HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 279, Issue 33, 34682-34690, August 13, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/33/34682    most recent M402999200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zhao, K. Articles by Szeto, H. H. Search for Related Content PubMed PubMed Citation Articles by Zhao, K. Articles by Szeto, H. H. Social Bookmarking                      What's this?

Cell-permeable Peptide Antioxidants Targeted to Inner Mitochondrial Membrane inhibit Mitochondrial Swelling, Oxidative Cell Death, and Reperfusion Injury^*

Kesheng Zhao, Guo-Min Zhao, Dunli Wu, Yi Soong, Alex V. Birk, Peter W. Schiller¶, and Hazel H. Szeto||

From the Departments of Pharmacology and Biochemistry, Joan and Sanford I. Weill Medical College of Cornell University, New York, New York 10021 and ^¶Laboratory of Chemical Biology and Peptide Research, Clinical Research Institute of Montreal, 110 Pine Avenue West, Montreal, Quebec, Canada H2W 1R7

Reactive oxygen species (ROS) play a key role in promoting mitochondrial cytochrome c release and induction of apoptosis. ROS induce dissociation of cytochrome c from cardiolipin on the inner mitochondrial membrane (IMM), and cytochrome c may then be released via mitochondrial permeability transition (MPT)-dependent or MPT-independent mechanisms. We have developed peptide antioxidants that target the IMM, and we used them to investigate the role of ROS and MPT in cell death caused by t-butylhydroperoxide (tBHP) and 3-nitropropionic acid (3NP). The structural motif of these peptides centers on alternating aromatic and basic amino acid residues, with dimethyltyrosine providing scavenging properties. These peptide antioxidants are cell-permeable and concentrate 1000-fold in the IMM. They potently reduced intracellular ROS and cell death caused by tBHP in neuronal N₂A cells (EC₅₀ in nM range). They also decreased mitochondrial ROS production, inhibited MPT and swelling, and prevented cytochrome c release induced by Ca²⁺ in isolated mitochondria. In addition, they inhibited 3NP-induced MPT in isolated mitochondria and prevented mitochondrial depolarization in cells treated with 3NP. ROS and MPT have been implicated in myocardial stunning associated with reperfusion in ischemic hearts, and these peptide antioxidants potently improved contractile force in an ex vivo heart model. It is noteworthy that peptide analogs without dimethyltyrosine did not inhibit mitochondrial ROS generation or swelling and failed to prevent myocardial stunning. These results clearly demonstrate that overproduction of ROS underlies the cellular toxicity of tBHP and 3NP, and ROS mediate cytochrome c release via MPT. These IMM-targeted antioxidants may be very beneficial in the treatment of aging and diseases associated with oxidative stress.

Received for publication, March 17, 2004 , and in revised form, June 2, 2004.

^* This work was supported by Multi-Center Program Project Grant DA08924 from the National Institute on Drug Abuse, National Institutes of Health. 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.

^|| To whom correspondence should be addressed. Tel.: 212-746-6232; Fax: 212-746-8835; E-mail: hhszeto{at}med.cornell.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				Z. Han, S. Varadharaj, R. J. Giedt, J. L. Zweier, H. H. Szeto, and B. R. Alevriadou Mitochondria-Derived Reactive Oxygen Species Mediate Heme Oxygenase-1 Expression in Sheared Endothelial Cells J. Pharmacol. Exp. Ther., April 1, 2009; 329(1): 94 - 101. [Abstract] [Full Text] [PDF]

				I. Zabbarova and A. Kanai Targeted Delivery of Radioprotective Agents to Mitochondria Mol. Interv., December 1, 2008; 8(6): 294 - 302. [Abstract] [Full Text] [PDF]

				Y. Mizuguchi, J. Chen, S. V. Seshan, D. P. Poppas, H. H. Szeto, and D. Felsen A novel cell-permeable antioxidant peptide decreases renal tubular apoptosis and damage in unilateral ureteral obstruction Am J Physiol Renal Physiol, November 1, 2008; 295(5): F1545 - F1553. [Abstract] [Full Text] [PDF]

				Y. Jiang, C. Guo, M. R. Vasko, and M. R. Kelley Implications of Apurinic/Apyrimidinic Endonuclease in Reactive Oxygen Signaling Response after Cisplatin Treatment of Dorsal Root Ganglion Neurons Cancer Res., August 1, 2008; 68(15): 6425 - 6434. [Abstract] [Full Text] [PDF]

				E. W. Childs, B. Tharakan, N. Byrge, J. H. Tinsley, F. A. Hunter, and W. R. Smythe Angiopoietin-1 inhibits intrinsic apoptotic signaling and vascular hyperpermeability following hemorrhagic shock Am J Physiol Heart Circ Physiol, May 1, 2008; 294(5): H2285 - H2295. [Abstract] [Full Text] [PDF]

				E. Robin, R. D. Guzy, G. Loor, H. Iwase, G. B. Waypa, J. D. Marks, T. L. V. Hoek, and P. T. Schumacker Oxidant Stress during Simulated Ischemia Primes Cardiomyocytes for Cell Death during Reperfusion J. Biol. Chem., June 29, 2007; 282(26): 19133 - 19143. [Abstract] [Full Text] [PDF]

				Q. Cheng, T. Nguyen, H. Song, and J. Bonanno Hypoxia Protects Human Corneal Endothelium from Tertiary Butyl Hydroperoxide and Paraquat-Induced Cell Death In Vitro Experimental Biology and Medicine, March 1, 2007; 232(3): 445 - 453. [Abstract] [Full Text] [PDF]

				S. Cho, H. H. Szeto, E. Kim, H. Kim, A. T. Tolhurst, and J. T. Pinto A Novel Cell-permeable Antioxidant Peptide, SS31, Attenuates Ischemic Brain Injury by Down-regulating CD36 J. Biol. Chem., February 16, 2007; 282(7): 4634 - 4642. [Abstract] [Full Text] [PDF]

				D. A. Thomas, C. Stauffer, K. Zhao, H. Yang, V. K. Sharma, H. H. Szeto, and M. Suthanthiran Mitochondrial Targeting with Antioxidant Peptide SS-31 Prevents Mitochondrial Depolarization, Reduces Islet Cell Apoptosis, Increases Islet Cell Yield, and Improves Posttransplantation Function J. Am. Soc. Nephrol., January 1, 2007; 18(1): 213 - 222. [Abstract] [Full Text] [PDF]

				E. J. Meredith, M. J. Holder, A. Rosen, A. D. Lee, M. J. S. Dyer, N. M. Barnes, and J. Gordon Dopamine targets cycling B cells independent of receptors/transporter for oxidative attack: Implications for non-Hodgkin's lymphoma PNAS, September 5, 2006; 103(36): 13485 - 13490. [Abstract] [Full Text] [PDF]

				M. W. Fariss, C. B. Chan, M. Patel, B. Van Houten, and S. Orrenius ROLE of MITOCHONDRIA in TOXIC OXIDATIVE STRESS Mol. Interv., April 1, 2005; 5(2): 94 - 111. [Abstract] [Full Text] [PDF]