title: PINK1-dependent recruitment of Parkin to mitochondria in mitophagy.
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.
authors: Department of Neurology, Columbia University, New York, NY 10032, USA.
authors: Cristofol
authors: C
authors: Vives-Bauza
authors: Chun
authors: C
authors: Zhou
authors: Yong
authors: Y
authors: Huang
authors: Mei
authors: M
authors: Cui
authors: Rosa L A
authors: RL
authors: de Vries
authors: Jiho
authors: J
authors: Kim
authors: Jessica
authors: J
authors: May
authors: Maja Aleksandra
authors: MA
authors: Tocilescu
authors: Wencheng
authors: W
authors: Liu
authors: Han Seok
authors: HS
authors: Ko
authors: Jordi
authors: J
authors: Magrané
authors: Darren J
authors: DJ
authors: Moore
authors: Valina L
authors: VL
authors: Dawson
authors: Regis
authors: R
authors: Grailhe
authors: Ted M
authors: TM
authors: Dawson
authors: Chenjian
authors: C
authors: Li
authors: Kim
authors: K
authors: Tieu
authors: Serge
authors: S
authors: Przedborski
mesh_terms: D001343:Autophagy / Q000502:physiology*; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000378:metabolism; D002460:Cell Line; D006801:Humans; D007476:Ionophores / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000502:physiology*; D008870:Microtubules / Q000378:metabolism / Q000648:ultrastructure; D008928:Mitochondria / Q000378:metabolism* / Q000648:ultrastructure; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D000099202:PTEN-Induced Putative Kinase
chemical_list: D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D007476:Ionophores; D011494:Protein Kinases; D044767:Ubiquitin-Protein Ligases; D000099202:PTEN-Induced Putative Kinase; C111567:parkin protein