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Mitochondrial Quality Control Mediated by PINK1 and Parkin: Links to Parkinsonism

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Mitochondrial Quality Control Mediated by PINK1 and Parkin: Links to Parkinsonism Downloaded from http://cshperspectives.cshlp.org/ on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press Mitochondrial Quality Control Mediated by PINK1 and Parkin: Links to Parkinsonism Derek Narendra,1,2 John E. Walker,2 and Richard Youle1 1Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892 2The Medical Research Council Mitochondrial Biology Unit, Hills Road, Cambridge CB0 2XY,United Kingdom Correspondence: [email protected] Mutations in Parkin or PINK1 are the most common cause of recessive familial parkinsonism. Recent studies suggest that PINK1 and Parkin form a mitochondria quality control pathway that identifies dysfunctional mitochondria, isolates them from the mitochondrial network, and promotes their degradation by autophagy. In this pathway the mitochondrial kinase PINK1 senses mitochondrial fidelity and recruits Parkin selectively to mitochondria that lose membrane potential. Parkin, an E3 ligase, subsequently ubiquitinates outer mitochon- drial membrane proteins, notably the mitofusins and Miro, and induces autophagic elimi- nation of the impaired organelles. Here we review the recent rapid progress in understanding the molecular mechanisms of PINK1- and Parkin-mediated mitophagy and the identification of Parkin substrates suggesting how mitochondrial fission and trafficking are involved. We also discuss how defects in mitophagy may be linked to Parkinson’s disease. arkinson’s disease (PD) is the second most Several lines of evidence also point to mito- Pcommon neurodegenerative disorder and is chondrial dysfunction as a central player in characterized by cardinal motor symptoms: the pathogenesis of PD. Complex I dysfunction slowness of movement, rigidity, rest tremor, and is associated with sporadic PD and is sufficient postural instability (Ropper et al. 2009). Al- to induce parkinsonism (reviewed in Schapira though these symptoms initially respond to 2008). The inhibitors of complex I, MPTP drugs that modulate dopamine metabolism or (Langston et al. 1983) and rotenone (Betarbet surgeriesthat alter basal gangliacircuitry, the dis- et al. 2000), replicate the symptoms of PD, and ease eventually progresses. With a modest excep- rotenone recapitulates key pathognomonic fea- tion (Olanow et al. 2009), no therapy has been tures of PD, such as the a-synuclein-rich inclu- shown to alter the disease course. sion bodies (Betarbet et al. 2000). The cause of The pathogenesis of sporadic Parkinson’s mitochondrial dysfunction in sporadic PD is disease is likely complex involving altered me- not entirely clear, but laser capture microdissec- tabolism of the protein a-synuclein, lysosomal tion of substantia nigra neurons from patients dysfunction, and a dysregulated inflammatory with PD reveal a higher burden of mitochon- response (reviewed in Shulman et al. 2011). drial DNA deletions relative to age-matched Editors: Douglas C. Wallace and Richard J. Youle Additional Perspectives on Mitochondria available at www.cshperspectives.org Copyright # 2012 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a011338 Cite this article as Cold Spring Harb Perspect Biol 2012;4:a011338 1 Downloaded from http://cshperspectives.cshlp.org/ on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press D. Narendra et al. controls (Bender et al. 2006). That such dele- et al. 2006; Yang et al. 2006). Moreover, overex- tions are sufficient to cause parkinsonism is sug- pression of dParkin in the dPink1 null Droso- gested by the occurrence of parkinsonism in phila and not the converse partially compensates patients with rare mutations in their mtDNA for this phenotype, indicating that dPink1 is up- replication machinery (e.g., the catalytic sub- stream of dParkin in the same pathway (Clark unit of the mtDNA polymerase POLG [Luoma et al. 2006; Park et al. 2006; Yang et al. 2006). et al. 2004] or the mtDNA helicase Twinkle [Ba- The function of the dPink1/dParkin path- loh et al. 2007]). The defective mtDNA replica- way at least in Drosophila is suggested by ultra- tive machinery generates high levels of mtDNA structural examination of the tissues before deletions throughout the body that are qualita- their degeneration. Mitochondria in the flight tively similar to those observed in the substantia muscles become swollen and fragmented early nigra in patients with sporadic PD (Reeve et al. in the course of the degeneration, suggesting 2008). Thus, mitochondrial dysfunction is both that a mitochondrial defect may be the primary associated with sporadic PD and sufficient to event (Greene et al. 2003; Whitworth et al. 2005; cause the parkinsonian syndrome. Clark et al. 2006; Park et al. 2006; Yang et al. As is discussed in this review, recent insights 2006). Overexpression of components of the from certain genetic forms of PD—resulting glutathione-dependent detoxification pathway from mutations in Parkin or PINK1—support partially prevents the mitochondrial damage, the model that mitochondrial damage is a cen- implying that mitochondria in Drosophila lack- traldriverof PD pathogenesis. Additionally,they ing the dPink1/dParkin pathway are less able to provide a rationale for targeting mitochondrial cope with oxidative stress (Whitworth et al. quality control pathways in patients with PD. 2005). The apparent damage to mitochondria in the flight muscles correlates with a severe bioenergetic deficit as well as increased oxida- GENETIC STUDIES SUPPORT A COMMON tive damage of the surrounding tissue, suggest- PINK1/PARKIN PATHWAY ing a mechanism for the subsequent apoptosis Mutations in Parkin or PINK1 are the leading of the muscle fibers (Greene et al. 2003; Whit- cause of recessive parkinsonism (Hardy 2010). worth et al. 2005; Clark et al. 2006; Park et al. The parkinsonian syndrome caused by loss of 2006; Yang et al. 2006). Parkin (Kitada et al. 1998) or PINK1 (Valente Studies in mice are largely consistent with et al. 2004) function is clinically indistinguish- the notion of a common Pink1/Parkin pathway able from idiopathic Parkinson’s disease at its important for maintaining mitochondrial in- outset, although it tends to present before the tegrity. Loss of Parkin or Pink1 causes one phe- age of 40 and to progress more slowly. Addition- notype similar to, albeit milder than, that in ally, only some patients with Parkin mutations man, in which nigrostriatal dysfunction corre- develop the a-synuclein-rich inclusions, known lates with mitochondrial dysfunction in the stri- as Lewy bodies and Lewy neurites, which are atum (Palacino et al. 2004; Gautier et al. 2008; pathognomonic for idiopathic Parkinson’s dis- Kitada et al. 2009). Interestingly, PINK1 knock ease (Pramstaller et al. 2005). out (KO) mice also display pronounced cardiac The clinical similarity between patients with hypertrophy (Billia et al. 2011) and Parkin KO Parkin or PINK1 mutations suggests that they mice display less subcutaneous fat, are resistant might function in a common pathway. Sup- to high-fat-diet-induced weight gain (Kim et al. porting this notion, deletion of either dParkin 2011a), and may be predisposed to hepatocel- or dPink1 in Drosophila melanogaster leads to a lular carcinomas (Fujiwara et al. 2008). It re- similar (and relatively unique) phenotype with mains to be determined if these non-neuronal the triad of muscle degeneration, disrupted phenotypes are shared between PINK1 and Par- spermatogenesis, and loss of dopaminergic neu- kin deficient mice. rons within a specific cluster (Greene et al. 2003; Although Parkin and PINK1 may have in- Whitworth et al. 2005; Clark et al. 2006; Park dependent functions in some cellular pathways, 2 Cite this article as Cold Spring Harb Perspect Biol 2012;4:a011338 Downloaded from http://cshperspectives.cshlp.org/ on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press PINK1/Parkin-Directed Mitophagy parsimony would suggest that they function to- PINK1 is usually not detected in proteomics gether in pathways relevant to PD pathogenesis. studies of mitochondrial proteins despite its Additionally, as is discussed in more depth be- relatively large size [see for instance the Mito- low, the difference in phenotype between insects Carta database (Pagliarini et al. 2008)].) Second, and mammals suggests that, although features PINK1 containsasecondweaker targeting signal (including substrates) of PINK1/Parkin path- that directs it to the outer mitochondrial mem- way are shared among insects and mammals, brane (Zhou et al. 2008), if the TOM/TIM im- likely there are differences in the physiologic port pathway is blocked by collapse of DC (Na- functions they serve. rendra et al. 2010b). Thus, PINK1 acts as a kind of scout, dispatched centrally to all the mito- chondria in the cell to assess their internal state. PINK1 SENSES MITOCHONDRIAL STRESS The healthy mitochondria with a strong inner PINK1 is a serine/threonine protein kinase tar- membrane potential quickly dispose of PINK1, geted to mitochondria (Valente et al. 2004; Sil- whereas failing mitochondria, unable to import vestri et al. 2005; Zhou et al. 2008). Under basal and degrade the kinase, accumulate it on their conditions, mammalian Parkin is an E3 ubiq- cysotolicface,ineffectdisplayingtheirinnerdys- uitin ligase residing (likely inert) in the cytosol. function on their outer surface. The accumula- Upon mitochondrial damage, however, Parkin tion appears to be very rapid with a several fold is activated and recruited
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