title: PINK1 triggers autocatalytic activation of Parkin to specify cell fate decisions.
abstract: 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 mitochondrial 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.
authors.affiliation: Department of Chemistry and Biochemistry, 3415 Colorado Avenue, Jennie Smoly Caruthers Biotechnology Building, University of Colorado Boulder, Boulder, CO 80303, USA.
authors.forename: Conggang
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Chemistry and Biochemistry, 3415 Colorado Avenue, Jennie Smoly Caruthers Biotechnology Building, University of Colorado Boulder, Boulder, CO 80303, USA.
authors.forename: Schuyler
authors.initials: S
authors.lastname: Lee
authors.affiliation: Department of Chemistry and Biochemistry, 3415 Colorado Avenue, Jennie Smoly Caruthers Biotechnology Building, University of Colorado Boulder, Boulder, CO 80303, USA.
authors.forename: Yinghua
authors.initials: Y
authors.lastname: Peng
authors.affiliation: Department of Chemistry and Biochemistry, 3415 Colorado Avenue, Jennie Smoly Caruthers Biotechnology Building, University of Colorado Boulder, Boulder, CO 80303, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Bunker
authors.affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital, Program in Neuroscience, Harvard Medical School, New Research Building, Room 636E, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Emilie
authors.initials: E
authors.lastname: Giaime
authors.affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital, Program in Neuroscience, Harvard Medical School, New Research Building, Room 636E, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Shen
authors.affiliation: Department of Chemistry and Biochemistry, 3415 Colorado Avenue, Jennie Smoly Caruthers Biotechnology Building, University of Colorado Boulder, Boulder, CO 80303, USA.
authors.forename: Zongyao
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Department of Chemistry and Biochemistry, 3415 Colorado Avenue, Jennie Smoly Caruthers Biotechnology Building, University of Colorado Boulder, Boulder, CO 80303, USA. Electronic address: xuedong.liu@colorado.edu.
authors.forename: Xuedong
authors.initials: X
authors.lastname: Liu
mesh_terms: D000595:Amino Acid Sequence; D017209:Apoptosis; D002460:Cell Line; D019610:Cytoprotection; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D010766:Phosphorylation; D011494:Protein Kinases / Q000235:genetics* / Q000378:metabolism*; D016415:Sequence Alignment; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism*; D054875:Ubiquitination; D000099202:PTEN-Induced Putative Kinase
chemical_list: D011494:Protein Kinases; D044767:Ubiquitin-Protein Ligases; D000099202:PTEN-Induced Putative Kinase; C111567:parkin protein
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