PINK1/Parkin-directed mitophagy pathway:A mechanistic linkage in Parki(2)
Increasing evidences demonstration that PINK1, Parkin and DJ-1 have primary roles in mitochondrial function and resistance to oxidative stress reinforce the central importance of these themes in Parkinson’s disease pathogenesis and have begun to enable understanding of these processes at the mechanistic level (Kubo et al.2001; Darios et al.2003; Shimura et al.2000). A great number of evidence suggest that both of the proteins control the mitochondrial morphology and function with PINK1 being upstream of Parkin (Clark et al. 2006; Exner et al. 2007; Park et al. 2006; Poole et al. 2008). Geirsler et al (2011) proved PINK1 can contribute to the Parkin mediated mitophagy and demonstrated that it is the second Parkinson’s disease associated gene in the mitophagy to strengthen the implication of mitophagy in PD pathogenesis.
, 百拇医药
Ubiquitylation
A logical link between parkinsonism and the ubiquitin-proteasome system can be deduced from the finding that the PD gene product Parkin has ubiquitin ligase activity (Shimura et al, 2000). In the presence of functional Parkin, poly-ubiquitin chains are formed at clustering mitochondria (Geirsler et al. 2011). In addition, they revealed the formation of different poly-ubiquitin chains, linked through K27 and K63 of ubiquitin. By using the p62/SQSTM1, Geirsler et al (2011) identified the missing linkage between ubiquitylation and mitophagy and proved the importance of p62 as an adaptor protein for Parkin-directed mitophagy. The ubiquitin-autophagy adaptor p62/SQSTM1 is crucial for the Parkin-dependent mitophagy. The voltage-dependent anion channel (VDAC), located in the outer mitochondrial membrane, acts as a gatekeeper for the entry and exit of mitochondrial metabolites N (Saskia et al.2010). VDAC1 is a target protein of Parkin E3 ligase activity in response to mitochondrial depolarization in non-neuronal and neuronal cells (Geirsler et al. 2011).
, 百拇医药
Discussion
To summarize, PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. PINK1 kinase activity and its mitochondrial localization sequence are prerequisites to induce translocation of the E3 ligase Parkin to depolarized mitochondria. Subsequently, Parkin mediates the formation of two distinct poly-ubiquitin chains, linked through Lys 63 and Lys 27. In addition, the autophagic adaptor p62/SQSTM1 is recruited to mitochondrial clusters and is essential for the clearance of mitochondria. Strikingly, VDAC1 was identified as a target for Parkin-mediated Lys 27 poly-ubiquitylation and mitophagy. Pathogenic Parkin mutations interfere with distinct steps of mitochondrial translocation, ubiquitylation and/or final clearance through mitophagy. PINK1, Parkin, ubiquitin , p62 and VDAC1 were identified as the key role in a sequential mitophagy process. Loss of PINK1 and Parkin results in failure of selective mitochondrial clearance and may therefore contribute to the pathogenesis of PD (Geirsler et al. 2011).
References:
[1]Bonifati V, Rizzu P, Van Baren MJ, et al. Mutations in the DJ–1 gene associated with autosomal recessive early–onset parkinsonism. Science 299:256–259, 2002., http://www.100md.com(Yingqing Du)
, 百拇医药
Ubiquitylation
A logical link between parkinsonism and the ubiquitin-proteasome system can be deduced from the finding that the PD gene product Parkin has ubiquitin ligase activity (Shimura et al, 2000). In the presence of functional Parkin, poly-ubiquitin chains are formed at clustering mitochondria (Geirsler et al. 2011). In addition, they revealed the formation of different poly-ubiquitin chains, linked through K27 and K63 of ubiquitin. By using the p62/SQSTM1, Geirsler et al (2011) identified the missing linkage between ubiquitylation and mitophagy and proved the importance of p62 as an adaptor protein for Parkin-directed mitophagy. The ubiquitin-autophagy adaptor p62/SQSTM1 is crucial for the Parkin-dependent mitophagy. The voltage-dependent anion channel (VDAC), located in the outer mitochondrial membrane, acts as a gatekeeper for the entry and exit of mitochondrial metabolites N (Saskia et al.2010). VDAC1 is a target protein of Parkin E3 ligase activity in response to mitochondrial depolarization in non-neuronal and neuronal cells (Geirsler et al. 2011).
, 百拇医药
Discussion
To summarize, PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. PINK1 kinase activity and its mitochondrial localization sequence are prerequisites to induce translocation of the E3 ligase Parkin to depolarized mitochondria. Subsequently, Parkin mediates the formation of two distinct poly-ubiquitin chains, linked through Lys 63 and Lys 27. In addition, the autophagic adaptor p62/SQSTM1 is recruited to mitochondrial clusters and is essential for the clearance of mitochondria. Strikingly, VDAC1 was identified as a target for Parkin-mediated Lys 27 poly-ubiquitylation and mitophagy. Pathogenic Parkin mutations interfere with distinct steps of mitochondrial translocation, ubiquitylation and/or final clearance through mitophagy. PINK1, Parkin, ubiquitin , p62 and VDAC1 were identified as the key role in a sequential mitophagy process. Loss of PINK1 and Parkin results in failure of selective mitochondrial clearance and may therefore contribute to the pathogenesis of PD (Geirsler et al. 2011).
References:
[1]Bonifati V, Rizzu P, Van Baren MJ, et al. Mutations in the DJ–1 gene associated with autosomal recessive early–onset parkinsonism. Science 299:256–259, 2002., http://www.100md.com(Yingqing Du)