Mechanism of neuroprotective mitochondrial remodeling by PKA/AKAP1.

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Merrill, RA; Dagda, RK; Dickey, AS; Cribbs, JT; Green, SH; Usachev, YM; Strack, S

Published Date

  • April 2011

Published In

Volume / Issue

  • 9 / 4

Start / End Page

  • e1000612 -

PubMed ID

  • 21526220

Pubmed Central ID

  • 21526220

Electronic International Standard Serial Number (EISSN)

  • 1545-7885

Digital Object Identifier (DOI)

  • 10.1371/journal.pbio.1000612

Language

  • eng

Conference Location

  • United States