Mechanism of neuroprotective mitochondrial remodeling by PKA/AKAP1.
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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.
SubjectA Kinase Anchor Proteins
Cyclic AMP-Dependent Protein Kinases
Published Version (Please cite this version)10.1371/journal.pbio.1000612
Publication InfoMerrill, Ronald A; Dagda, Ruben K; Dickey, Audrey S; Cribbs, J Thomas; Green, Steven H; Usachev, Yuriy M; & Strack, Stefan (2011). Mechanism of neuroprotective mitochondrial remodeling by PKA/AKAP1. PLoS Biol, 9(4). pp. e1000612. 10.1371/journal.pbio.1000612. Retrieved from https://hdl.handle.net/10161/15678.
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Assistant Professor in Neurology
By incorporating different and novel approaches, my team is able to make connections not readily apparent and follow up with comprehensive experiments to thoroughly test the hypothesis. Basic molecular/cellular benchwork is vital to defining aspects of the problem and early testing of solutions, and I stress the translation of these results from bench to bedside. Broadly, my research is focused on determining how alterations in activity of a transcription factor can have wide-ranging do