Journal Article

Mechanism of Neuroprotective Mitochondrial Remodeling by PKA/AKAP1

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

2011

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: A Kinase Anchor Proteins - metabolism / Animals / Apoptosis - drug effects / Cell Biology/Cellular Death and Stress Responses / Cell Biology/Neuronal and Glial Cell Biology / Cell Biology/Neuronal Signaling Mechanisms / Cell Survival - drug effects / Cells, Cultured / Cellular proteins / Colforsin - pharmacology / Cyclic AMP - pharmacology / Cyclic AMP-Dependent Protein Kinases - antagonists & inhibitors / Cyclic AMP-Dependent Protein Kinases - metabolism / Dynamins - metabolism / Enzymes / Hippocampus - cytology / Hippocampus - enzymology / Homeostasis / Humans / Kinases / Mitochondria / Mitochondria - drug effects / Mitochondria - enzymology / Mitochondria - physiology / Mitochondrial Membranes - enzymology / Mutation / Neurons - drug effects / Neurons - enzymology / Neurons - physiology / Neuroscience/Neuronal and Glial Cell Biology / Neuroscience/Neuronal Signaling Mechanisms / Organelle Shape - drug effects / Phosphorylation / Physiological aspects / Protein kinases / Protein Multimerization / Protein Transport / Proteins / Rats