Deciphering the Molecular Signals of PINK1/Parkin Mitophagy. Issue 10 (October 2016)

• Record Type: Journal Article
• Authors: Nguyen, Thanh N.; Padman, Benjamin S.; Lazarou, Michael
• Is Part Of: Trends in cell biology. Volume 26:Issue 10(2016)
• Page Start: 733
• Page End: 744
• Publication Date: 2016-10
• Subjects: PINK1 -- Parkin -- mitophagy -- ubiquitin -- autophagy -- Parkinson's disease; Cytology -- Periodicals; Cytology -- Research -- Periodicals; 571.6
• DOI: 10.1016/j.tcb.2016.05.008
• Languages: English
• ISSNs: 0962-8924

Abstract

Abstract : Functional mitochondria are critically important for the maintenance of cellular integrity and survival. Mitochondrial dysfunction is a major contributor to neurodegenerative diseases including Parkinson's disease (PD). Two gene products mutated in familial Parkinsonism, PINK1 and Parkin, function together to degrade damaged mitochondria through a selective form of autophagy termed mitophagy. PINK1 accumulates on the surface of dysfunctional mitochondria where it simultaneously recruits and activates Parkin's E3 ubiquitin ligase activity. This forms the basis of multiple signaling events that culminate in engulfment of damaged mitochondria within autophagosomes and degradation by lysosomes. This review discusses the molecular signals of PINK1/Parkin mitophagy and the ubiquitin code that drives not only Parkin recruitment and activation by PINK1 but also the downstream signaling events of mitophagy. Trends: PINK1 phosphorylates ubiquitin at S65 to recruit and activate Parkin to damaged mitochondria. Structural and biochemical studies have revealed that S65 phosphorylated ubiquitin activates Parkin by driving conformational changes that release Parkin from its autoinhibited state and activate its ubiquitin ligase activity. NDP52 and Optineurin are the primary mitophagy receptors and function by promoting ULK1 recruitment to initiate autophagosome formation around mitochondria. pS65-Ub is the primary mitophagy signal and engages the autophagy machinery by preferentially recruiting Optineurin and NDP52.