Mitochondrial function is required for hydrogen peroxide-induced growth factor receptor transactivation and downstream signaling

J Biol Chem. 2004 Aug 13;279(33):35079-86. doi: 10.1074/jbc.M404859200. Epub 2004 Jun 4.

Abstract

The transactivation of growth factor receptors is an early event in H(2)O(2)-induced signaling, although proximal targets in this process remain unclear. We found that inhibition of flavin- or heme-containing proteins eliminated H(2)O(2)-induced transactivation of the epidermal growth factor receptor and stimulation of its downstream targets, JNK and Akt. Inhibition of mitochondrial function with rotenone, antimycin A, KCN, carbonylcyanide-m-chlorophenylhydrazone, or oligomycin reproduced this effect, as did generation of mitochondrial DNA-deficient (pseudo-rho(0)) cells. Mitochondrial function had no role in JNK activation in response to UV irradiation or tumor necrosis factor-alpha. The impact of mitochondrial function on H(2)O(2)-induced growth factor transactivation was ubiquitous and applied to both the vascular endothelial growth factor (VEGF)-2 receptor and the platelet-derived growth factor-beta receptor in endothelium and fibroblasts, respectively. In contrast, ligand-induced growth factor activation was unrelated to mitochondrial function. Growth factor receptor transactivation and its downstream signaling in response to H(2)O(2) appeared to involve redox-sensitive mitochondrial events as they were abrogated by a mitochondrial-targeted antioxidants but not their nontargeted counterparts. Functionally, we found that mitochondrial-targeted antioxidants inhibited H(2)O(2)-induced apoptosis and cell death but had no effect with UV irradiation. These data establish a novel role for the mitochondrion as a proximal target specific to H(2)O(2)-induced signaling and growth factor transactivation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antimycin A / pharmacology
  • Apoptosis
  • Blotting, Western
  • COS Cells
  • Carbonyl Cyanide m-Chlorophenyl Hydrazone / pharmacology
  • DNA, Mitochondrial / metabolism
  • Enzyme Activation
  • Epidermal Growth Factor / metabolism
  • Flow Cytometry
  • Hydrogen Peroxide / pharmacology*
  • JNK Mitogen-Activated Protein Kinases*
  • MAP Kinase Kinase 4
  • Mice
  • Mitochondria / metabolism
  • Mitochondria / pathology*
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • NIH 3T3 Cells
  • Oligomycins / pharmacology
  • Oxidative Stress
  • Potassium Cyanide / pharmacology
  • Precipitin Tests
  • Receptors, Growth Factor / metabolism*
  • Receptors, Platelet-Derived Growth Factor / metabolism
  • Receptors, Vascular Endothelial Growth Factor / metabolism
  • Rotenone / pharmacology
  • Signal Transduction
  • Transcriptional Activation*
  • Tumor Necrosis Factor-alpha / metabolism
  • Ultraviolet Rays

Substances

  • DNA, Mitochondrial
  • Oligomycins
  • Receptors, Growth Factor
  • Tumor Necrosis Factor-alpha
  • Rotenone
  • Carbonyl Cyanide m-Chlorophenyl Hydrazone
  • Epidermal Growth Factor
  • Antimycin A
  • Hydrogen Peroxide
  • Receptors, Platelet-Derived Growth Factor
  • Receptors, Vascular Endothelial Growth Factor
  • JNK Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 4
  • Mitogen-Activated Protein Kinase Kinases
  • Potassium Cyanide