PINK1 Triggers Autocatalytic Activation of Parkin to Specify Cell Fate Decisions

• Published in: Current biology Vol. 24; no. 16; pp. 1854 - 1865
• Main Authors: Zhang, Conggang, Lee, Schuyler, Peng, Yinghua, Bunker, Eric, Giaime, Emilie, Shen, Jie, Zhou, Zongyao, Liu, Xuedong
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 18.08.2014
• Subjects: Amino Acid Sequence; Apoptosis; Cell Line; Cytoprotection; HEK293 Cells; HeLa Cells; Humans; Phosphorylation; Protein Kinases - genetics; Protein Kinases - metabolism; Sequence Alignment; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Ubiquitination
• DOI: 10.1016/j.cub.2014.07.014
• ISSN: 0960-9822; 1879-0445

The PINK1-Parkin pathway is known to play important roles in regulating mitochondria dynamics, motility, and quality control. Activation of this pathway can be triggered by a variety of cellular stress signals that cause mitochondrial damage. How this pathway senses different levels of mitochondrial damage and mediates cell fate decisions accordingly is incompletely understood. Here, we present evidence that PINK1-Parkin has both cytoprotective and proapoptotic functions. PINK1-Parkin operates as a molecular switch to dictate cell fate decisions in response to different cellular stressors. Cells exposed to severe and irreparable mitochondrial damage agents such as valinomycin can undergo PINK1-Parkin-dependent apoptosis. The proapoptotic response elicited by valinomycin is associated with the degradation of Mcl-1. PINK1 directly phosphorylates Parkin at Ser65 of its Ubl domain and triggers activation of its E3 ligase activity through an autocatalytic mechanism that amplifies its E3 ligase activity toward Mcl-1. Autocatalytic activation of Parkin bolsters its accumulation on mitochondria and apoptotic response to valinomycin. Our results suggest that PINK1-Parkin constitutes a damage-gated molecular switch that governs cellular-context-specific cell fate decisions in response to variable stress stimuli. [Display omitted] •PINK1-Parkin operates as a damage-gated molecular switch for cell fate decisions•Parkin catalyzes ubiquitination of selective substrates in response to specific stimuli•Parkin is the E3 ligase for Mcl-1 and mediates valinomycin-induced apoptosis•PINK1 triggers autocatalytic activation of Parkin by phosphorylating Ser65 of Parkin Zhang et al. show that the PINK1-Parkin pathway can mediate different cell fates in response to different cell stress stimuli. Exposure to mitochondrial damage reveals a proapoptotic function of PINK1 and Parkin. PINK1 directly phosphorylates Parkin, triggering its autocatalytic activation and amplifying its E3 ligase activity toward Mcl-1.