Mitochondrial dysfunction and defective autophagy in the pathogenesis of collagen VI muscular dystrophies

Ullrich Congenital Muscular Dystrophy (UCMD), Bethlem Myopathy (BM), and Congenital Myosclerosis are diseases caused by mutations in the genes encoding the extracellular matrix protein collagen VI. A dystrophic mouse model, where collagen VI synthesis was prevented by targeted inactivation of the Co...

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Bibliographic Details
Published in:Cold Spring Harbor perspectives in biology 2013-05, Vol.5 (5), p.a011387-a011387
Main Authors: Bernardi, Paolo, Bonaldo, Paolo
Format: Article
Language:English
Subjects:
Animals
Autophagy - physiology
Collagen Type VI - genetics
Collagen Type VI - metabolism
Collagen Type VI - physiology
Disease Models, Animal
Humans
Intracellular Membranes - physiology
Mice
Mitochondria - physiology
Muscular Dystrophies - genetics
Muscular Dystrophies - pathology
Permeability
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Summary:Ullrich Congenital Muscular Dystrophy (UCMD), Bethlem Myopathy (BM), and Congenital Myosclerosis are diseases caused by mutations in the genes encoding the extracellular matrix protein collagen VI. A dystrophic mouse model, where collagen VI synthesis was prevented by targeted inactivation of the Col6a1 gene, allowed the investigation of pathogenesis, which revealed the existence of a Ca(2+)-mediated dysfunction of mitochondria and sarcoplasmic reticulum, and of defective autophagy. Key events are dysregulation of the mitochondrial permeability transition pore, an inner membrane high-conductance channel that for prolonged open times causes mitochondrial dysfunction, and inadequate removal of defective mitochondria, which amplifies the damage. Consistently, the Col6a1(-/-) myopathic mice could be cured through inhibition of cyclophilin D, a matrix protein that sensitizes the pore to opening, and through stimulation of autophagy. Similar defects contribute to disease pathogenesis in patients irrespective of the genetic lesion causing the collagen VI defect. These studies indicate that permeability transition pore opening and defective autophagy represent key elements for skeletal muscle fiber death, and provide a rationale for the use of cyclosporin A and its nonimmunosuppressive derivatives in patients affected by collagen VI myopathies, a strategy that holds great promise for treatment.
ISSN:1943-0264
1943-0264
DOI:10.1101/cshperspect.a011387