PINK1 regulates mitochondrial trafficking in dendrites of cortical neurons through mitochondrial PKA
| Autor: | Charleen T. Chu, Raul Y. Dagda, Tania Das Banerjee, Emmanuel Vázquez-Mayorga, Monica Rice, Marisela Dagda, Ruben K. Dagda |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
A-kinase-anchoring protein Ubiquitin-Protein Ligases PINK1 Dendrite Mitochondrion Biology Biochemistry Article Cell Line Mitochondrial Proteins 03 medical and health sciences Cellular and Molecular Neuroscience medicine Animals Protein kinase A Neurons Kinase Parkinson Disease Dendrites Cyclic AMP-Dependent Protein Kinases Mitochondria Cell biology Mice Inbred C57BL Protein Transport 030104 developmental biology medicine.anatomical_structure COS Cells Phosphorylation Female Signal transduction Protein Kinases |
| Zdroj: | Journal of Neurochemistry. 142:545-559 |
| ISSN: | 0022-3042 |
| DOI: | 10.1111/jnc.14083 |
| Popis: | Mitochondrial Protein Kinase A (PKA) and PTEN-induced kinase 1 (PINK1), which is linked to Parkinson's disease, are two neuroprotective serine/threonine kinases that regulate dendrite remodeling, and mitochondrial function. We have previously shown that PINK1 regulates dendrite morphology by enhancing PKA activity. Here, we show the molecular mechanisms by which PINK1 and PKA in the mitochondrion interact to regulate dendrite remodeling, mitochondrial morphology, content, and trafficking in dendrites. PINK1-deficient cortical neurons exhibit impaired mitochondrial trafficking, reduced mitochondrial content, fragmented mitochondria, and a reduction in dendrite outgrowth compared to wild-type neurons. Transient expression of wild-type, but not a PKA-binding deficient mutant of the PKA-mitochondrial scaffold dual-specificity A Kinase Anchoring Protein 1 (D-AKAP1), restores mitochondrial trafficking, morphology, and content in dendrites of PINK1-deficient cortical neurons suggesting that recruiting PKA to the mitochondrion reverses mitochondrial pathology in dendrites induced by loss of PINK1. Mechanistically, full-length and cleaved forms of PINK1 increase the binding of the regulatory subunit β of PKA (PKA/RIIβ) to D-AKAP1 to enhance the autocatalytic-mediated phosphorylation of PKA/RIIβ and PKA activity. D-AKAP1/PKA governs mitochondrial trafficking in dendrites via the Miro-2/TRAK2 complex and by increasing the phosphorylation of Miro-2. Our study identifies a new role of D-AKAP1 in regulating mitochondrial trafficking through Miro-2, and supports a model in which PINK1 and mitochondrial PKA participate in a similar neuroprotective signaling pathway to maintain dendrite connectivity. This article is protected by copyright. All rights reserved. |
| Databáze: | OpenAIRE |
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