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

TitleMitochondrial function is required for hydrogen peroxide-induced growth factor receptor transactivation and downstream signaling.
Publication TypeJournal Article
Year of Publication2004
AuthorsChen, K, Thomas, SR, Albano, A, Murphy, MP, Keaney, JF
JournalJ Biol Chem
Volume279
Issue33
Pagination35079-86
Date Published2004 Aug 13
ISSN0021-9258
KeywordsAnimals, Antimycin A, Apoptosis, Blotting, Western, Carbonyl Cyanide m-Chlorophenyl Hydrazone, COS Cells, DNA, Mitochondrial, Enzyme Activation, Epidermal Growth Factor, Flow Cytometry, Hydrogen Peroxide, JNK Mitogen-Activated Protein Kinases, MAP Kinase Kinase 4, Mice, Mitochondria, Mitogen-Activated Protein Kinase Kinases, NIH 3T3 Cells, Oligomycins, Oxidative Stress, Potassium Cyanide, Precipitin Tests, Receptors, Growth Factor, Receptors, Platelet-Derived Growth Factor, Receptors, Vascular Endothelial Growth Factor, Rotenone, Signal Transduction, Transcriptional Activation, Tumor Necrosis Factor-alpha, Ultraviolet Rays
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.

DOI10.1074/jbc.M404859200
Alternate JournalJ. Biol. Chem.
Citation Key10.1074/jbc.M404859200
PubMed ID15180991
Grant ListDK 55656 / DK / NIDDK NIH HHS / United States
HL 60886 / HL / NHLBI NIH HHS / United States
HL 67206 / HL / NHLBI NIH HHS / United States
HL 68758 / HL / NHLBI NIH HHS / United States