Mechanism of neuroprotective mitochondrial remodeling by PKA/AKAP1.
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...
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doaj-9416d933b26d4774ad931fda500fafb02021-07-02T17:20:02ZengPublic Library of Science (PLoS)PLoS Biology1544-91731545-78852011-04-0194e100061210.1371/journal.pbio.1000612Mechanism of neuroprotective mitochondrial remodeling by PKA/AKAP1.Ronald A MerrillRuben K DagdaAudrey S DickeyJ Thomas CribbsSteven H GreenYuriy M UsachevStefan StrackMitochondrial 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.https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21526220/?tool=EBI |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Ronald A Merrill Ruben K Dagda Audrey S Dickey J Thomas Cribbs Steven H Green Yuriy M Usachev Stefan Strack |
spellingShingle |
Ronald A Merrill Ruben K Dagda Audrey S Dickey J Thomas Cribbs Steven H Green Yuriy M Usachev Stefan Strack Mechanism of neuroprotective mitochondrial remodeling by PKA/AKAP1. PLoS Biology |
author_facet |
Ronald A Merrill Ruben K Dagda Audrey S Dickey J Thomas Cribbs Steven H Green Yuriy M Usachev Stefan Strack |
author_sort |
Ronald A Merrill |
title |
Mechanism of neuroprotective mitochondrial remodeling by PKA/AKAP1. |
title_short |
Mechanism of neuroprotective mitochondrial remodeling by PKA/AKAP1. |
title_full |
Mechanism of neuroprotective mitochondrial remodeling by PKA/AKAP1. |
title_fullStr |
Mechanism of neuroprotective mitochondrial remodeling by PKA/AKAP1. |
title_full_unstemmed |
Mechanism of neuroprotective mitochondrial remodeling by PKA/AKAP1. |
title_sort |
mechanism of neuroprotective mitochondrial remodeling by pka/akap1. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS Biology |
issn |
1544-9173 1545-7885 |
publishDate |
2011-04-01 |
description |
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. |
url |
https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21526220/?tool=EBI |
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