Park J, Lee SB, Lee S, Kim Y, Song S, Kim S, Bae E, Kim J, Shong M, Kim JM, Chung J.
Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin.
Nature. 2006 Jun 29;441(7097):1157-61.
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The parkin-PINK Connection: Bridging Together Proteasome and Mitochondria
The identification over the past few years of several genes causative of autosomal dominant and recessive forms of parkinson disease has represented a true revolution in PD research. A huge body of research has been performed aimed at understanding the physiological role of proteins encoded by PD genes and the mechanisms by which mutated proteins lead to neurodegeneration. These findings have elucidated two major pathways related to neuronal cell death, namely mitochondrial dysfunction and impairment of the ubiquitin-proteasome system (UPS). While PINK1 and DJ-1 are stress-related proteins exerting a protective role against mitochondrial dysfunction and oxidative stress, other proteins, such as parkin and UCH-L1, play crucial roles for the integrity of the UPS. In this light, it looked as if there were two well distinct mechanisms, possibly leading to a common final pathway of neuronal cell death. Studies on α-synuclein, another PD-related protein, have shown that its pathogenic forms can induce both mitochondrial and UPS impairment, thus building the first link between these two pathways. Additional evidence in support of a mitochondrial-UPS connection came from parkin animal models (such as mouse and Drosophila), surprisingly showing signs of mitochondrial damage and increased oxidative stress.
Now, three papers, two published in Nature (Clark et al., 2006; Park et al., 2006) and one in PNAS (Lu et al., 2006), independently reported that PINK1 knockout Drosophila models develop a mitochondrial phenotype remarkably similar to parkin knockouts, and—most interestingly—that parkin overexpression can rescue this phenotype. These findings unequivocally put PINK1 and parkin within the same pathway, with parkin acting downstream of PINK1, and definitely establish a tight connection between mitochondria and the UPS.
What could be the function of parkin within mitochondria? Is this related to its ubiquitin-ligase activity, or does it represent a distinct, still unknown function of this protein? Previous studies had already provided hints of a possible mitochondrial role of parkin. For instance, Moore et al. showed an interaction between parkin and DJ-1 under oxidative stress conditions, while Darios and coworkers demonstrated a protective role of parkin against mitochondrial swelling and cytochrome c release in a model of mitochondrial-related cell death induced by the toxin ceramide. However, how parkin can exert its protective function within the mitochondria is still obscure. On the other hand, while it is now established that PINK1 is imported and processed within the mitochondria, it is still unclear whether a proportion of the mature protein could be exported back to the cytosol, as suggested by Beilina and coworkers. Thus, it appears more and more clear that, instead of two (or more) distinct pathways, we are facing a complex scenario where PD-related proteins can variably interact at different cellular levels. To understand this scenario and all its players is now the most enthralling challenge of PD research.
Clark IE, Dodson MW, Jiang C, Cao JH, Huh JR, Seol JH, Yoo SJ, Hay BA, Guo M.
Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin.
Nature. 2006 Jun 29;441(7097):1162-6.
Moore DJ, Zhang L, Troncoso J, Lee MK, Hattori N, Mizuno Y, Dawson TM, Dawson VL.
Association of DJ-1 and parkin mediated by pathogenic DJ-1 mutations and oxidative stress.
Hum Mol Genet. 2005 Jan 1;14(1):71-84.
Darios F, Corti O, Lücking CB, Hampe C, Muriel MP, Abbas N, Gu WJ, Hirsch EC, Rooney T, Ruberg M, Brice A.
Parkin prevents mitochondrial swelling and cytochrome c release in mitochondria-dependent cell death.
Hum Mol Genet. 2003 Mar 1;12(5):517-26.
Beilina A, Van Der Brug M, Ahmad R, Kesavapany S, Miller DW, Petsko GA, Cookson MR.
Mutations in PTEN-induced putative kinase 1 associated with recessive parkinsonism have differential effects on protein stability.
Proc Natl Acad Sci U S A. 2005 Apr 19;102(16):5703-8.