PINK1/Parkin-directed mitophagy pathway:A mechanistic linkage in Parki(1)
[Abstract]Parkinson disease (PD) is a progressive and incurable Disease, which is the most common neurodegenerative movement disorder. Mutations in PINK1 and PARKIN are the most frequent causes of recessive PD. This review was focus on the latest progress of the functional PINK1/Parkin-directed pathway to reveal the key michanistic steps of PD, which is linking mitochondrial damage, ubiquitylation and autophagy, and highlight the importance of Parkin-midiated mitophagy in the pathogenesis of PD.
, http://www.100md.com
[Key words]Parkinson disease; PINK1; PARKIN; mitophagy; mechanism
Parkinson disease (PD) is the most common neurodegenerative movement disorder, which is a clinicopathologic construct defined by a clinical syndrome with variable combinations of akinesia, rigidity, tremor and postural instability, and a characteristic pattern of neurodegeneration, predominantly, but not exclusively, of dopaminergic neurons of the substantia nigra, leading to a deficiency of dopamine in their striatal projection areas (Rogaeva et al.2004; Valente et al.2004; Savitt et al.2006). Mutations in PARKIN and PINK1 are the most frequent causes of recessive Parkinson’s disease. (Kitada et al. 1998; Valente et al. 2004; Bonifati et al. 2002). Recently, the important mechanistic steps of a PINK1/Parkin-directed pathway linking mitochondrial damage, ubiquitylation and autophagy in non-neuronal and neuronal were revealed.
, http://www.100md.com
Mitochondrial mitophagy
Mitochondrial integrity is crucial to cellular homeostasis. A great number data indicate that the stress-protection role of PINK1 may be mediated via Parkin and may involve repair and clearance pathways. PINK1-mediated phosphorylation of Parkin is a requirement for this translocation, and the interaction of PINK1 and Parkin has mutual effects on their solubility (Kim et al. 2008; Shiba et al. 2009; Xiong et al. 2009). Consequently Parkin can rescue mitochondrial dysfunction after knockout of PINK1 in D. melanogaster (Park et al. 2006; Yang et al. 2006) and also in HeLa cells (Exner et al. 2007). Loss of Parkin in D. melanogaster causes abnormal mitochondrial morphologies and neuropathological dysfunction. It has also been reported that PINK1 acts through phosphorylation of Omi/HtrA2 to preserve mitochondrial integrity. An inhibition of proteasomal degradation led to strongly increased mitochondrial aggregation (Gispert et al. 2009). The latest research show that Parkin translocates to mitochondria upon dissipation of the mitochondrial membrane potential (ΔΨm) by the uncoupler carbonyl cyanide m‑chlorophenylhydrazone (CCCP) or in response to ROS (Narendra et al. 2008).
, http://www.100md.com
Overview of Parkin and PINK1
Parkin encodes an multifunctional E3 ubiquitin-protein ligase whereas PINK1 gene encodes a mitochondrially targeted Ser/Thr kinase. PINK1 regulates normal mitochondrial function and possibly mitochondrial transport, which is critical to normal functioning of neurons (Rintoul et al.). Parkin functions in ubiquitylation of itself and of several diverse target proteins, and has been show that it can mediate both classical and non-classical ubiquitin linked. Both of the proteins can contribute to rare forms of parkinsonian neurodegeneration (Rogaeva et al. 2004; Valente et al. 2004). Loss of protein function resulting from autosomal-recessive mutations in PINK1 and Parkin has been linked to mitochondrial dysfunction, accumulation of abnormal and misfolded proteins, impaired protein clearance and oxidative stress., http://www.100md.com(Yingqing Du)
, http://www.100md.com
[Key words]Parkinson disease; PINK1; PARKIN; mitophagy; mechanism
Parkinson disease (PD) is the most common neurodegenerative movement disorder, which is a clinicopathologic construct defined by a clinical syndrome with variable combinations of akinesia, rigidity, tremor and postural instability, and a characteristic pattern of neurodegeneration, predominantly, but not exclusively, of dopaminergic neurons of the substantia nigra, leading to a deficiency of dopamine in their striatal projection areas (Rogaeva et al.2004; Valente et al.2004; Savitt et al.2006). Mutations in PARKIN and PINK1 are the most frequent causes of recessive Parkinson’s disease. (Kitada et al. 1998; Valente et al. 2004; Bonifati et al. 2002). Recently, the important mechanistic steps of a PINK1/Parkin-directed pathway linking mitochondrial damage, ubiquitylation and autophagy in non-neuronal and neuronal were revealed.
, http://www.100md.com
Mitochondrial mitophagy
Mitochondrial integrity is crucial to cellular homeostasis. A great number data indicate that the stress-protection role of PINK1 may be mediated via Parkin and may involve repair and clearance pathways. PINK1-mediated phosphorylation of Parkin is a requirement for this translocation, and the interaction of PINK1 and Parkin has mutual effects on their solubility (Kim et al. 2008; Shiba et al. 2009; Xiong et al. 2009). Consequently Parkin can rescue mitochondrial dysfunction after knockout of PINK1 in D. melanogaster (Park et al. 2006; Yang et al. 2006) and also in HeLa cells (Exner et al. 2007). Loss of Parkin in D. melanogaster causes abnormal mitochondrial morphologies and neuropathological dysfunction. It has also been reported that PINK1 acts through phosphorylation of Omi/HtrA2 to preserve mitochondrial integrity. An inhibition of proteasomal degradation led to strongly increased mitochondrial aggregation (Gispert et al. 2009). The latest research show that Parkin translocates to mitochondria upon dissipation of the mitochondrial membrane potential (ΔΨm) by the uncoupler carbonyl cyanide m‑chlorophenylhydrazone (CCCP) or in response to ROS (Narendra et al. 2008).
, http://www.100md.com
Overview of Parkin and PINK1
Parkin encodes an multifunctional E3 ubiquitin-protein ligase whereas PINK1 gene encodes a mitochondrially targeted Ser/Thr kinase. PINK1 regulates normal mitochondrial function and possibly mitochondrial transport, which is critical to normal functioning of neurons (Rintoul et al.). Parkin functions in ubiquitylation of itself and of several diverse target proteins, and has been show that it can mediate both classical and non-classical ubiquitin linked. Both of the proteins can contribute to rare forms of parkinsonian neurodegeneration (Rogaeva et al. 2004; Valente et al. 2004). Loss of protein function resulting from autosomal-recessive mutations in PINK1 and Parkin has been linked to mitochondrial dysfunction, accumulation of abnormal and misfolded proteins, impaired protein clearance and oxidative stress., http://www.100md.com(Yingqing Du)