Dynein mutations associated with hereditary motor neuropathies impair mitochondrial morphology and function with age

Eschbach, Judith and Sinniger, Jérôme and Bouitbir, Jamal and Fergani, Anissa and Schlagowski, Anna-Isabel and Zoll, Joffrey and Geny, Bernard and René, Frédérique and Larmet, Yves and Marion, Vincent and Baloh, Robert H. and Harms, Matthew B. and Shy, Michael E. and Messadeq, Nadia and Weydt, Patrick and Loeffler, Jean-Philippe and Ludolph, Albert C. and Dupuis, Luc. (2013) Dynein mutations associated with hereditary motor neuropathies impair mitochondrial morphology and function with age. Neurobiology of disease, 58. pp. 220-230.

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Official URL: https://edoc.unibas.ch/78246/

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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.
Faculties and Departments:03 Faculty of Medicine > Bereich Medizinische Fächer (Klinik) > Klinische Pharmakologie > Klinische Pharmakologie (Krähenbühl)
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Medizinische Fächer (Klinik) > Klinische Pharmakologie > Klinische Pharmakologie (Krähenbühl)
05 Faculty of Science > Departement Pharmazeutische Wissenschaften
UniBasel Contributors:Bouitbir, Jamal
Item Type:Article, refereed
Article Subtype:Research Article
ISSN: 0969-9961
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:03 Nov 2020 16:33
Deposited On:03 Nov 2020 16:33

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