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

Abstract

Mutations in the tail domain of dynein heavy chain (DYNC1H1) 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 the tail domain of dynein, similar to human mutations, show profoundly abnormal mitochondrial morphology associated with loss of mitofusin 1. Furthermore, heterozygous dynein mutant mice display mitochondrial dysfunction in multiple tissues and mitochondria progressively increase in size and invade sarcomeres in muscles. As a likely consequence of systemic mitochondrial dysfunction, dynein mutant mice develop hyperinsulinemia and hyperglycemia and progress to glucose intolerance with age. Last, similar defects in mitochondrial morphology and mitofusin levels are observed in fibroblasts from patients with SMA-LED. Our results show that dynein function is required for the maintenance of mitochondrial morphology and function with ageing and suggest that mitochondrial dysfunction contributes to dyneindependent neurological diseases, such as SMA-LED.

Utility of next generation sequencing in genetic diagnosis of early onset neuromuscular disorders

“…DYNC1H1 codes for a cytoplasmic dynein heavy chain that is involved in retrograde transport along microtubules. Mutations in DYNC1H1 have been associated with autosomal dominant spinal muscular atrophy and Charcot–Marie–Tooth disease 36. Moreover mutations have also been associated with malformations of cortical development37 and intellectual disability 38.…”

DYNC1H1 mutations associated with neurological diseases compromise processivity of dynein–dynactin–cargo adaptor complexes

“…This observation, together with the failure to detect nonsense, frameshift, or deletion alleles of DYNC1H1 in humans with SMALED or MCD, indicates that disease-associated mutations have a dominant-negative or dominant gain-of-function effect. However, with the exception of the mouse Legs at odd angles (Loa) mutation (20)(21)(22)(23)(24), the effects of human and mouse mutations on the motility of the dynein complex have not been investigated in detail.…”

Atomic-resolution structure of the CAP-Gly domain of dynactin on polymeric microtubules determined by magic angle spinning NMR spectroscopy

“…1), which binds to MTs and the associated protein EB1, have been described in patients with Perry syndrome, distal spinal bulbar muscular atrophy, and amyotrophic lateral sclerosis (ALS) (3)(4)(5)(6). Mutations in the cargo-binding domain and other regions of the dynein-dynactin motor complex lead to developmental defects and neurological diseases, such as ALS, Charcot-Marie-Tooth disease, and Huntington's disease (7)(8)(9)(10). Despite their prevalent and critical roles in cellular processes, there remains a significant gap, particularly at the atomic level, in understanding how MTs and their associated proteins function (generate directional force and maintain processivity), both in healthy and in diseased states.…”