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Curr Biol. 2014 Aug 18;24(16):1854-65. doi: 10.1016/j.cub.2014.07.014. Epub 2014 Jul 31.

PINK1 triggers autocatalytic activation of Parkin to specify cell fate decisions.

Author information

1
Department of Chemistry and Biochemistry, 3415 Colorado Avenue, Jennie Smoly Caruthers Biotechnology Building, University of Colorado Boulder, Boulder, CO 80303, USA.
2
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.
3
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.

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.

PMID:
25088558
PMCID:
PMC4143385
DOI:
10.1016/j.cub.2014.07.014
[Indexed for MEDLINE]
Free PMC Article

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