PINK1-dependent recruitment of Parkin to mitochondria in mitophagy.
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.
Vives-Bauza
Cristofol
C
Department of Neurology, Columbia University, New York, NY 10032, USA.
Zhou
Chun
C
Huang
Yong
Y
Cui
Mei
M
de Vries
Rosa L A
RL
Kim
Jiho
J
May
Jessica
J
Tocilescu
Maja Aleksandra
MA
Liu
Wencheng
W
Ko
Han Seok
HS
Magrané
Jordi
J
Moore
Darren J
DJ
Dawson
Valina L
VL
Grailhe
Regis
R
Dawson
Ted M
TM
Li
Chenjian
C
Tieu
Kim
K
Przedborski
Serge
S
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
D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D007476:Ionophores; D011494:Protein Kinases; D044767:Ubiquitin-Protein Ligases; D000099202:PTEN-Induced Putative Kinase; C111567:parkin protein