Mitochondrial protein import regulates cytosol protein homeostasis and neuronal integrity
作者单位：Life Sciences Institute and Innovation Center for Cell Signaling Network Zhejiang University
会议名称：《中国神经科学学会第十二届全国学术会议》
会议日期：2017年
学科分类：1002[医学-临床医学] 100204[医学-神经病学] 10[医学]
关 键 词：Neurodegeneration mitochondria TOM Complex protein aggregates autophagy Drosophila
摘 要：Neurodegeneration is characterized by protein aggregate deposits and mitochondrial malfunction. It is not clear whether these two phenomena are intrinsically linked or not. RNAi screening data revealed that the loss of Tom40, a key subunit of the translocase of the outer mitochondrial membrane complex, leads to abnormal accumulation of large ubiquitin-positive protein aggregates engulfed by autophagosome membranes in cytosol. Autophagy was induced in Tom40 RNAi tissues. However, the giant autophagosomes were often not sealed and they failed to fuse with lysosomes. The manipulation of the autophagy pathway in Tom40 RNAi tissues indicated that the giant autophagosome-like structures were formed through the fusion of small autophagosomes. The ectopic expression of Pink1 and Park greatly reduced aggregate formation in Tom40 RNAi tissues by increasing autophagy/mitophagy. In nerve tissues, the reduction in Tom40 activity leads to aggregate formation and neurodegeneration. Surprisingly, rather than diminishing the neurodegeneration phenotypes, the overexpression of Pink1 enhanced the neurodegeneration phenotypes. We proposed a model to demonstrate the mechanism by which mitochondrial protein import defects led to reduced proteasome activity and defective autophagy.