A pivotal role for PINK1 and autophagy in mitochondrial quality control: implications for Parkinson disease.
The PTEN-induced putative kinase 1 (PINK1) is a mitochondrially targeted serine-threonine kinase, which is linked to autosomal recessive familial parkinsonism. Current literature implicates PINK1 as a pivotal regulator of mitochondrial quality control, promoting maintenance of respiring mitochondrial networks through cristae stabilization, phosphorylation of chaperones and possibly regulation of mitochondrial transport or autophagy. Pulse-chase studies indicate that PINK1 is rapidly processed into at least two shorter forms, which are distributed in both mitochondrial and cytosolic compartments. Through indirect regulation of mitochondrial proteases and Drp1, PINK1 may act to facilitate localized repair and fusion in response to minor mitochondrial stress. With severe mitochondrial damage, PINK1 facilitates aggregation and clearance of depolarized mitochondria through interactions with Parkin and possibly Beclin1. This switch in function most probably involves altered processing, post-translational modification and/or localization of PINK1, as overexpression of full-length PINK1 is required for mitochondrial Parkin recruitment. Under conditions of PINK1 deficiency, dysregulation of reactive oxygen species, electron transport chain function and calcium homeostasis trigger altered mitochondrial dynamics, indicating compromise of mitochondrial quality control mechanisms. Nevertheless, Parkin- and Beclin1-regulated mitochondrial autophagy remains effective at recycling PINK1-deficient mitochondria; failure of this final tier of mitochondrial quality control contributes to cell death. Thus, PINK1 plays a pivotal, multifactorial role in mitochondrial homeostasis. As autophagic recycling represents the final tier of mitochondrial quality control, whether PINK1 levels are enhanced or reduced, strategies to promote selective mitophagy and mitochondrial biogenesis may prove effective for multiple forms of Parkinson's disease.
Chu
Charleen T
CT
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. ctc4@pitt.edu
D001343:Autophagy; D006801:Humans; D008928:Mitochondria / Q000502:physiology*; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D011494:Protein Kinases / Q000235:genetics / Q000502:physiology*; D011499:Protein Processing, Post-Translational; D017382:Reactive Oxygen Species / Q000378:metabolism; D000099202:PTEN-Induced Putative Kinase
D011494:Protein Kinases; D017382:Reactive Oxygen Species; D000099202:PTEN-Induced Putative Kinase
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