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PINK1-dependent recruitment of Parkin to mitochondria in mitophagy.

TitlePINK1-dependent recruitment of Parkin to mitochondria in mitophagy.
Publication TypeJournal Article
Year of Publication2010
AuthorsVives-Bauza C, Zhou C, Huang Y, Cui M, de Vries RLA, Kim J, May J, Tocilescu MAleksandra, Liu W, Ko HSeok, Magrané J, Moore DJ, Dawson VL, Grailhe R, Dawson TM, Li C, Tieu K, Przedborski S
JournalProc Natl Acad Sci U S A
Volume107
Issue1
Pagination378-83
Date Published2010 Jan 5
ISSN1091-6490
KeywordsAutophagy, Carbonyl Cyanide m-Chlorophenyl Hydrazone, Cell Line, Humans, Ionophores, Membrane Potential, Mitochondrial, Microtubules, Mitochondria, Parkinson Disease, Protein Binding, Protein Kinases, Protein Transport, Ubiquitin-Protein Ligases
Abstract

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 (DeltaPsi(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 DeltaPsi(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 DeltaPsi(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.

DOI10.1073/pnas.0911187107
Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID19966284
PubMed Central IDPMC2806779
Grant ListAG021617 / AG / NIA NIH HHS / United States
ES014899 / ES / NIEHS NIH HHS / United States
ES017470 / ES / NIEHS NIH HHS / United States
NS042269 / NS / NINDS NIH HHS / United States
NS054773 / NS / NINDS NIH HHS / United States
NS062180 / NS / NINDS NIH HHS / United States
NS064191 / NS / NINDS NIH HHS / United States
NS38370 / NS / NINDS NIH HHS / United States
NS38377 / NS / NINDS NIH HHS / United States
NS48206 / NS / NINDS NIH HHS / United States
R01 ES014899-04 / ES / NIEHS NIH HHS / United States
R21 ES017470-01 / ES / NIEHS NIH HHS / United States