PINK1- and Parkin-mediated mitophagy at a glance

Abstract

PTEN-induced kinase 1 (PINK1) and Parkin are mutated in many cases of early-onset familial Parkinson's disease (PD), but how these proteins are related to the pathogenesis of PD was unclear. Recently, work in cultured cells has shown that Parkin can mediate autophagy of damaged mitochondria (termed mitophagy) (Narendra et al., 2008) downstream of PINK1 (Geisler et al., 2010a; Matsuda et al., 2010; Narendra et al., 2010b; Vives-Bauza et al., 2010). These reports suggest that a quality control pathway maintains the mitochondrial homeostasis in many cell types, including in dopaminergic neurons, whose malfunction causes the motor deficits in PD. Here, we briefly summarize how defective mitochondria in a cell are specifically recognized and committed to mitophagy by PINK1 and Parkin.Mitophagy is the selective engulfment of mitochondria by autophagosomes and their subsequent catabolism by lysosomes (see Poster). Starvation induces a less-selective form of autophagy in which cytosol and a variety of organelles are engulfed into autophagosomes, which leads to their degradation in order to supply nutrients to compensate for the loss of external supplies. It was initially found that mitochondria are selectively engulfed by autophagosomes following a loss in membrane potential (Lemasters et al., 1998), suggesting that mitophagy mediates selective removal of damaged mitochondria. This idea has been supported by recent knockout mouse models, where loss-of-function of ATG7, which functions in the autophagy pathway, results in an accumulation of defective mitochondria in certain tissues (Komatsu et al., 2005; Wu et al., 2009). Among the first events in quality control by mitophagy is the distinction between damaged mitochondria and healthy mitochondria. Following their identification by PINK1, defective mitochondria are engulfed in double-membraned autophagosomes that fuse with lysosomes, thereby merging their contents and allowing hydrolytic degradation (reviewed by Kim et al., 2007). In addition to quality control, mitophagy occurs to regulate mitochondrial number (Zhang et al., 2009b) and eliminate mitochondria during the development of specialized cells or tissues such as reticulocytes (Kundu et al., 2008; Mortensen et al., 2010; Zhang et al., 2009a). Overexpression of Parkin has been found to induce the complete removal of mitochondria from cells by mitophagy when mitochondria lose their membrane potential (Narendra et al., 2008). As Parkin has also been found to selectively bind only to damaged mitochondria it has been suggested that Parkin might mediate a quality control pathway of mitophagy.Parkin was initially identified as a cytosolic E3 ubiquitin ligase that is mutated in familial forms of PD (Kitada et al., 1998), and mutations in this protein are now known to be the most prevalent cause of autosomal recessive monogenic PD. It has been found that the gene encoding PINK1, a serine/threonine kinase, is also mutated in other autosomal recessive cases of PD (Valente et al., 2004). Parkin was first linked to mitochondrial maintenance by studies of loss-of-function mutations in Drosophila melanogaster (Greene et al., 2003). Remarkably, Drosophila that lack Parkin or Pink1 display very similar defects in mitochondria (Clark et al., 2006; Park et al., 2006). In this organism, the Pink1-knockout phenotype is rescued by overexpression of Parkin, whereas the Parkin-knockout phenotype is not rescued by PINK1 overexpression, indicating that PINK1 is an upstream regulator of Parkin function. On the basis of these reports, and the finding that Parkin translocates to depolarized mitochondria and induces mitophagy (Narendra et al., 2008), in 2010 several groups reported that the recruitment of Parkin to impaired mitochondria requires PINK1 expression and its kinase activity (Geisler et al., 2010b; Matsuda et al., 2010; Narendra et al., 2010b; Vives-Bauza et al., 2010).Following translocation to the mitochondrial surface, Parkin ubiquitylates numerous outer mitochondrial membrane (OMM) proteins, which in turn recruit other proteins to mitochondria to initiate mitophagy (Chan et al., 2011; Geisler et al., 2010a; Lee et al., 2010b; Narendra et al., 2010a; Tanaka et al., 2010; Yoshii et al., 2011) (see Poster). One proviso, in most experiments, is that overexpression of Parkin is typically used to identify mitochondrial E3 ligase substrates and to induce mitophagy because endogenous Parkin expression is low in many cell lines. However, endogenous PINK1 has been shown to regulate mitochondrial mass in M17 and SH-SY5Y cells that express only endogenous Parkin (Gegg et al., 2010; Narendra et al., 2010b). So far, two mitochondrial substrates of endogenous Parkin have been identified, the closely related mitochondrial fusion proteins mitofusin (MFN) 1 and 2 (Gegg et al., 2010; Poole et al., 2010; Rakovic et al., 2011; Tanaka et al., 2010; Ziviani et al., 2010). Parkin is proposed to prevent mitochondrial fusion through mediating the d