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J. Biol. Chem. 279 (33): 35079-35086

© 2004 by The American Society for Biochemistry and Molecular Biology, Inc.

Mitochondrial Function Is Required for Hydrogen Peroxide-induced Growth Factor Receptor Transactivation and Downstream Signaling*

Kai Chen{ddagger}§, Shane R. Thomas{ddagger}¶, Adam Albano, Michael P. Murphy**, , and John F. Keaney, Jr., This work was performed while Dr. Keaney was an Established Investigator of the American Heart Association||

Evans Memorial Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts, 02118 and the **MRC-Dunn Human Nutrition Unit, Cambridge, CB2 2XY, United Kingdom

Abstract: The transactivation of growth factor receptors is an early event in H2O2-induced signaling, although proximal targets in this process remain unclear. We found that inhibition of flavin- or heme-containing proteins eliminated H2O2-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 H2O2-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 H2O2 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 H2O2-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 H2O2-induced signaling and growth factor transactivation.

Received for publication April 30, 2004. Revision received June 2, 2004.

* This work was supported by National Institutes of Health Grants DK55656, HL60886, HL67206, and HL68758 and by a Juvenile Diabetes Research Foundation Complications Center grant (to J. F. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

{ddagger} These authors contributed equally to this work.

§ The recipient of a Scientist Development Grant from the American Heart Association.

The recipient of a C. J. Martin post-doctoral fellowship (Fellowship number 07158) awarded by the Australian National Health and Medical Research Council.

|| To whom correspondence should be addressed: Boston University School of Medicine, Whitaker Cardiovascular Institute, 715 Albany St., Rm. W507, Boston, MA 02118. Tel.: 617-638-4894; Fax: 617-638-5437; E-mail: jkeaney{at}

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