Abstract
Mutations in the E3 ubiquitin ligase Parkin or the mitochondrial kinase PINK1 cause autosomal recessive forms of Parkinson’s disease [1, 2]. Genetic and cell biological studies have implicated PINK1 and Parkin as critical elements in mitophagy, a mitochondrial quality control pathway that involves the ubiquitin-proteasome system (UPS) and the autophagy-lysosomal system [1, 2]. Under basal conditions, PINK1 is processed by mitochondrial proteases and targeted for degradation by the UPS [1, 2]. Following persistent mitochondrial damage (e.g., treatment with the mitochondrial uncoupling agent CCCP) PINK1 is stabilized and accumulates in an active form on the outer mitochondrial membrane [1, 2]. Although PINK1 activity is essential for the mitochondrial recruitment of cytoplasmic Parkin and for the subsequent ubiquitin-dependent clearance of damaged mitochondria, the mode of Parkin activation and recruitment has been elusive [1, 2].
Highlights
A series of recent papers indicates that PINK1 initiates mitophagy by a two-pronged mechanism involving direct phosphorylation of ubiquitin at serine 65 [3,4,5] and the ubiquitin-like domain (UbL) of Parkin, at serine 65 [6,7,8] (Fig. 1A, steps 1–2)
In December’s issue of PLOS Genetics, Shiba-Fukushima et al provide compelling data indicating that PINK1 directly phosphorylates polyubiquitin chains to mediate the mitochondrial recruitment and activation of Parkin (Fig. 1A, steps 3–4) [15]
The second feedforward loop involves the generation of mitochondrial polyubiquitin chains by PINK1-activated Parkin, and/or another mitochondrial E3 ligase, and their subsequent phosphorylation by PINK1
Summary
Genetic and cell biological studies have implicated PINK1 and Parkin as critical elements in mitophagy, a mitochondrial quality control pathway that involves the ubiquitin-proteasome system (UPS) and the autophagy-lysosomal system [1, 2]. A series of recent papers indicates that PINK1 initiates mitophagy by a two-pronged mechanism involving direct phosphorylation of ubiquitin at serine 65 [3,4,5] and the ubiquitin-like domain (UbL) of Parkin, at serine 65 [6,7,8] (Fig. 1A, steps 1–2).
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