title: Mechanism of neuroprotective mitochondrial remodeling by PKA/AKAP1.
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.
authors.affiliation: Department of Pharmacology, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Ronald A
authors.initials: RA
authors.lastname: Merrill
authors.forename: Ruben K
authors.initials: RK
authors.lastname: Dagda
authors.forename: Audrey S
authors.initials: AS
authors.lastname: Dickey
authors.forename: J Thomas
authors.initials: JT
authors.lastname: Cribbs
authors.forename: Steven H
authors.initials: SH
authors.lastname: Green
authors.forename: Yuriy M
authors.initials: YM
authors.lastname: Usachev
authors.forename: Stefan
authors.initials: S
authors.lastname: Strack
mesh_terms: D054758:A Kinase Anchor Proteins / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D034281:Dynamins / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000201:enzymology; D006706:Homeostasis; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D051336:Mitochondrial Membranes / Q000201:enzymology; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D053140:Organelle Shape / Q000187:drug effects; D010766:Phosphorylation; D055503:Protein Multimerization; D021381:Protein Transport; D051381:Rats
chemical_list: D054758:A Kinase Anchor Proteins; C486332:Akap1 protein, rat; D005576:Colforsin; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; C519851:Dnm1l protein, rat; D034281:Dynamins