes rares héréditaires, AVENIR-Inserm, EA3949, Université de Strasbourg, 11 Rue Humann, 67085 Strasbourg, FranceCedars-Sinai Medical Center, 8730 Alden Drive, Los Angeles, CA 90048, USAWashington University, 660 S. Euclid Avenue, St. Louis, MO 63110, USADepartment of Neurology, University of Iowa, 200 Hawkins Drive, Iowa City, IA 52242, USAInstitut 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, FranceDepartment of Neurology, Ulm University, Ulm 89081, GermanyInserm U1118, Strasbourg F-67085, France; Université de Strasbourg, Faculté de Médecine, UMRS1118, Strasbourg F-67085, FranceDepartment of Neurology, Ulm University, Ulm 89081, GermanyInserm U1118, Strasbourg F-67085, France; Université de Strasbourg, Faculté de Médecine, UMRS1118, Strasbourg F-67085, France; Department of Neurology, Ulm University, Ulm 89081, Germany; Corresponding author at: INSERM U1118, Faculté de Médecine, bat 3, 8e étage, 11 rue Humann, STRASBOURG, F-67085, France. Fax: +33 3 68 85 30 65.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.http://www.sciencedirect.com/science/article/pii/S0969996113001575DyneinSpinal muscular atrophyMotor neuron diseaseCharcot–Marie–Tooth diseaseMitochondriaDiabetes |