TY - JOUR
T1 - PINK1-dependent recruitment of Parkin to mitochondria in mitophagy
AU - Vives-Bauza, Cristofol
AU - Zhou, Chun
AU - Huang, Yong
AU - Cui, Mei
AU - De Vries, Rosa L.A.
AU - Kim, Jiho
AU - May, Jessica
AU - Tocilescu, Maja Aleksandra
AU - Liu, Wencheng
AU - Ko, Han Seok
AU - Magrané, Jordi
AU - Moore, Darren J.
AU - Dawson, Valina L.
AU - Grailhe, Regis
AU - Dawson, Ted M.
AU - Li, Chenjian
AU - Tieu, Kim
AU - Przedborski, Serge
PY - 2010
Y1 - 2010
N2 - 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 (Δψm) 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 Δψm relies on PINK1 expression and that overexpression of WT but not of mutated PINK1 causes Parkin translocation to mitochondria, even in cells with normal Δψm. 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.
AB - 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 (Δψm) 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 Δψm relies on PINK1 expression and that overexpression of WT but not of mutated PINK1 causes Parkin translocation to mitochondria, even in cells with normal Δψm. 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.
KW - Autophagy
KW - Parkinson's disease
KW - Phosphatase and tensin homolog-induced putative kinase 1
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U2 - 10.1073/pnas.0911187107
DO - 10.1073/pnas.0911187107
M3 - Article
C2 - 19966284
AN - SCOPUS:75949098487
SN - 0027-8424
VL - 107
SP - 378
EP - 383
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 1
ER -