Review
Mitophagy: the latest problem for Parkinson's disease

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Parkinson's disease (PD) is a common neurodegenerative disorder of unknown cause. Some familial forms of PD are provoked by mutations in the genes encoding for the PTEN (phosphatase and tensin homolog)-induced putative kinase-1 (PINK1) and Parkin. Mounting evidence indicates that PINK1 and Parkin might function in concert to modulate mitochondrial degradation, termed mitophagy. However, the molecular mechanisms by which PINK1/Parkin affect mitophagy are just beginning to be elucidated. Herein, we review the main advances in our understanding of the PINK1/Parkin pathway. Because of the phenotypic similarities among the different forms of PD, a better understanding of PINK1/Parkin biology might have far-reaching pathogenic and therapeutic implications for both the inherited and the sporadic forms of PD.

Section snippets

Parkinson's disease

Parkinson's disease (PD) is one of the most common neurodegenerative disorders affecting 1% of the population over the age of 65 [1]. Clinically, PD is characterized mainly by motor manifestations such as bradykinesia, resting tremor, rigidity and postural instability [1]. One of the most salient neuropathological features of PD is the loss of the dopamine-containing neurons in the substantia nigra pars compacta (SNpc), which is responsible for the profound reduction of dopamine in the striatum

Mitophagy

As reminded by DiMauro and Schon [8], the story of mitochondria in eukaryotic cells is fascinating. Indeed, a billion years ago, aerobic bacteria colonized anaerobic eukaryotic cells. Through this symbiotic relationship, bacteria evolved into mitochondria and the host cells acquired the ability to metabolically use oxygen. By all accounts, it seems that eukaryotic cells have lived ‘happily ever after’ with mitochondria. For instance, each eukaryotic cell from multicellular organisms is

Familial forms of PD point to a relation between PD and mitophagy

PD commonly arises sporadically but, in some cases, the disease is inherited. PARK6/PINK1 is one of the gene products associated with familial PD 30, 31. This 581-amino acid polypeptide is a serine/threonine kinase with a high degree of homology to the Ca2+/calmodulin kinase family that localizes to mitochondria. Loss-of-function mutations in the gene encoding PARK2/Parkin (an E3 ubiquitin ligase) can cause an autosomal recessive form of familial PD 31, 32. Drosophila carrying pink1 mutations

Do PINK1 and Parkin modify each other?

Parkin translocation to mitochondria relies on PINK1 expression (Figure 1), and if wild type but not functionally deficient mutated PINK1 is overexpressed, Parkin can be recruited to mitochondria with normal ΔΨm 4, 5, 6, 37. The latter observation suggests that PINK1, probably through its kinase activity, is a key signaling molecule in mitophagy and that it operates downstream to the intramitochondrial molecular alterations provoked by the loss of ΔΨm. PD-linked loss-of-function mutations in

Signaling and regulation of PINK1 and Parkin

Although we are gaining insights into the PINK1/Parkin molecular pathway, several important outstanding questions remain (Figure 1). For instance, regarding PINK1 biology, we still do not know how the loss of ΔΨm engages PINK1 signaling or how PINK1 triggers Parkin recruitment. Some recent observations might help clarify these intriguing questions. In mitochondria with normal ΔΨm, PINK1, which has a short half-life, is present in low amounts 5, 37. However, a loss in ΔΨm is associated with an

Mitophagy and fusion/fission

In connection to one of the above issues, one might wonder whether PINK1/Parkin modulates mitophagy through the fusion/fission machinery. Indeed, it is reasonable to believe that the smaller the mitochondrion, the better it can be handled by the autophagy machinery. Consistent with this speculation are reports that knocking down the fission proteins DRP1 and FIS1 or overexpressing the fusion protein OPA1 reduces mitophagy 19, 36. By contrast, an excess of fission, driven by the overexpression

Emerging united pathogenic theme

The multiplicity of genetic defects giving rise to similar PD phenotypes has prompted researchers to consider the possibility that a common pathogenic cascade could underlie neurodegeneration in many if not all forms of familial PD. To date, however, there is no clear and compelling pathway unifying these different PD-linked mutant proteins. Only PINK1 and Parkin seem to converge functionally. In familial forms of PD, owing to mutations in either of these genes, impaired Parkin recruitment to

Concluding remarks

The identification and understanding of PD-related proteins are valuable for providing insight into the pathogenic mechanisms of this neurodegenerative disorder. Impairment in quality control autophagy (i.e. autophagy triggered to enforce intracellular quality control by eliminating toxic protein aggregates or damaged organelles) has emerged as a prominent new pathogenic mechanism. Whether the scenario proposed for PINK1/Parkin familial PD (Figure 1) can be extrapolated to sporadic PD remains

Acknowledgments

The authors are supported by NIH Grants AG021617, NS042269, NS062180, NS064191 and NS38370; US Department of Defense grants (W81XWH-08-1-0522, W81XWH-08-1-0465); the Parkinson Disease Foundation (New York, NY, USA); the Thomas Hartman Foundation For Parkinson's Research; and the MDA/Wings-over-Wall Street. S.P. is the Page and William Black Professor of Neurology.

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