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PKA/AKAP1 and PP2A/Bβ2 regulate neuronal morphogenesis via Drp1 phosphorylation and mitochondrial bioenergetics

Audrey S Dickey1, Stefan Strack

  • 1Department of Pharmacology and Neuroscience Graduate Program, University of Iowa, Iowa City, Iowa 52242, USA.

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience
|November 4, 2011
PubMed

Insights

Mitochondrial fission protein 1 (Drp1) phosphorylation by PKA/AKAP1 and PP2A/Bβ2 kinase/phosphatase regulates neuronal development. This impacts mitochondrial dynamics, affecting dendrite and synapse formation in rat hippocampal neurons.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Mitochondrial Dynamics

Background:

  • Mitochondrial shape is crucial for neuronal health, with fission and fusion processes impacting injury and disease.
  • Dynamin-related protein 1 (Drp1) is a key regulator of mitochondrial fission, particularly in neurons, and is influenced by posttranslational modifications like phosphorylation.

Purpose of the Study:

  • To investigate the role of outer mitochondrial kinase (PKA/AKAP1) and phosphatase (PP2A/Bβ2) in regulating Drp1 phosphorylation.
  • To determine how Drp1 phosphorylation impacts dendrite and synapse development in cultured rat hippocampal neurons.

Main Methods:

  • Utilized cultured rat hippocampal neurons to study Drp1 phosphorylation.
  • Investigated the effects of PKA/AKAP1-mediated phosphorylation and PP2A/Bβ2-mediated dephosphorylation of Drp1 at Ser656.
  • Manipulated intracellular calcium levels and mitochondrial membrane potential (using l-carnitine) to observe effects on neuronal morphology.

Main Results:

  • PKA/AKAP1 phosphorylation of Drp1 at Ser656 increased mitochondrial length, enhanced dendritic outgrowth, but reduced synapse number and density.
  • PP2A/Bβ2 dephosphorylation of Drp1 at Ser656 fragmented mitochondria, stunted dendritic outgrowth, and increased synapse formation.
  • Altered intracellular calcium mimicked the effects of Drp1 phosphorylation/dephosphorylation on neuronal development.

Conclusions:

  • Outer mitochondrial PKA and PP2A regulate neuronal development by controlling mitochondrial division via Drp1 phosphorylation.
  • The bioenergetic state of mitochondria, influenced by Drp1 activity, is a critical factor in modulating neuronal morphology and connectivity through calcium homeostasis.

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