Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 107, Issue 1, Pages 378-383Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0911187107
Keywords
autophagy; Parkinson's disease; phosphatase and tensin homolog-induced putative kinase 1
Categories
Funding
- National Institutes of Health [AG021617, ES014899, ES017470, NS042269, NS054773, NS062180, NS064191, NS38370, NS38377, NS48206]
- US Department of Defense [W81XWH-08-1-0522, W81XWH-08-1-0465, DAMD 17-03-1]
- Parkinson Disease Foundation
- Thomas Hartman Foundation for Parkinson's Research
- Muscular Dystrophy Association's Wings-over-Wall Street
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Phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1) and PARK2/Parkin mutations cause autosomal recessive forms of Parkinson's disease. Upon a loss of mitochondrial membrane potential (Delta psi(m)) in human cells, cytosolic Parkin has been reported to be recruited to mitochondria, which is followed by a stimulation of mitochondrial autophagy. Here, we show that the relocation of Parkin to mitochondria induced by a collapse of Delta psi(m) relies on PINK1 expression and that overexpression of WT but not of mutated PINK1 causes Parkin translocation to mitochondria, even in cells with normal Delta psi(m). We also show that once at the mitochondria, Parkin is in close proximity to PINK1, but we find no evidence that Parkin catalyzes PINK1 ubiquitination or that PINK1 phosphorylates Parkin. However, co-overexpression of Parkin and PINK1 collapses the normal tubular mitochondrial network into mitochondrial aggregates and/or large perinuclear clusters, many of which are surrounded by autophagic vacuoles. Our results suggest that Parkin, together with PINK1, modulates mitochondrial trafficking, especially to the perinuclear region, a subcellular area associated with autophagy. Thus by impairing this process, mutations in either Parkin or PINK1 may alter mitochondrial turnover which, in turn, may cause the accumulation of defective mitochondria and, ultimately, neurodegeneration in Parkinson's disease.
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