Das Banerjee Tania, Dagda Raul Y, Dagda Marisela, Chu Charleen T, Rice Monica, Vazquez-Mayorga Emmanuel, Dagda Ruben K
Department of Pharmacology, University of Nevada, Reno School of Medicine, Reno, Nevada, USA.
Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
J Neurochem. 2017 Aug;142(4):545-559. doi: 10.1111/jnc.14083. Epub 2017 Jun 23.
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.
线粒体蛋白激酶A（PKA）和与帕金森病相关的PTEN诱导激酶1（PINK1）是两种神经保护型丝氨酸/苏氨酸激酶，它们调节树突重塑和线粒体功能。我们之前已经表明，PINK1通过增强PKA活性来调节树突形态。在这里，我们展示了线粒体中的PINK1和PKA相互作用以调节树突重塑、线粒体形态、含量以及树突中线粒体运输的分子机制。与野生型神经元相比，PINK1缺陷的皮质神经元表现出线粒体运输受损、线粒体含量减少、线粒体碎片化以及树突生长减少。野生型而非PKA线粒体支架双特异性A激酶锚定蛋白1（D-AKAP1）的PKA结合缺陷突变体的瞬时表达，恢复了PINK1缺陷皮质神经元树突中的线粒体运输、形态和含量，这表明将PKA募集到线粒体可逆转因PINK1缺失而诱导的树突中线粒体病变。从机制上讲，全长和裂解形式的PINK1增加了PKA调节亚基β（PKA/RIIβ）与D-AKAP1的结合，以增强PKA/RIIβ的自催化介导的磷酸化和PKA活性。D-AKAP1/PKA通过Miro-2/TRAK2复合物并通过增加Miro-2的磷酸化来控制树突中的线粒体运输。我们的研究确定了D-AKAP1在通过Miro-2调节线粒体运输中的新作用，并支持了一种模型，即PINK1和线粒体PKA参与类似的神经保护信号通路以维持树突连接性。
