Parkin, an E3 Ubiquitin Ligase, Plays an Essential Role in Mitochondrial Quality Control in Parkinson's Disease

Abstract

Parkinson's disease (PD), as one of the complex neurodegenerative disorders, affects millions of aged people. Although the precise pathogenesis remains mostly unknown, a significant number of studies have demonstrated that mitochondrial dysfunction acts as a major role in the pathogeny of PD. Both nuclear and mitochondrial DNA mutations can damage mitochondrial integrity. Especially, mutations in several genes that PD-linked have a closed association with mitochondrial dysfunction (e.g., Parkin, PINK1, DJ-1, alpha-synuclein, and LRRK2). Parkin, whose mutation causes autosomal-recessive juvenile parkinsonism, plays an essential role in mitochondrial quality control of mitochondrial biogenesis, mitochondrial dynamics, and mitophagy. Therefore, we summarized the advanced studies of Parkin's role in mitochondrial quality control and hoped it could be studied further as a therapeutic target for PD.

Keywords: Mitochondrial biogenesis; Mitochondrial dynamics; Mitophagy; Parkin; Parkinson’s disease.

Fig. 1

The domain structure of Parkin. Parkin consists of a ubiquitin-like (Ubl) domain in the N-terminal and four RING-like domains, i.e., including RING0, RING1, IBR, and RING2. There is a linker following the Ubl domain and a conserved region named REP between the IBR and RING2 domains. Together, RING1, IBR, and RING2 form the RING-in-between-RING (RBR) module. There is an E2 binding site and a Cys431 situated in the RING1 and RING2 domains, respectively, which play essential roles in Parkin activation

Fig. 2

Model of Parkin activation. In the normal state, the activity of Parkin is repressed. PINK1 can activate Parkin by directly phosphorylating S65 in the Ubl domain and indirectly phosphorylating Ub S65 at the same position as Parkin. Phosphorylated S65 at the Ub binding site on the RING1 domain results in a complete release of the Ubl domain of Parkin, thereby promoting PINK1-mediated phosphorylation of Ser65 in the UBL. Subsequently, released REP and RING2 lead to exposure of the E2 binding site and Cys431, thereby leading to a fully active conformation of Parkin

Fig. 3

Model of Parkin-dependent mitophagy. (a) In healthy mitochondria, PINK1 undergoes sequential cleavage by mitochondrial processing peptidase (MPP) and presenilin-associated rhomboid-like protease (PARL) in the matrix and inner membrane, respectively. Then, cleaved Parkin is released from mitochondria and degraded by the 26S proteasome. (b) When mitochondria are damaged, PINK1 carries on autophosphorylation on the mitochondrial surface to promote the translocation of Parkin into mitochondria. (c) Phospho-ubiquitin chains on the mitochondria recruit Parkin; then, PINK1 activates Parkin via direct phosphorylation of Parkin and indirect phosphorylation of Ub. The fully activated Parkin, through the ubiquitination of more substrate proteins, attracts more Parkin, thereby amplifying mitophagy. (d) Accumulated Ubs recruit several autophagy receptors forming autophagosomes, which then fuses with lysosomes, leading to degradation of damaged mitochondria by lysosomal proteases

Fig. 4

Parkin is involved in mitochondrial quality control, including mitochondrial biogenesis, dynamics, and mitophagy. (a) Parkin can affect mitochondrial biogenesis via the PARIS-PGC1α pathway. (b) Parkin can preserve mitochondrial integrity by regulating mitochondrial fusion and fission. (c) Parkin and PINK1 cooperatively participate in mitophagy to clear damaged mitochondria. (d) Parkin participates in cargo sorting, budding of vesicles, and matrix delivery to the lysosome via mitochondrial-derived vesicles