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

详细信息    查看全文

• 作者：Judith Eschbach ; J¨¦r?me Sinniger ; Jamal Bouitbir ; Anissa Fergani ; Anna-Isabel Schlagowski ; Joffrey Zoll ; Bernard Geny ; Fr¨¦d¨¦rique Ren¨¦ ; 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
• 关键词：CMT ; Charcot Marie Tooth disease ; Cra ; Cramping allele of the Dync1h1 gene (p.Y1055C mutation) ; IPGTT ; intra-peritoneal glucose tolerance test ; LPL ; lipoprotein lipase ; MEF ; mouse embryonic fibroblast ; MFN ; mitofusin ; PPAR¦Á ; peroxisome proliferation acti
• 刊名：Neurobiology of Disease
• 出版年：2013
• 出版时间：October, 2013
• 年：2013
• 卷：58
• 期：Complete
• 页码：220-230
• 全文大小：1681 K

文摘

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.