Collapse of mitochondrial quality control mediated by PINK1 and Parkin causes Parkinson disease

1)我们筛选了新的帕金底物，并确定线粒体己糖激酶I（HKI）作为候选者。随着膜电位的降低，HKI的帕金泛素化导致其蛋白酶体降解。此外，帕金的大多数疾病相关突变阻碍了这一事件，并且内源性HKI在线粒体膜电位耗散后在表达细胞中被泛素化，表明其生理重要性。2)PINK1的稳态控制机制仍然未知。我们发现，PINK1在膜电位降低后自磷酸化，大多数疾病相关突变都会阻碍这一事件。我们证明了PINK1自身磷酸化发生在Ser228和Ser402处，这两个残基在结构上聚集在一起。我们认为PINK1中Ser228和Ser402的自磷酸化对于Parkin的有效线粒体定位是必不可少的。

1) We screened for novel Parkin substrate(s) and identified mitochondrial hexokinase I (HKI) as a candidate. Following a decrease in membrane potential, Parkin ubiquitylation of HKI leads to its proteasomal degradation. Moreover, most disease-relevant mutations of Parkin hinder this event and endogenous HKI is ubiquitylated upon dissipation of mitochondrial membrane potential in genuine-Parkin expressing cells, suggesting its physiological importance. 2) The mechanism underlying the homeostatic control of PINK1 remains unknown. We revealed that PINK1 is autophosphorylated following a decrease in membrane potential and that most disease-relevant mutations hinder this event. We demonstrated that PINK1 autophosphorylation occurs at Ser228 and Ser402, residues that are structurally clustered together. We propose that autophosphorylation of Ser228 and Ser402 in PINK1 is essential for efficient mitochondrial localization of Parkin.