Intramembrane protease PARL defines a negative regulator of PINK1- and PARK2/Parkin-dependent mitophagy

Abstract

Mutations in PINK1 and PARK2/Parkin are a main risk factor for familial Parkinson disease. While the physiological mechanism of their activation is unclear, these proteins have been shown in tissue culture cells to serve as a key trigger for autophagy of depolarized mitochondria. Here we show that ablation of the mitochondrial rhomboid protease PARL leads to retrograde translocation of an intermembrane space-bridging PINK1 import intermediate. Subsequently, it is rerouted to the outer membrane in order to recruit PARK2, which phenocopies mitophagy induction by uncoupling agents. Consistent with a role of this retrograde translocation mechanism in neurodegenerative disease, we show that pathogenic PINK1 mutants which are not cleaved by PARL affect PINK1 kinase activity and the ability to induce PARK2-mediated mitophagy. Altogether we suggest that PARL is an important intrinsic player in mitochondrial quality control, a system substantially impaired in Parkinson disease as indicated by reduced removal of damaged mitochondria in affected patients.

A predicted plastid rhomboid protease affects phosphatidic acid metabolism in Arabidopsis thaliana

“…Aside from directly initiating a signaling cascade, as in the case of Rhomboid‐1 and the epidermal‐growth factor pathway (Lee et al ., ; Urban et al ., ), rhomboids can also influence assembly of complexes, for example Providencia stuartii rhomboid AarA, which processes TatA and directs the oligomerization of the twin‐arginine translocase complex used in quorum sensing (Stevenson et al ., ). In humans, rhomboids have been implicated in Parkinson's disease by maintaining mitochondrial integrity through proteolysis of Pink1 by the mitochondrial PARL protein, which affects Pink1 trafficking (Meissner et al ., , ). Much like in animals, 13 rhomboids have been predicted to exist in Arabidopsis (Garcia‐Lorenzo et al ., ; Lemberg and Freeman, ; Page and Di Cera, ), and although they have been compared to characterized animal rhomboids (Kanaoka et al ., ), a detailed molecular mechanism for any of them has yet to be described.…”

Common variants in the PARL and PINK1 genes increase the risk to leprosy in Han Chinese from South China

“…The cleavage of PINK1 was mediated by PARL and this was affected by mitochondrial membrane potential31. This scenario negatively regulated the PINK1- and PARK2/Parkin-dependent mitophagy32. Mutations in PINK1 have been reported to be associated with Parkinson’s disease2833 and schizophrenia34, but there was a controversy27.…”

Coordinating Mitochondrial Biology Through the Stress-Responsive Regulation of Mitochondrial Proteases

“…Rare PARL mutations have also been suggested to influence PD (Heinitz et al, 2011; Shi et al, 2011; Wust et al, 2015). A potential role for PARL in PD could reflect the involvement of this protease in regulating the PINK1-Parkin mitophagy axis (Greene et al, 2012; Jin et al, 2010; Meissner et al, 2015; Yamano and Youle, 2013), which would be consistent with the link between PD and other proteins involved in this pathway (Youle and Narendra, 2011). YME1L1 mutations have also been found to be causatively associated with mitochondriopathy in familial optic atrophy (Hartmann et al, 2016).…”