UM76, Université Pierre et Marie Curie-Paris 6, Paris, F-75013, France.
Traffic. 2012 Jun;13(6):869-79. doi: 10.1111/j.1600-0854.2012.01348.x. Epub 2012 Apr 3.
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.
动力蛋白 2（Dnm2）通过其在不同膜隔室中形成小泡的功能参与内吞作用和细胞内膜运输。DNM2 基因的杂合（HTZ）突变导致显性中心核肌病或 Charcot-Marie-Tooth 神经病。我们生成了表达最常见人类突变的 Dnm2R465W 敲入小鼠模型，最近报道 HTZ 小鼠逐渐发展出肌病。我们在这里研究了在纯合（HMZ）小鼠中发生的新生儿致死性的原因。我们表明，HMZ 小鼠在出生时体重减轻、低血糖、肝糖原含量增加和肝肿大，这与新生儿自噬缺陷一致。在 HMZ 胚胎成纤维细胞中进行的体外研究表明，自噬通量在自噬溶酶体降解之前降低。我们表明，饥饿的 HMZ 细胞具有更多的不成熟自噬相关结构，这可能是由于酸化缺陷所致。我们的研究结果强调了 Dnm2 在内体和自噬途径之间的串扰中的作用，并证明了 Dnm2 依赖性膜运输在自噬中的新作用，这在与 DNM2 相关的人类疾病中可能是相关的。
