title: PKA/AKAP1 and PP2A/Bβ2 regulate neuronal morphogenesis via Drp1 phosphorylation and mitochondrial bioenergetics.
abstract: Mitochondrial shape is determined by fission and fusion reactions, perturbation of which can contribute to neuronal injury and disease. Mitochondrial fission is catalyzed by dynamin-related protein 1 (Drp1), a large GTPase of the dynamin family that is highly expressed in neurons and regulated by various posttranslational modifications, including phosphorylation. We report here that reversible phosphorylation of Drp1 at a conserved Ser residue by an outer mitochondrial kinase (PKA/AKAP1) and phosphatase (PP2A/Bβ2) impacts dendrite and synapse development in cultured rat hippocampal neurons. PKA/AKAP1-mediated phosphorylation of Drp1 at Ser656 increased mitochondrial length and dendrite occupancy, enhancing dendritic outgrowth but paradoxically decreasing synapse number and density. Opposing PKA/AKAP1, PP2A/Bβ2-mediated dephosphorylation of Drp1 at Ser656 fragmented and depolarized mitochondria and depleted them from dendrites, stunting dendritic outgrowth but augmenting synapse formation. Raising and lowering intracellular calcium reproduced the effects of dephospho-Drp1 and phospho-Drp1on dendrite and synapse development, respectively, while boosting mitochondrial membrane potential with l-carnitine-fostered dendrite at the expense of synapse formation without altering mitochondrial size or distribution. Thus, outer mitochondrial PKA and PP2A regulate neuronal development by inhibiting and promoting mitochondrial division, respectively. We propose that the bioenergetic state of mitochondria, rather than their localization or shape per se, is the key effector of Drp1, altering calcium homeostasis to modulate neuronal morphology and connectivity.
authors: Department of Pharmacology and Neuroscience Graduate Program, University of Iowa, Iowa City, Iowa 52242, USA.
authors: Audrey S
authors: AS
authors: Dickey
authors: Stefan
authors: S
authors: Strack
mesh_terms: D054758:A Kinase Anchor Proteins / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D002331:Carnitine / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003712:Dendrites / Q000502:physiology; D034281:Dynamins / Q000378:metabolism*; D004622:Embryo, Mammalian; D004734:Energy Metabolism / Q000502:physiology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000502:physiology; D026901:Membrane Transport Proteins; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000378:metabolism*; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D024101:Mitochondrial Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000502:physiology* / Q000648:ultrastructure*; D009924:Organ Culture Techniques; D010766:Phosphorylation / Q000502:physiology; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013569:Synapses / Q000502:physiology; D013779:Tetrodotoxin / Q000494:pharmacology; D013997:Time Factors; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D033921:Vesicular Transport Proteins / Q000378:metabolism
chemical_list: D054758:A Kinase Anchor Proteins; C486332:Akap1 protein, rat; D018691:Excitatory Amino Acid Antagonists; D026901:Membrane Transport Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D024101:Mitochondrial Proteins; D009419:Nerve Tissue Proteins; D011956:Receptors, Cell Surface; D018160:Receptors, Cytoplasmic and Nuclear; D026941:Sodium Channel Blockers; C489998:Tomm20 protein, rat; D033921:Vesicular Transport Proteins; D049452:Green Fluorescent Proteins; D013779:Tetrodotoxin; C056639:2-amino-5-phosphopentanoic acid; D017868:Cyclic AMP-Dependent Protein Kinases; D054648:Protein Phosphatase 2; C519851:Dnm1l protein, rat; D034281:Dynamins; D014633:Valine; D002331:Carnitine