Drosophila PINK1 is required for mitochondrial function and interacts genetically with Parkin

Nature (Impact Factor: 41.46). 05/2006; 441(7097):1162-1166. DOI: 10.1038/nature04779
Source: PubMed


Parkinson's disease is the second most common neurodegenerative disorder and is characterized by the degeneration of dopaminergic neurons in the substantia nigra. Mitochondrial dysfunction has been implicated as an important trigger for Parkinson's disease-like pathogenesis because exposure to environmental mitochondrial toxins leads to Parkinson's disease-like pathology

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    • "Numerous studies over the last 10 years have implicated Parkin and PINK1 in a common mitochondrial quality control pathway (Narendra et al, 2012). In Drosophila, loss of PINK1 causes mitochondrial dysfunction that can be complemented by Parkin (Clark et al, 2006; Park et al, 2006). Parkin is a cytosolic E3 ubiquitin ligase that is recruited to mitochondria damaged by depolarization, reactive oxygen species (ROS), or accumulation of unfolded proteins (Narendra et al, 2008; Jin & Youle, 2013; Ashrafi et al, 2014). "
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    ABSTRACT: Mutations in Parkin and PINK1 cause an inherited early-onset form of Parkinson's disease. The two proteins function together in a mitochondrial quality control pathway whereby PINK1 accumulates on damaged mitochondria and activates Parkin to induce mitophagy. How PINK1 kinase activity releases the auto-inhibited ubiquitin ligase activity of Parkin remains unclear. Here, we identify a binding switch between phospho-ubiquitin (pUb) and the ubiquitin-like domain (Ubl) of Parkin as a key element. By muta-genesis and SAXS, we show that pUb binds to RING1 of Parkin at a site formed by His302 and Arg305. pUb binding promotes disengagement of the Ubl from RING1 and subsequent Parkin phospho-rylation. A crystal structure of Parkin D86–130 at 2.54 Å resolution allowed the design of mutations that specifically release the Ubl domain from RING1. These mutations mimic pUb binding and promote Parkin phosphorylation. Measurements of the E2 ubiqui-tin-conjugating enzyme UbcH7 binding to Parkin and Parkin E3 ligase activity suggest that Parkin phosphorylation regulates E3 ligase activity downstream of pUb binding.
    The EMBO Journal 08/2015; 34(20). DOI:10.15252/embj.201592237 · 10.43 Impact Factor
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    • "mitochondrion for mitophagy (Narendra et al., 2010a, 2008; Sarraf et al., 2013). Before their biochemical interaction was recognized, PINK1 was placed upstream of park in a genetic pathway in Drosophila (Clark et al., 2006; Park et al., 2006; Yang et al., 2006). "
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    ABSTRACT: Loss of mitochondrial function often leads to neurodegeneration and is thought to be one of the underlying causes of neurodegenerative diseases such as Parkinson's disease (PD). However, the precise events linking mitochondrial dysfunction to neuronal death remain elusive. PTEN-induced putative kinase 1 (PINK1) and Parkin (Park), either of which, when mutated, are responsible for early-onset PD, mark individual mitochondria for destruction at the mitochondrial outer membrane. The specific molecular pathways that regulate signaling between the nucleus and mitochondria to sense mitochondrial dysfunction under normal physiological conditions are not well understood. Here, we show that Drosophila Clueless (Clu), a highly conserved protein required for normal mitochondrial function, can associate with Translocase of the outer membrane (TOM) 20, Porin and PINK1, and is thus located at the mitochondrial outer membrane. Previously, we found that clu genetically interacts with park in Drosophila female germ cells. Here, we show that clu also genetically interacts with PINK1, and our epistasis analysis places clu downstream of PINK1 and upstream of park. In addition, Clu forms a complex with PINK1 and Park, further supporting that Clu links mitochondrial function with the PINK1-Park pathway. Lack of Clu causes PINK1 and Park to interact with each other, and clu mutants have decreased mitochondrial protein levels, suggesting that Clu can act as a negative regulator of the PINK1-Park pathway. Taken together, these results suggest that Clu directly modulates mitochondrial function, and that Clu's function contributes to the PINK1-Park pathway of mitochondrial quality control. © 2015. Published by The Company of Biologists Ltd.
    Disease Models and Mechanisms 06/2015; 8(6):577-589. DOI:10.1242/dmm.019208 · 4.97 Impact Factor
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    • "Remarkably, PINK1-null flies exhibited a very similar phenotype that could be rescued by overexpressing human PARKIN. Conversely, overexpression of PINK1 failed to rescue the PARKIN mutant phenotype, suggesting that PINK1 acts upstream of PARKIN in a common genetic pathway that impacts mitochondrial function (Clark et al. 2006; Park et al. 2006; Yang et al. 2006). Clues to explain the cellular basis of this interaction came from the seminal studies from the laboratory of Richard Youle (Narendra et al. 2008), who found that in the presence of the uncoupler carbonyl cyanide m-chlorophenylhydrazone (CCCP), which dissipates the mitochondrial membrane potential (ΔΨm), PARKIN massively relocalized from the cytosol to the mitochondria. "
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    ABSTRACT: Two Parkinson's disease (PD)-associated proteins, the mitochondrial kinase PINK1 and the E3-ubiquitin (Ub) ligase PARKIN, are central to mitochondrial quality control. In this pathway, PINK1 accumulates on defective mitochondria, eliciting the translocation of PARKIN from the cytosol to mediate the clearance of damaged mitochondria via autophagy (mitophagy). Throughout the different stages of mitophagy, post-translational modifications (PTMs) are critical for the regulation of PINK1 and PARKIN activity and function. Indeed, activation and recruitment of PARKIN onto damaged mitochondria involves PINK1-mediated phosphorylation of both PARKIN and Ub. Through a stepwise cascade, PARKIN is converted from an autoinhibited enzyme into an active phospho-Ub-dependent E3 ligase. Upon activation, PARKIN ubiquitinates itself in concert with many different mitochondrial substrates. The Ub conjugates attached to these substrates can in turn be phosphorylated by PINK1, which triggers further cycles of PARKIN recruitment and activation. This feed-forward amplification loop regulates both PARKIN activity and mitophagy. However, the precise steps and sequence of PTMs in this cascade are only now being uncovered. For instance, the Ub conjugates assembled by PARKIN consist predominantly of noncanonical K6-linked Ub chains. Moreover, these modifications are reversible and can be disassembled by deubiquitinating enzymes (DUBs), including Ub-specific protease 8 (USP8), USP15, and USP30. However, PINK1-mediated phosphorylation of Ub can impede the activity of these DUBs, adding a new layer of complexity to the regulation of PARKIN-mediated mitophagy by PTMs. It is therefore evident that further insight into how PTMs regulate the PINK1-PARKIN pathway will be critical for our understanding of mitochondrial quality control. © 2015 Durcan and Fon; Published by Cold Spring Harbor Laboratory Press.
    Genes & Development 05/2015; 29(10):989. DOI:10.1101/gad.262758.115 · 10.80 Impact Factor
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