title: Dynein mutations associated with hereditary motor neuropathies impair mitochondrial morphology and function with age.
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.
authors.affiliation: Inserm U1118, Strasbourg F-67085, France.
authors.forename: Judith
authors.initials: J
authors.lastname: Eschbach
authors.forename: Jérôme
authors.initials: J
authors.lastname: Sinniger
authors.forename: Jamal
authors.initials: J
authors.lastname: Bouitbir
authors.forename: Anissa
authors.initials: A
authors.lastname: Fergani
authors.forename: Anna-Isabel
authors.initials: AI
authors.lastname: Schlagowski
authors.forename: Joffrey
authors.initials: J
authors.lastname: Zoll
authors.forename: Bernard
authors.initials: B
authors.lastname: Geny
authors.forename: Frédérique
authors.initials: F
authors.lastname: René
authors.forename: Yves
authors.initials: Y
authors.lastname: Larmet
authors.forename: Vincent
authors.initials: V
authors.lastname: Marion
authors.forename: Robert H
authors.initials: RH
authors.lastname: Baloh
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Harms
authors.forename: Michael E
authors.initials: ME
authors.lastname: Shy
authors.forename: Nadia
authors.initials: N
authors.lastname: Messadeq
authors.forename: Patrick
authors.initials: P
authors.lastname: Weydt
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Loeffler
authors.forename: Albert C
authors.initials: AC
authors.lastname: Ludolph
authors.forename: Luc
authors.initials: L
authors.lastname: Dupuis
mesh_terms: D000375:Aging / Q000473:pathology*; D000818:Animals; D002478:Cells, Cultured; D056445:Cytoplasmic Dyneins / Q000235:genetics*; D004622:Embryo, Mammalian; D005260:Female; D005934:Glucagon / Q000097:blood; D018698:Glutamic Acid / Q000235:genetics; D006801:Humans; D007328:Insulin / Q000097:blood; D008239:Lysine / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000473:pathology* / Q000648:ultrastructure; D009134:Muscular Atrophy, Spinal / Q000235:genetics* / Q000473:pathology*; D009154:Mutation / Q000235:genetics*; D013482:Superoxide Dismutase / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D014162:Transfection
chemical_list: C511240:DYNC1H1 protein, human; D007328:Insulin; C000606290:SOD1 protein, human; D018698:Glutamic Acid; D005934:Glucagon; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D056445:Cytoplasmic Dyneins; D008239:Lysine
keywords: CMT; Charcot Marie Tooth disease; Charcot–Marie–Tooth disease; Cra; Cramping allele of the Dync1h1 gene (p.Y1055C mutation); Diabetes; Dynein; IPGTT; LPL; MEF; MFN; Mitochondria; Motor neuron disease; PPARα; SMA–LED; Spinal muscular atrophy; UCP3; intra-peritoneal glucose tolerance test; lipoprotein lipase; mitofusin; mouse embryonic fibroblast; peroxisome proliferation activated receptor, alpha; spinal muscular atrophy with lower extremity dominance; uncoupling protein 3