Abstract
ABSTRACTDysfunction of PTEN-induced putative kinase 1 (PINK1), a Ser/Thr kinase with an N-terminal mitochondrial-targeting sequence (MTS), causes familial recessive parkinsonism. Reduction of the mitochondrial membrane potential limits MTS-mediated matrix import and promotes PINK1 accumulation on the outer mitochondrial membrane (OMM) of depolarized mitochondria. PINK1 then undergoes autophosphorylation and phosphorylates ubiquitin and Parkin, a cytosolic ubiquitin ligase, for clearance of damaged mitochondria. The molecular basis for PINK1 localization on the OMM of depolarized mitochondria rather than release to the cytosol is poorly understood. Here, we disentangle the PINK1 localization mechanism using deletion mutants and a newly established constitutively active PINK1 mutant. Disruption of the MTS through N-terminal insertion of aspartic acid residues results in OMM localization of PINK1 in energized mitochondria. Unexpectedly, the MTS and putative transmembrane domain (TMD) are dispensable for OMM localization, whereas mitochondrial translocase Tom40 (also known as TOMM40) and an alternative mitochondrial localization signal that resides between the MTS and TMD are required. PINK1 utilizes a mitochondrial localization mechanism that is distinct from that of conventional MTS proteins and that presumably functions in conjunction with the Tom complex in OMM localization when the conventional N-terminal MTS is inhibited.
Highlights
Parkinson’s disease and its relative parkinsonism are pervasive neurodegenerative diseases
We show that inactivation of the PINK1 Nterminus mitochondrial-targeting sequence (MTS) alone is sufficient to promote PINK1 localization on the OMM through a second ‘latent’ outer mitochondrial membrane localization signal (OMS) that subsequently enhances the recruitment and activation of Parkin
Our results provide a molecular basis for how inhibition of PINK1 import through the inner mitochondrial membrane (IMM) autonomously triggers PINK1 OMM localization, Parkin recruitment and mitochondrial degradation
Summary
Parkinson’s disease and its relative parkinsonism are pervasive neurodegenerative diseases. Because patients with familial parkinsonism present symptoms similar to sporadic Parkinson’s disease, functional analysis of familial Parkinson’s disease-related proteins such as PINK1 provides insights into the pathogenic mechanism of the. Drosophila lacking pink have abnormal mitochondrial morphology in flight muscles, short life span and male sterility (Clark et al, 2006; Park et al, 2006; Yang et al, 2006) These phenotypes are rescued by a component of the mitochondrial electron transport chain complex, a mitochondrial electron carrier or a positive regulator for mitochondrial protective genes (Koh et al, 2012; Vilain et al, 2012; Vos et al, 2012). These reports suggest that PINK1 plays important roles in maintaining mitochondrial robustness
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