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The function of PINK1 and parkin in mitochondrial quality control (234.2)
Author(s) -
Fon Edward
Publication year - 2014
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.28.1_supplement.234.2
Subject(s) - pink1 , parkin , mitophagy , mitochondrion , microbiology and biotechnology , ubiquitin ligase , biology , autophagy , cytosol , ubiquitin , biochemistry , parkinson's disease , medicine , enzyme , disease , gene , apoptosis
Parkinson’s disease (PD) is a common, devastating neurodegenerative disorder. Both genetic and environmental models strongly implicate mitochondrial dysfunction in PD. In particular, PINK1 and Parkin, two recessive PD genes, function in a common pathway regulating mitochondrial quality‐control. In healthy mitochondria, PINK1, a mitochondrial kinase, is rapidly degraded in a process involving both mitochondrial proteases and the cytosolic proteasome. This process is highly dependent upon the membrane potential across the mitochondrial inner membrane (ΔΨm), which drives PINK1 import into mitochondria. Indeed, mitochondrial damage that dissipates ΔΨm blocks PINK1 import and leads to its accumulation on the surface of mitochondria. PINK1 accumulation triggers the translocation of parkin, an E3 ubiquitin ligase, from the cytosol to mitochondria, where it mediates the elimination of dysfunctional mitochondria by autophagy (mitophagy). From these studies, a concept of PD pathogenesis is emerging whereby defects in PINK1 or parkin function reduce the efficiency with which damaged mitochondria, a major source of toxic reactive oxygen species, are eliminated. We will present recent work, based on the crystal structure of parkin and on genetic screens to identify regulators of parkin function, exploring how parkin is activated upon its recruitment to damaged mitochondria.