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) 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. Overexpression 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 PKA-related signaling pathways. Our data supports a novel role for PINK1 in regulating dendritic morphogenesis.

Beyond Mitophagy: Cytosolic PINK1 as a Messenger of Mitochondrial Health

“…3). A significant fraction of processed PINK1 is also found in the cytoplasm (7,24,26,30,43,66,77,98,112). A recent study using a cell-free import system may help unify these observations (6).…”

“…Interestingly, Vitamin K 2 is able to reverse ATP deficiencies in PINK1 null flies by acting as an electron carrier downstream of complex I (109). PINK1 may also regulate mitochondrial biology through activation of protein kinase A (PKA) (26). PKA regulates the biosynthesis of mtDNA encoded proteins, and enhances complex I activity through direct phosphorylation of the NDUFS4 subunit (85).…”

“…However, a number of recent studies also implicate PINK1 in the regulation of mitochondrial function, particularly in relation to complex I or IV activity (37,71,80). Moreover, cytosolic pools of PINK1 trigger pro-survival and trophic signaling pathways (26,83), suppressing autophagy and mitophagy (24,30) to promote dendritic extension (26). This review focuses on these emerging functions of PINK1.…”

Mitochondrial O-GlcNAc Transferase (mOGT) Regulates Mitochondrial Structure, Function, and Survival in HeLa Cells

“…We analyzed mitochondrial morphology and mitochondrial content in cells transfected with the validated mOGT siRNAs 1 and 2 ( Fig. 1) by using well characterized parameters of mitochondrial morphology (28,29) as described under "Experimental Procedures." In control cells transfected with NT siRNA, mitochondria predominantly showed a tubular and elongated morphology, some of which colocalized with OGT ( Fig.…”

Cytosolic PTEN-induced Putative Kinase 1 Is Stabilized by the NF-κB Pathway and Promotes Non-selective Mitophagy

“…Supporting this, accumulation of PINK1-53 has been reported in the brains of both idiopathic and PINK1-related Parkinson disease patients (13,14). Moreover, recent studies have also implicated several functional roles for PINK1-53 (including being a neuroprotectant and a promoter of neurite outgrowth as well as an inhibitor of mitophagy) (15)(16)(17), although none of these studies describe how this labile species of PINK1 may attain an adequate expression level in the first place to fulfil the suggested roles.…”