Mechanism of neuroprotective mitochondrial remodeling by PKA/AKAP1

PLoS Biol. 2011 Apr;9(4):e1000612. doi: 10.1371/journal.pbio.1000612. Epub 2011 Apr 19.

Abstract

Mitochondrial shape is determined by fission and fusion reactions catalyzed by large GTPases of the dynamin family, mutation of which can cause neurological dysfunction. While fission-inducing protein phosphatases have been identified, the identity of opposing kinase signaling complexes has remained elusive. We report here that in both neurons and non-neuronal cells, cAMP elevation and expression of an outer-mitochondrial membrane (OMM) targeted form of the protein kinase A (PKA) catalytic subunit reshapes mitochondria into an interconnected network. Conversely, OMM-targeting of the PKA inhibitor PKI promotes mitochondrial fragmentation upstream of neuronal death. RNAi and overexpression approaches identify mitochondria-localized A kinase anchoring protein 1 (AKAP1) as a neuroprotective and mitochondria-stabilizing factor in vitro and in vivo. According to epistasis studies with phosphorylation site-mutant dynamin-related protein 1 (Drp1), inhibition of the mitochondrial fission enzyme through a conserved PKA site is the principal mechanism by which cAMP and PKA/AKAP1 promote both mitochondrial elongation and neuronal survival. Phenocopied by a mutation that slows GTP hydrolysis, Drp1 phosphorylation inhibits the disassembly step of its catalytic cycle, accumulating large, slowly recycling Drp1 oligomers at the OMM. Unopposed fusion then promotes formation of a mitochondrial reticulum, which protects neurons from diverse insults.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • A Kinase Anchor Proteins / metabolism*
  • Animals
  • Apoptosis / drug effects
  • Cell Survival / drug effects
  • Cells, Cultured
  • Colforsin / pharmacology
  • Cyclic AMP / pharmacology
  • Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors
  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • Dynamins / metabolism
  • Hippocampus / cytology
  • Hippocampus / enzymology
  • Homeostasis
  • Humans
  • Mitochondria / drug effects
  • Mitochondria / enzymology
  • Mitochondria / physiology*
  • Mitochondrial Membranes / enzymology
  • Neurons / drug effects
  • Neurons / enzymology
  • Neurons / physiology*
  • Organelle Shape / drug effects
  • Phosphorylation
  • Protein Multimerization
  • Protein Transport
  • Rats

Substances

  • A Kinase Anchor Proteins
  • Akap1 protein, rat
  • Colforsin
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • Dnm1l protein, rat
  • Dynamins