PINK1, Parkin, and Mitochondrial Quality Control: What can we Learn about Parkinson's Disease Pathobiology?

Abstract

The first clinical description of Parkinson's disease (PD) will embrace its two century anniversary in 2017. For the past 30 years, mitochondrial dysfunction has been hypothesized to play a central role in the pathobiology of this devastating neurodegenerative disease. The identifications of mutations in genes encoding PINK1 (PTEN-induced kinase 1) and Parkin (E3 ubiquitin ligase) in familial PD and their functional association with mitochondrial quality control provided further support to this hypothesis. Recent research focused mainly on their key involvement in the clearance of damaged mitochondria, a process known as mitophagy. It has become evident that there are many other aspects of this complex regulated, multifaceted pathway that provides neuroprotection. As such, numerous additional factors that impact PINK1/Parkin have already been identified including genes involved in other forms of PD. A great pathogenic overlap amongst different forms of familial, environmental and even sporadic disease is emerging that potentially converges at the level of mitochondrial quality control. Tremendous efforts now seek to further detail the roles and exploit PINK1 and Parkin, their upstream regulators and downstream signaling pathways for future translation. This review summarizes the latest findings on PINK1/Parkin-directed mitochondrial quality control, its integration and cross-talk with other disease factors and pathways as well as the implications for idiopathic PD. In addition, we highlight novel avenues for the development of biomarkers and disease-modifying therapies that are based on a detailed understanding of the PINK1/Parkin pathway.

Keywords: PINK1; Parkin; Parkinson’s disease; mitochondria; mitophagy; ubiquitin.

Fig.1

PINK1 and Parkin domain structures and PD-related mutations. (A-B) Given are schematic, color-coded domain representations of PINK1 and Parkin. PD-associated missense and nonsense mutations from the PD Mutation Database (http://www.molgen.vib-ua.be/PDMutDB/) are displayed on top of each structure with their respective locations. Mutations in red have been experimentally verified as loss-of-function mutations and are considered pathogenic, while functional defects for variants shown in black remain unclear. Underlined mutations are common variants based on the ExAC database (http://exac.broadinstitute.org) with allele frequencies greater than 1:10 000. (A) Domain structure of PINK1 (581 amino acids): mitochondrial targeting sequence (MTS, orange), transmembrane region (TM, red), N-terminal regulatory region (NT, gray), N-lobe of the kinase domain (cyan), C-lobe of the kinase domain (purple) and the C-terminal domain (CTD, blue). PD-associated mutations are listed on the top. Mitochondrial protease (MPP and PARL) cleavage sites and PINK1 auto-phosphorylation sites are displayed at the bottom. (B) Domain structure of Parkin (465 amino acids): ubiquitin-like domain (UBL, red), linker (gray), really-interesting-new-gene (RING)/unique Parkin domain (R0/UPD, green), RING1 (R1, cyan), in-between-RING (IBR, purple), repressor element of Parkin (REP, yellow), and RING2 (R2, pink). E2 co-enzyme and p-Ser65-Ub binding sites as well as Ser65 phosphorylation and Cys431 catalytic sites are displayed at the bottom. (C) Closed, inactive conformation of full-length human Parkin (left: front view and right: back view). The structure is shown in colored ribbons that correspond to the respective domain colors. The solvent-accessible surface area of each domain is shown in semi-transparent rendering in the same color. Ser65 is highlighted in Van der Waal representation with standard atom coloring (hydrogen: white, oxygen: red, nitrogen: blue). The zinc-finger motifs of Parkin are rendered in licorice stick with standard atom coloring and the corresponding zinc ions as spheres (cyan).

Fig.2

PINK1/Parkin-directed mitochondria quality control. Shown is a cartoon of the PINK1/Parkin pathway(s). (A) In healthy mitochondria, PINK1 is imported and it undergoes cleavage by the mitochondrial proteases MPP and PARL. N-terminally cleaved PINK1 is then subsequently degraded by the Ub/proteasome system. Parkin remains inactive in the cytosol. (B) Upon mitochondrial damage, PINK1 is no longer imported, but accumulates on the outer mitochondrial membrane (OMM) to activate Parkin. PINK1-mediated phosphorylation of Ub and Parkin enable its E3 Ub ligase functions in concert with E2 Ub-conjugating enzymes. p-Ser65-Ub on OMM substrates acts as the Parkin receptor for its recruitment from the cytosol. Together, PINK1 and Parkin then engage a feed-forward loop amplification. Formed poly-Ub chains can be cleaved by DUBs to reverse PINK1/Parkin functions. (C) Individual OMM proteins decorated with poly-Ub can be extracted from the membrane and degraded by the 26 S proteasome (mitochondria-associated degradation; MAD). Greater, but localized mitochondrial damage is sequestered by the formation of mitochondria-derived vesicles (MDV). Severely damaged mitochondria are decorated with high levels of p-Ser65-Ub that serves as the mitophagy tag for autophagy receptors that direct their degradation in lysosomes.