Mechanism of Neuroprotective Mitochondrial Remodeling by PKA/AKAP1

Ronald A Merrill; Ruben K Dagda; Audrey S Dickey; J Thomas Cribbs; Steven H Green; Yuriy M Usachev

doi:10.1371/journal.pbio.1000612

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Mechanism of Neuroprotective Mitochondrial Remodeling by PKA/AKAP1

Journal article

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Mechanism of Neuroprotective Mitochondrial Remodeling by PKA/AKAP1

Ronald A Merrill, Ruben K Dagda, Audrey S Dickey, J Thomas Cribbs, Steven H Green and Yuriy M Usachev

PLoS biology, Vol.9(4), e1000612

04/01/2011

DOI: 10.1371/journal.pbio.1000612

PMCID: PMC3079583

PMID: 21526220

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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.

Biology (General)

Cell Biology/Neuronal and Glial Cell Biology

Neuroscience/Neuronal and Glial Cell Biology

Cell Biology/Cellular Death and Stress Responses

Cell Biology/Neuronal Signaling Mechanisms

Research Article

Neuroscience/Neuronal Signaling Mechanisms

Details

Title: Subtitle: Mechanism of Neuroprotective Mitochondrial Remodeling by PKA/AKAP1
Creators: Ronald A Merrill
Ruben K Dagda
Audrey S Dickey
J Thomas Cribbs
Steven H Green
Yuriy M Usachev
Resource Type: Journal article
Publication Details: PLoS biology, Vol.9(4), e1000612
DOI: 10.1371/journal.pbio.1000612
PMID: 21526220
PMCID: PMC3079583
NLM abbreviation: PLoS Biol
ISSN: 1544-9173
eISSN: 1545-7885
Publisher: Public Library of Science
Grant note: 5R01NS056244-03 / National Institutes of Health (nih_________::NIH) 5R01NS054614-03 / National Institutes of Health (nih_________::NIH) 5R01DC002961-02 / National Institutes of Health (nih_________::NIH) 5R01NS043254-05 / National Institutes of Health (nih_________::NIH)
Language: English
Date published: 04/01/2011
Academic Unit: Iowa Neuroscience Institute; Biology; Anesthesia; Neuroscience and Pharmacology; Otolaryngology; Ophthalmology and Visual Sciences
Record Identifier: 9984040534402771

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