期刊
CURRENT BIOLOGY
卷 24, 期 16, 页码 1854-1865出版社
CELL PRESS
DOI: 10.1016/j.cub.2014.07.014
关键词
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资金
- Butcher Award from the University of Colorado
- Cancer League of Colorado
- NIH [CA107098]
- NCRR grant from the NIH [S10 RR026680]
- U.S. Army Research Office
Background: 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 mitochondria! damage. How this pathway senses different levels of mitochondrial damage and mediates cell fate decisions accordingly is incompletely understood. Results: 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. Conclusions: 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.
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