2018 年 64 巻 1 号 p. 17-30
Background: Mutations in the recessive genes PINK1 and PARKIN are the most common causes of early-onset Parkinson’s disease (PD). The mitochondrial ubiquitin (Ub) kinase PINK1 mediates, together with the cytosolic E3 Ub ligase PARKIN, mitochondrial quality control. Thereby, damaged mitochondria are identified to prevent their accumulation and eventually cell death. A detailed understanding of PINK1 mutations will help to further our understanding of PD.
Objective: The aim of this study was to examine the exact molecular pathogenic mechanisms of PINK1 p.I368N.
Methods: We investigated molecular mechanisms on the structural and functional level in patients’ fibroblasts and in cell-based, biochemical assays.
Results: Under endogenous conditions, PINK1 p.I368N is expressed, imported in healthy mitochondria similar to PINK1 wild type. Upon mitochondrial damage, however, full-length PINK1 p.I368N is unstable on the outer mitochondrial membrane and consequently mitochondrial quality control declines. We found that stress-induced interaction between PINK1 p.I368N and TOM40 of the mitochondrial protein import machinery is abolished. Analysis of a structural PINK1 p.I368N model additionally suggested impairments of Ub kinase activity. We further confirmed experimentally that the kinase activity of the PINK1 p.I368N mutant is abolished.
Conclusions: We revealed two mechanisms that lead to loss of function of PINK1 upon mutation.
