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A Centronuclear Myopathy – Dynamin 2 Mutation Impairs Autophagy in Mice
Author(s) -
Durieux AnneCécile,
Vassilopoulos Stéphane,
Lainé Jeanne,
Fraysse Bodvaël,
Briñas Laura,
Prudhon Bernard,
Castells Josiane,
Freyssenet Damien,
Bonne Gisèle,
Guicheney Pascale,
Bitoun Marc
Publication year - 2012
Publication title -
traffic
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.677
H-Index - 130
eISSN - 1600-0854
pISSN - 1398-9219
DOI - 10.1111/j.1600-0854.2012.01348.x
Subject(s) - autophagy , dynamin , biology , endocytosis , microbiology and biotechnology , myopathy , phenocopy , dnm1l , lysosome , mutation , neonatal hypoglycemia , congenital myopathy , autophagosome , endocytic cycle , endosome , intracellular , phenotype , genetics , mitochondrion , medicine , mitochondrial fission , cell , biochemistry , gene , apoptosis , enzyme , gestation , gestational diabetes , biopsy , pregnancy , muscle biopsy
Dynamin 2 (Dnm2) is involved in endocytosis and intracellular membrane trafficking through its function in vesicle formation from distinct membrane compartments. Heterozygous (HTZ) mutations in the DNM2 gene cause dominant centronuclear myopathy or Charcot–Marie–Tooth neuropathy. We generated a knock‐in Dnm2R465W mouse model expressing the most frequent human mutation and recently reported that HTZ mice progressively developed a myopathy. We investigated here the cause of neonatal lethality occurring in homozygous (HMZ) mice. We show that HMZ mice present at birth with a reduced body weight, hypoglycemia, increased liver glycogen content and hepatomegaly, in agreement with a defect in neonatal autophagy. In vitro studies performed in HMZ embryonic fibroblasts point out to a decrease in the autophagy flux prior to degradation at the autolysosome. We show that starved HMZ cells have a higher number of immature autophagy‐related structures probably due to a defect of acidification. Our results highlight the role of Dnm2 in the cross talk between endosomal and autophagic pathways and evidence a new role of Dnm2‐dependent membrane trafficking in autophagy which may be relevant in DNM2‐related human diseases.