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Beyond the mitochondrion: cytosolic PINK 1 remodels dendrites through Protein Kinase A
Author(s) -
Dagda Ruben K.,
Pien Irene,
Wang Ruth,
Zhu Jianhui,
Wang Kent Z. Q.,
Callio Jason,
Banerjee Tania Das,
Dagda Raul Y.,
Chu Charleen T.
Publication year - 2014
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.12494
Subject(s) - microbiology and biotechnology , cytosol , neurite , biology , pink1 , mitochondrion , kinase , apoptosis , autophagy , biochemistry , mitophagy , in vitro , enzyme
The subcellular compartmentalization of kinase activity allows for regulation of distinct cellular processes involved in cell differentiation or survival. The PTEN ‐induced kinase 1 ( PINK 1), which is linked to Parkinson's disease, is a neuroprotective kinase localized to cytosolic and mitochondrial compartments. While mitochondrial targeting of PINK 1 is important for its activities regulating mitochondrial homeostasis, the physiological role of the cytosolic pool of PINK 1 remains unknown. Here, we demonstrate a novel role for cytosolic PINK 1 in neuronal differentiation/neurite maintenance. Over‐expression of wild‐type PINK 1, but not a catalytically inactive form of PINK 1(K219M), promoted neurite outgrowth in SH ‐ SY 5Y cells and increased dendritic lengths in primary cortical and midbrain dopaminergic neurons. To identify the subcellular pools of PINK 1 involved in promoting neurite outgrowth, we transiently transfected cells with PINK 1 constructs designed to target PINK 1 to the outer mitochondrial membrane (OMM‐PINK1) or restrict PINK 1 to the cytosol (ΔN111‐ PINK 1). Both constructs blocked cell death associated with loss of endogenous PINK 1. However, transient expression of ΔN111‐ PINK 1, but not of OMM‐ PINK 1 or ΔN111‐ PINK 1(K219M), promoted dendrite outgrowth in primary neurons, and rescued the decreased dendritic arborization of PINK 1‐deficient neurons. Mechanistically, the cytosolic pool of PINK 1 regulated neurite morphology through enhanced anterograde transport of dendritic mitochondria and amplification of protein kinase A‐related signaling pathways. Our data support a novel role for PINK 1 in regulating dendritic morphogenesis.Mutations in PINK1 cause recessive Parkinson's disease, but the neuronal function(s) of the PINK1 protein remain elusive. We found that cytosolic PINK1 promotes neuronal differentiation in naïve cells, reversing dendritic shortening and cell death in Pink1 −/− neurons, by increasing PKA activity and mitochondrial transport to dendrites. Release of processed PINK1 from healthy mitochondria may serve as a pro‐differentiation signal in cortical and dopaminergic neurons.