A centronuclear myopathy--dynamin 2 mutation impairs autophagy in mice

Area of Science:

• Cell Biology
• Molecular Biology
• Genetics

Background:

• Dynamin 2 (Dnm2) is crucial for endocytosis and intracellular membrane trafficking.
• Heterozygous mutations in DNM2 cause centronuclear myopathy and Charcot-Marie-Tooth neuropathy.
• A Dnm2R465W knock-in mouse model mimics human mutations.

Purpose of the Study:

• To investigate the cause of neonatal lethality in homozygous Dnm2R465W (HMZ) mice.
• To elucidate the role of Dnm2 in neonatal autophagy and related pathways.

Main Methods:

• Analysis of HMZ mice at birth for physiological and metabolic parameters.
• In vitro studies using HMZ embryonic fibroblasts to assess autophagy flux.
• Investigation of autophagy-related structures and cellular acidification in HMZ cells.

Main Results:

• HMZ mice exhibit reduced body weight, hypoglycemia, hepatomegaly, and increased liver glycogen at birth.
• HMZ embryonic fibroblasts show a decreased autophagy flux prior to lysosomal degradation.
• Starved HMZ cells accumulate immature autophagic structures, suggesting impaired acidification.

Conclusions:

• Dnm2 plays a critical role in the autophagy pathway, particularly in the cross-talk between endosomal and autophagic pathways.
• Defects in Dnm2-dependent membrane trafficking contribute to impaired autophagy and neonatal lethality in HMZ mice.
• These findings highlight a novel function of Dnm2 in autophagy relevant to human diseases caused by DNM2 mutations.