title: Mitochondrial function is required for hydrogen peroxide-induced growth factor receptor transactivation and downstream signaling.
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.
authors.affiliation: Evans Memorial Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, 715 Albany Street, MA 02118, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Chen
authors.forename: Shane R
authors.initials: SR
authors.lastname: Thomas
authors.forename: Adam
authors.initials: A
authors.lastname: Albano
authors.forename: Michael P
authors.initials: MP
authors.lastname: Murphy
authors.forename: John F
authors.initials: JF
authors.lastname: Keaney
mesh_terms: D000818:Animals; D000968:Antimycin A / Q000494:pharmacology; D017209:Apoptosis; D015153:Blotting, Western; D019556:COS Cells; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000494:pharmacology; D004272:DNA, Mitochondrial / Q000378:metabolism; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000378:metabolism; D005434:Flow Cytometry; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D051379:Mice; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D041681:NIH 3T3 Cells; D009840:Oligomycins / Q000494:pharmacology; D018384:Oxidative Stress; D011190:Potassium Cyanide / Q000494:pharmacology; D011233:Precipitin Tests; D017978:Receptors, Growth Factor / Q000378:metabolism*; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism; D012402:Rotenone / Q000494:pharmacology; D015398:Signal Transduction; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014466:Ultraviolet Rays
chemical_list: D004272:DNA, Mitochondrial; D009840:Oligomycins; D017978:Receptors, Growth Factor; D014409:Tumor Necrosis Factor-alpha; D012402:Rotenone; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D004815:Epidermal Growth Factor; D000968:Antimycin A; D006861:Hydrogen Peroxide; D017479:Receptors, Platelet-Derived Growth Factor; D040262:Receptors, Vascular Endothelial Growth Factor; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D011190:Potassium Cyanide