Read the Editorial Highlight for this article on doi: 10.1111/jnc.12529
Beyond the mitochondrion: cytosolic PINK1 remodels dendrites through Protein Kinase A
Article first published online: 13 NOV 2013
© 2013 International Society for Neurochemistry
Journal of Neurochemistry
Volume 128, Issue 6, pages 864–877, March 2014
How to Cite
J. Neurochem. (2014) 128, 864–877.
- Issue published online: 7 MAR 2014
- Article first published online: 13 NOV 2013
- Accepted manuscript online: 23 OCT 2013 12:35PM EST
- Manuscript Accepted: 4 OCT 2013
- Manuscript Revised: 1 OCT 2013
- Manuscript Received: 10 AUG 2013
- National Institutes of Health. Grant Numbers: R01 NS065789, F32 AG030821, GM103554
- Parkinson's disease;
The subcellular compartmentalization of kinase activity allows for regulation of distinct cellular processes involved in cell differentiation or survival. The PTEN-induced kinase 1 (PINK1), which is linked to Parkinson's disease, is a neuroprotective kinase localized to cytosolic and mitochondrial compartments. While mitochondrial targeting of PINK1 is important for its activities regulating mitochondrial homeostasis, the physiological role of the cytosolic pool of PINK1 remains unknown. Here, we demonstrate a novel role for cytosolic PINK1 in neuronal differentiation/neurite maintenance. Over-expression of wild-type PINK1, but not a catalytically inactive form of PINK1(K219M), promoted neurite outgrowth in SH-SY5Y cells and increased dendritic lengths in primary cortical and midbrain dopaminergic neurons. To identify the subcellular pools of PINK1 involved in promoting neurite outgrowth, we transiently transfected cells with PINK1 constructs designed to target PINK1 to the outer mitochondrial membrane (OMM-PINK1) or restrict PINK1 to the cytosol (ΔN111-PINK1). Both constructs blocked cell death associated with loss of endogenous PINK1. However, transient expression of ΔN111-PINK1, but not of OMM-PINK1 or ΔN111-PINK1(K219M), promoted dendrite outgrowth in primary neurons, and rescued the decreased dendritic arborization of PINK1-deficient neurons. Mechanistically, the cytosolic pool of PINK1 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 PINK1 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.