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PINK 1 regulates mitochondrial trafficking in dendrites of cortical neurons through mitochondrial PKA
Author(s) -
Das Banerjee Tania,
Dagda Raul Y.,
Dagda Marisela,
Chu Charleen T.,
Rice Monica,
VazquezMayorga Emmanuel,
Dagda Ruben K.
Publication year - 2017
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.14083
Subject(s) - pink1 , mitochondrion , microbiology and biotechnology , protein kinase a , dendrite (mathematics) , biology , mitochondrial apoptosis induced channel , kinase , neuroprotection , mitochondrial fission , phosphorylation , scaffold protein , inner mitochondrial membrane , mitophagy , chemistry , biochemistry , signal transduction , neuroscience , apoptosis , geometry , mathematics , autophagy
Abstract Mitochondrial Protein Kinase A ( PKA ) and PTEN ‐induced kinase 1 ( PINK 1), 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 PINK 1 regulates dendrite morphology by enhancing PKA activity. Here, we show the molecular mechanisms by which PINK 1 and PKA in the mitochondrion interact to regulate dendrite remodeling, mitochondrial morphology, content, and trafficking in dendrites. PINK 1‐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‐ AKAP 1), restores mitochondrial trafficking, morphology, and content in dendrites of PINK 1‐deficient cortical neurons suggesting that recruiting PKA to the mitochondrion reverses mitochondrial pathology in dendrites induced by loss of PINK 1. Mechanistically, full‐length and cleaved forms of PINK 1 increase the binding of the regulatory subunit β of PKA ( PKA / RII β) to D‐ AKAP 1 to enhance the autocatalytic‐mediated phosphorylation of PKA / RII β and PKA activity. D‐ AKAP 1/ PKA governs mitochondrial trafficking in dendrites via the Miro‐2/ TRAK 2 complex and by increasing the phosphorylation of Miro‐2. Our study identifies a new role of D‐ AKAP 1 in regulating mitochondrial trafficking through Miro‐2, and supports a model in which PINK 1 and mitochondrial PKA participate in a similar neuroprotective signaling pathway to maintain dendrite connectivity.