Rapid accumulation of Akt in mitochondria following phosphatidylinositol 3-kinase activation.
We describe here a new component of the phosphatidylinositol 3-kinase/Akt signaling pathway that directly impacts mitochondria. Akt (protein kinase B) was shown for the first time to be localized in mitochondria, where it was found to reside in the matrix and the inner and outer membranes, and the level of mitochondrial Akt was very dynamically regulated. Stimulation of a variety of cell types with insulin-like growth factor-1, insulin, or stress (induced by heat shock), induced translocation of Akt to the mitochondria within only several minutes of stimulation, causing increases of nearly eight- to 12-fold, and the mitochondrial Akt was in its phosphorylated, active state. Two mitochondrial proteins were identified to be phosphorylated following stimulation of mitochondrial Akt, the beta-subunit of ATP synthase and glycogen synthase kinase-3beta. The finding that mitochondrial glycogen synthase kinase-3beta was rapidly and substantially modified by Ser9 phosphorylation, which inhibits its activity, following translocation of Akt to the mitochondria is the first evidence for a regulatory mechanism affecting mitochondrial glycogen synthase kinase-3beta. These results demonstrate that signals emanating from plasma membrane receptors or generated by stress rapidly modulate Akt and glycogen synthase kinase-3beta in mitochondria.
Bijur
Gautam N
GN
Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
Jope
Richard S
RS
D000730:Androstadienes / Q000494:pharmacology; D001932:Brain Neoplasms / Q000201:enzymology; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000494:pharmacology; D002458:Cell Fractionation / Q000379:methods; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000201:enzymology; D045304:Cytochromes c / Q000378:metabolism; D003600:Cytosol / Q000187:drug effects / Q000201:enzymology; D004347:Drug Interactions; D003576:Electron Transport Complex IV / Q000378:metabolism; D004622:Embryo, Mammalian; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D015151:Immunoblotting / Q000379:methods; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D007668:Kidney; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology*; D025261:Mitochondrial Proton-Translocating ATPases / Q000378:metabolism; D009447:Neuroblastoma / Q000201:enzymology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D018272:Porins / Q000378:metabolism; D011233:Precipitin Tests / Q000379:methods; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D012694:Serine / Q000378:metabolism; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization / Q000295:instrumentation / Q000379:methods; D013482:Superoxide Dismutase / Q000378:metabolism; D013912:Threonine / Q000378:metabolism; D013997:Time Factors; D050995:Voltage-Dependent Anion Channel 1; D000077191:Wortmannin
D000730:Androstadienes; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D045304:Cytochromes c; D003576:Electron Transport Complex IV; D004791:Enzyme Inhibitors; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D007334:Insulin-Like Growth Factor I; D007476:Ionophores; D025261:Mitochondrial Proton-Translocating ATPases; D019869:Phosphatidylinositol 3-Kinases; D018272:Porins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D012694:Serine; D013482:Superoxide Dismutase; D013912:Threonine; D050995:Voltage-Dependent Anion Channel 1; D000077191:Wortmannin; C494762:VDAC1 protein, human; C494918:AKT1 protein, human; C000605506:GSK3B protein, human