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
Date Published2004 Aug 13
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

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.

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