title: Beyond the mitochondrion: cytosolic PINK1 remodels dendrites through protein kinase A.
abstract: 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.
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA; Department of Pharmacology, University of Nevada School of Medicine, Reno, Nevada, USA.
authors.forename: Ruben K
authors.initials: RK
authors.lastname: Dagda
authors.forename: Irene
authors.initials: I
authors.lastname: Pien
authors.forename: Ruth
authors.initials: R
authors.lastname: Wang
authors.forename: Jianhui
authors.initials: J
authors.lastname: Zhu
authors.forename: Kent Z Q
authors.initials: KZ
authors.lastname: Wang
authors.forename: Jason
authors.initials: J
authors.lastname: Callio
authors.forename: Tania Das
authors.initials: TD
authors.lastname: Banerjee
authors.forename: Raul Y
authors.initials: RY
authors.lastname: Dagda
authors.forename: Charleen T
authors.initials: CT
authors.lastname: Chu
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002540:Cerebral Cortex / Q000166:cytology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D003712:Dendrites / Q000502:physiology*; D005260:Female; D006801:Humans; D008297:Male; D008636:Mesencephalon / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D009447:Neuroblastoma; D010300:Parkinson Disease / Q000378:metabolism; D011247:Pregnancy; D061251:Primary Cell Culture; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D000099202:PTEN-Induced Putative Kinase
chemical_list: D017868:Cyclic AMP-Dependent Protein Kinases; D011494:Protein Kinases; D000099202:PTEN-Induced Putative Kinase
keywords: PINK1; PKA; Parkinson's disease; dendrite; differentiation; mitochondria