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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Autores principales:	Ronald A Merrill, Ruben K Dagda, Audrey S Dickey, J Thomas Cribbs, Steven H Green, Yuriy M Usachev, Stefan Strack
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/9416d933b26d4774ad931fda500fafb0
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spelling	oai:doaj.org-article:9416d933b26d4774ad931fda500fafb02021-11-18T05:36:14ZMechanism of neuroprotective mitochondrial remodeling by PKA/AKAP1.1544-91731545-788510.1371/journal.pbio.1000612https://doaj.org/article/9416d933b26d4774ad931fda500fafb02011-04-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21526220/?tool=EBIhttps://doaj.org/toc/1544-9173https://doaj.org/toc/1545-7885Mitochondrial 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.Ronald A MerrillRuben K DagdaAudrey S DickeyJ Thomas CribbsSteven H GreenYuriy M UsachevStefan StrackPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Biology, Vol 9, Iss 4, p e1000612 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 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.
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.
format	article
author	Ronald A Merrill Ruben K Dagda Audrey S Dickey J Thomas Cribbs Steven H Green Yuriy M Usachev Stefan Strack
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)
publishDate	2011
url	https://doaj.org/article/9416d933b26d4774ad931fda500fafb0
work_keys_str_mv	AT ronaldamerrill mechanismofneuroprotectivemitochondrialremodelingbypkaakap1 AT rubenkdagda mechanismofneuroprotectivemitochondrialremodelingbypkaakap1 AT audreysdickey mechanismofneuroprotectivemitochondrialremodelingbypkaakap1 AT jthomascribbs mechanismofneuroprotectivemitochondrialremodelingbypkaakap1 AT stevenhgreen mechanismofneuroprotectivemitochondrialremodelingbypkaakap1 AT yuriymusachev mechanismofneuroprotectivemitochondrialremodelingbypkaakap1 AT stefanstrack mechanismofneuroprotectivemitochondrialremodelingbypkaakap1
_version_	1718424927746392064

Mechanism of neuroprotective mitochondrial remodeling by PKA/AKAP1.

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