Relevance of PINK1-Parkin mitophagy in stress, aging, and disease

Identification: Springer, Wolfdieter


Description

Relevance of PINK1-Parkin mitophagy in stress, aging, and disease
 
Wolfdieter Springer1,2
1Mayo Clinic, Department of Neuroscience; 2Mayo Clinic Graduate School of Biomedical Sciences
      
Mutations in the PINK1/PARK6 and Parkin/PARK2 genes cause early-onset Parkinson's disease (EOPD). The encoded proteins functionally cooperate in a stress-induced mitochondrial quality control to selectively identify, label, and direct damaged mitochondria via autophagy to degradation in lysosomes (mitophagy). Both PINK1 and Parkin are broadly neuroprotective and impairment of either is thought to result in the buildup of damaged mitochondria and eventually neuronal death. In addition to the unequivocal involvement in EOPD, accumulating evidence suggests that reduced levels/activities of PINK1 and Parkin may also contribute to at least progression of idiopathic PD and other age-dependent neurodegenerative disorders. Over the last few years only, molecular and cellular mechanisms have been detailed describing PINK1/Parkin-directed mitophagy as a complex regulated, sequential pathway with numerous potential therapeutic targets. The mitochondrial kinase PINK1 is typically imported into healthy mitochondria, cleaved and degraded. Upon stress, PINK1 accumulates locally at the outer mitochondrial membrane and rapidly phosphorylates its substrates: the small modifier ubiquitin (Ub) and the E3 Ub ligase Parkin. Both phosphorylations are required to fully activate structurally inhibited Parkin and recruit it from the cytosol. Together, PINK1 and Parkin then decorate damaged mitochondria with phosphorylated poly-Ub chains that serve as the 'mitophagy tag'. This transient, but highly specific degradation label is decoded by autophagy receptors such as OPTN that co-recruit the autophagic machinery. This in turn facilitates engulfment of damaged organelles and fusion with lysosomes for final clearance. While the dynamic nature of mitophagy is difficult to capture, it is evident that flux through the pathway can be impaired on multiple levels at the intersection of mitochondria, trafficking, autophagy, and lysosomes. As such PINK1/Parkin-dependent mitophagy provides a platform for a potentially large functional overlap between different disease pathways. Together with emerging translational studies in animal models and patient's specimens, detailed understanding of the underlying mechanisms now sets the stage for the development of novel biomarkers and future disease-modifying therapeutics.

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