Rapid accumulation of Akt in mitochondria following phosphatidylinositol 3-kinase activation

J Neurochem. 2003 Dec;87(6):1427-35. doi: 10.1046/j.1471-4159.2003.02113.x.

Abstract

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.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Androstadienes / pharmacology
  • Brain Neoplasms / enzymology
  • Carbonyl Cyanide m-Chlorophenyl Hydrazone / pharmacology
  • Cell Fractionation / methods
  • Cell Line
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Cell Nucleus / drug effects
  • Cell Nucleus / enzymology
  • Cytochromes c / metabolism
  • Cytosol / drug effects
  • Cytosol / enzymology
  • Drug Interactions
  • Electron Transport Complex IV / metabolism
  • Embryo, Mammalian
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / pharmacology
  • Glycogen Synthase Kinase 3 / metabolism
  • Glycogen Synthase Kinase 3 beta
  • Humans
  • Immunoblotting / methods
  • Insulin-Like Growth Factor I / pharmacology
  • Ionophores / pharmacology
  • Kidney
  • Mitochondria / drug effects
  • Mitochondria / enzymology*
  • Mitochondrial Proton-Translocating ATPases / metabolism
  • Neuroblastoma / enzymology
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphorylation / drug effects
  • Porins / metabolism
  • Precipitin Tests / methods
  • Protein-Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-akt
  • Serine / metabolism
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization / instrumentation
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization / methods
  • Superoxide Dismutase / metabolism
  • Threonine / metabolism
  • Time Factors
  • Voltage-Dependent Anion Channel 1
  • Wortmannin

Substances

  • Androstadienes
  • Enzyme Inhibitors
  • Ionophores
  • Porins
  • Proto-Oncogene Proteins
  • VDAC1 protein, human
  • Threonine
  • Serine
  • Carbonyl Cyanide m-Chlorophenyl Hydrazone
  • Insulin-Like Growth Factor I
  • Cytochromes c
  • Superoxide Dismutase
  • Voltage-Dependent Anion Channel 1
  • Electron Transport Complex IV
  • Phosphatidylinositol 3-Kinases
  • AKT1 protein, human
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Glycogen Synthase Kinase 3
  • Mitochondrial Proton-Translocating ATPases
  • Wortmannin