Sci. Signal., 9 February 2010
Neuroscience From PINK1 to Parkin to Mitophagy
Elizabeth M. Adler
Science Signaling, AAAS, Washington, DC 20005, USA
The identification of mutations in the genes encoding the ubiquitin ligase Parkin and PTEN-induced putative kinase 1 (PINK1) in inherited forms of the neurodegenerative disorder Parkinsons disease (PD) have highlighted the role of mitochondrial dysfunction in its pathogenesis. PINK1 bears a mitochondrial targeting sequence (MTS), and Parkin, which interacts with PINK1, is recruited to dysfunctional mitochondria, leading to their elimination through autophagy (mitophagy). Geisler et al. expressed labeled Parkin or PD-associated Parkin mutants in HeLa cells (which lack detectable endogenous Parkin) and visualized their behavior after treatment with the mitochondrial uncoupler CCCP. Nine of 14 missense mutations led to defects in mitophagy through disruption of distinct steps in the overall process. For instance, some mutants failed to translocate promptly to mitochondria depolarized by CCCP, whereas others were recruited to mitochondria but failed to elicit their clearance. Similarly, wild-type Parkin, but not nonfunctional mutant forms, accelerated mitophagy when overexpressed in a dopaminergic neuroblastoma cell line (SH-SY5Y cells). CCCP increased the coimmunoprecipitation of endogenous Parkin and PINK1 from SH-SY5Y cells. Moreover, introduction of wild-type PINK1 restored Parkin translocation and mitophagy in SH-SY5Y cells in which endogenous PINK1 had been knocked down with siRNA, whereas mutant forms lacking catalytic activity or the MTS did not. CCCP treatment of cells with functional Parkin led to formation of polyubiquitin chains at clustered mitochondria; analyses of the effects of expressing ubiquitin mutants determined that these were Lys27- and Lys63-linked chains. CCCP also stimulated the Parkin-dependent recruitment of the polyubiquitin-binding protein p62 (also known as SQSTM1) to mitochondria, and p62 knockdown inhibited mitochondrial clearance without affecting Parkin recruitment. Voltage-dependent anion channel 1 (VDAC1), which is present in the mitochondrial outer membrane, underwent Parkin-dependent Lys27 ubiquitylation after CCCP treatment, and its knockdown inhibited Parkin translocation to mitochondria and mitochondrial clearance. Thus, these data define a mechanistic pathway linking PINK1 activity to mitophagy through Parkin-dependent ubiquitylation of VDAC1. Wild and Dikic provided commentary, noting that a second group, Vives-Bauza et al., have also recently identified a role for PINK1 in recruiting Parkin to mitochondria.
S. Geisler, K. M. Holmström, D. Skujat, F. C. Fiesel, O. C. Rothfuss, P. J. Kahle, W. Springer, PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nat. Cell Biol. 12, 119–131 (2010). [PubMed]
P. Wild, I. Dikic, Mitochondria get a Parkin' ticket. Nat. Cell Biol. 12, 104–106 (2010). [PubMed]
C. Vives-Bauza, C. Zhou, Y. Huang, M. Cui, R. L.A. de Vries, J. Kim, J. May, M. A. Tocilescu, W. Liu, H. S. Ko, J. Magrané, D. J. Moore, V. L. Dawson, R. Grailhe, T. M. Dawson, C. Li, K. Tieu, S. Przedborski, PINK1-dependent recruitment of Parkin to mitochondria in mitophagy. Proc. Natl. Acad. Sci. U.S.A. 107, 378–383 (2010). [Abstract] [Full Text]
Citation: E. M. Adler, From PINK1 to Parkin to Mitophagy. Sci. Signal. 3, ec49 (2010).
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