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The PINK‐Parkin Circuit in Mitochondrial Quality Control
Author(s) -
Liu Xuedong,
Zhang Conggang,
Peng Yinghua,
Bunker Eric,
Lee Schuyler
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.595.7
Subject(s) - parkin , pink1 , mitophagy , ubiquitin ligase , microbiology and biotechnology , mitochondrion , ubiquitin , biology , chemistry , apoptosis , biochemistry , autophagy , medicine , disease , pathology , parkinson's disease , gene
Mutations in E3 ubiquitin ligase Parkin and Ser/Thr protein kinase Pink1 cause autosomally inherited parkinsonism. Genetic studies have shown that Pink1 and Parkin act in the same pathway that regulates mitochondria dynamics, motility, and quality control. Activation of this pathway can be triggered by a variety of cellular stressor signals that cause mitochondrial damage. Here, we present evidence that PINK1‐Parkin has both cytoprotective and pro‐apoptotic 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 which amplifies its E3 ligase activity towards Mcl‐1. Autocatalytic activation of Parkin bolsters it 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. We developed an analog sensitive PINK1 allele and demonstrated that PINK1 is required for triggering Parkin translocation to mitochondria, but is dispensable for sustaining Parkin accumulation and consequent mitophagy. Support or Funding Information This work was supported by grants from a Butcher Award from the University of Colorado and National Institutes of Health CA107098 and GM113141 to Xuedong Liu. The ImageXpress MicroXL was supported by a NCRR grant S10 RR026680 from NIH.