Abstract
PTEN-induced kinase 1 (PINK1) is a Parkinson's disease gene that acts as a sensor for mitochondrial damage. Its best understood role involves phosphorylating ubiquitin and the E3 ligase Parkin (PRKN) to trigger a ubiquitylation cascade that results in selective clearance of damaged mitochondria through mitophagy. Here we focus on other physiological roles of PINK1. Some of these also lie upstream of Parkin but others represent autonomous functions, for which alternative substrates have been identified. We argue that PINK1 orchestrates a multi-arm response to mitochondrial damage that impacts on mitochondrial architecture and biogenesis, calcium handling, transcription and translation. We further discuss a role for PINK1 in immune signalling co-ordinated at mitochondria and consider the significance of a freely diffusible cleavage product, that is constitutively generated and degraded under basal conditions.
Highlights
The protein PTEN-induced kinase 1 (PINK1) was associated with early onset Parkinson’s disease (PD) around the turn of the millennium.[1,2] It was shortly thereafter linked to a second PD associated gene, the ubiquitin E3 ligase PRKN (Parkin), using Drosophila models.[3,4,5] Whilst a genetic association was established, the cellular pathway governed by these two genes remained unknown, until the pioneering work of Richard Youle and co-workers demonstrated PINK1 accumulation and activation at damaged or depolarised mitochondria.[6]
This leads to the recruitment and activation of Parkin, resulting in wide scale ubiquitylation of mitochondrial proteins followed by selective autophagy of the damaged mitochondria, otherwise known as mitophagy.[7]
The explanatory power of these findings and the dazzling array of subsequent studies, which have filled in many of the details, have taken the limelight. After briefly describing this pathway, here we will focus on Abbreviations: ETC, electron transport chain; ISR, integrated stress response; MDV, mitochondrial derived vesicle; MERC, mitochondria—endoplasmic reticulum contact; mitAP, mitochondrial antigen presentation; nRCC, nuclear-encoded respiratory chain complex; OMM, outer mitochondrial membrane; PD, Parkinson’s disease other aspects of PINK1 function, linked to mitochondrial quality control and beyond
Summary
The protein PTEN-induced kinase 1 (PINK1) was associated with early onset Parkinson’s disease (PD) around the turn of the millennium.[1,2] It was shortly thereafter linked to a second PD associated gene, the ubiquitin E3 ligase PRKN (Parkin), using Drosophila models.[3,4,5] Whilst a genetic association was established, the cellular pathway governed by these two genes remained unknown, until the pioneering work of Richard Youle and co-workers demonstrated PINK1 accumulation and activation at damaged or depolarised mitochondria.[6]. Many ribosomes can be seen directly interacting with the TOMM complex and strong evidence for co-translational import has been provided.[71,72] ATF4, the key transcription factor controlling the ISR, is elevated in PINK1 and Parkin mutant Drosophila.[73] a pathway has recently been elucidated that links stress-induced release of the inner mitochondrial membrane protein DELE1 to activation of HRI and consequent induction of ATF4.[74] under basal conditions, PINK1 most likely suppresses the ISR by virtue of maintaining healthy mitochondria.
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