Abstract
Cellular oxidative injury has been implicated in aging and a wide array of clinical disorders including ischemia-reperfusion injury; neurodegenerative diseases; diabetes; inflammatory diseases such as atherosclerosis, arthritis, and hepatitis; and drug-induced toxicity. However, available antioxidants have not proven to be particularly effective against many of these disorders. A possibility is that some of the antioxidants do not reach the relevant sites of free radical generation, especially if mitochondria are the primary source of reactive oxygen species (ROS). The SS (Szeto-Schiller) peptide antioxidants represent a novel approach with targeted delivery of antioxidants to the inner mitochondrial membrane. The structural motif of these SS peptides centers on alternating aromatic residues and basic amino acids (aromatic-cationic peptides). These SS peptides can scavenge hydrogen peroxide and peroxynitrite and inhibit lipid peroxidation. Their antioxidant action can be attributed to the tyrosine or dimethyltyrosine residue. By reducing mitochondrial ROS, these peptides inhibit mitochondrial permeability transition and cytochromec release, thus preventing oxidant-induced cell death. Because these peptides concentrate >1000-fold in the inner mitochondrial membrane, they prevent oxidative cell death with EC50 in the nM range. Preclinical studies support their potential use for ischemia-reperfusion injury and neurodegenerative disorders. Although peptides have often been considered to be poor drug candidates, these small peptides have excellent “druggable” properties, making promising agents for many diseases with unment needs.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Turrens JF. Superoxide production by the mitochondrial respiratory chain.Biosci Rep. 1997;17:3–8.
Petrosillo G, Ruggiero FM, Pistolese M Paradies G. Reactive oxygen species generated from the mitochondrial electron transport chain induce, cytochrome c dissociation from beef-heart submitochondrial particles via cardiolipin peroxidation: possible role in the apoptosis.FEBS Lett. 2001;509:435–438.
Petrosillo G, Ruggiero FM, Paradies G. Role of reactive oxygen species and cardiolipin, in the release, of cytochrome c from mitochondria.FASEB J. 2003;17:2202–2208.
Shidoji Y, Hayashi K, Komura S, Ohishi N, Yagi K. Loss of molecular interaction between cytochrome c and cardiolipin due to lipid peroxidation.Biochem Biophys Res Commun. 1999;264:343–347.
Vieira HL, Belzacq AS, Haouzi D, et al. The adenine nucleotide translocator: a target of nitric oxide, peroxynitrite, and 4-hydroxynonenal.Oncogene. 2001;20:4305–4316.
Ott M, Robertson JD, Gogvadze V, Zhivotovsky B, Orrenius S. Cytochrome c release from mitochondria proceeds by a two-step process.Proc Natl Acad Sci USA. 2002;99:1259–1263.
Liu X, Kim CN, Yang J, Jemmerson R, Wang X. Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c.Cell. 1996;86:147–157.
Li P, Nijhawan D, Budihardjo I, et al. Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates and apoptotic protease cascade.Cell 1997;91:479–489.
Halliwell B. The antioxidant paradox.Lancet. 2000;355:1179–1180.
Patterson C, Madamanchi NR, Runge MS. The oxidative paradox: another piece in the puzzle.Circ Res. 2000;87:1074–1076.
Flaherty JT, Pitt B, Gruber JW, et al. Recombinant human superoxide dismutase (h-SOD) fails to improve receovery of ventricular function in patients undergoing coronary angioplasty for acute myocardial infarction.Circulation. 1994;89:1982–1991.
Maiorino M, Zamburlini A, Roveri A, Ursini F. Prooxidant role of vitamin E in copper induced lipid peroxidation.FEBS Lett. 1993;330:174–176.
Murphy MP, Smith RA. Drug delivery to mitochondria: the key to mitochondrial medicine.Adv Drug Deliv Rev. 2000;41:235–250.
Smith RA, Porteous CM, Coulter CV, Murphy MP. Selective targeting of an antioxidant to mitochondria.Eur J Biochem. 1999;263:709–716.
Kelso GF, Porteous CM, Coulter CV, et al. Selective, targeting of a redox-active ubiquinone to mitochondria within cells: antioxidant and antiapoptotic propertiesJ Biol Chem. 2001;276:4588–4596.
Zhao K, Zhao GM, Wu D, et al. Cell-permeable peptide antioxidants targeted to inner mitochondrial membrane inhibit mitochondrial swelling., oxidative cell death, and reperfusion injury.J Biol Chem. 2004;279:34682–34690.
Winterbourn CC, Parsons-Mair HN, Gebicki S, Gebicki JM, Davies MJ. Requirements for superoxide-dependent tyrosine hydroperoxide formation in peptides.Biochem. J. 2004;381:241–248.
Zhao K, Luo G, Zhao GM, Schiller PW, Szeto HH. Transcellular transport of a highly polar 3_ net charge opioid tetrapeptide.J Pharmacol Exp Ther. 2003;304:425–432.
Drin G, Cottin S, Blanc E, Rees AR, Temsamani J. Studies on the internalization mechanism of cationic cell-penetrating peptides.J Biol Chem. 2003;278:31192–31201.
Derossi D, Calvet S, Trembleau A, Brunissen A, Chassaing G, Prochiantz A. Cell internalization of the third helix of the Antennapedia homeodomain is receptor-independent.J Biol Chem. 1996;271:18188–18193.
Haidara K, Morel I, Abalea V, Gascon BM, Denizeau F. Mechanism of tert-butylhydroperoxide-induced apoptosis in rat hepatocytes: involvement of mitochondria and endoplasmic reticulum.Biochim Biophys Acta 2002;1542:173–185.
Piret JP, Arnould T, Fuks B, Chatelain P, Remacle J, Michiels C. Mitochondria permeability transition-dependent tert-butyl hydroperoxide-induced apoptosis in hepatoma HepG2 cells.Biochem Pharmacol. 2004;67:611–620.
Byrne AM, Lemasters JJ, Nieminen AL. Contribution of increased mitochondrial free Ca2+ to the mitochondrial permeability transition induced by tert-butylhydroperoxide in rat hepatocytes.Hepatology. 1999;29:1523–1531.
Nieminen AL, Byrne AM, Herman B, Lemasters JJ. Mitochondrial permeability transition in hepatocytes induced by t-BuOOH: NAD(P)H and reactive oxygen species.Am J Physiol. 1997;272:C1286-C1294.
Jauslin ML, Meier T, Smith RA, Murphy MP. Mitochondria-targeted antioxidants protect Friedreich Ataxia fibroblasts from endogenous oxidative stress more effectively than untargeted antioxidants.FASEB J. 2003;17:1972–1974.
Pias EK, Ekshyyan OY, Rhoads CA, Fuseler J, Harrison L, Aw TY. Differential effects of superoxide dismutase isoform expression on hydroperoxide-induced apoptosis in PC-12 cells.J Biol Chem. 2003;278:13294–13301.
Batandier C, Leverve X, Fontaine E. Opening of the mitochondrial permeability transition pore induces reactive oxygen species production at the level of the respiratory chain complex I.J Biol Chem. 2004;279:17197–17204.
Przyklenk K. Pharmacologic treatment of the stunned myocardium: the concepts and the challenges.Coron Artery Dis. 2001;12:263–369.
Wu D, Soong Y, Zhao GM, Szeto HH. A highly potent peptide analgesic that protects against ischemia-reperfusion-induced myocardial stunning.Am J Physiol Heart Circ Physiol. 2002;283:H783-H791.
Song W, Shin J, Lee J, et al. A potent opiate agonist protects against myocardial stunning during myocardial ischemia and reperfusion in rats.Coron Artery Dis. 2005;16:407–410.
Zhao GM, Wu D, Soong Y, et al. Profound spinal tolerance after repeated exposure to a highly selective mu-opioid peptide agonist: role of delta-opioid receptors.J Pharmacol Exp Ther. 2002;302:188–196.
Szeto HH, Lovelace JL, Fridland G, et al. In vivo pharmacokinetics of selective mu-opioid peptide agonists.J Pharmacol Exp Ther. 2001;298:57–61.
Author information
Authors and Affiliations
Corresponding author
Additional information
Published: April 21, 2006
Rights and permissions
About this article
Cite this article
Szeto, H.H. Cell-permeable, mitochondrial-targeted, peptide antioxidants. AAPS J 8, 32 (2006). https://doi.org/10.1007/BF02854898
Received:
Accepted:
DOI: https://doi.org/10.1007/BF02854898