Journal Article

PreJuSER-8402

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Mitochondrial targeting of electron scavenging antioxidants: Regulation of selective oxidation vs random chain reactions

Kagan, V. E. ; Wipf, P. ; Stoyanovsky, D. ; Greenberger, J. S. ; Borisenko, G. ; Belikova, N. A. ; Yanamala, N. ; Samhan Arias, A. K. ; Tungekar, M. A. ; Jiang, J. ; Tyurina, Y. Y. ; Ji, J. ; Klein-Seetharaman, J.FZJ* ; Pitt, B. R. ; Shvedova, A. A. ; Bayir, H.

2009
Elsevier Science Amsterdam [u.a.]

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Please use a persistent id in citations: doi:10.1016/j.addr.2009.06.008

Abstract: Effective regulation of highly compartmentalized production of reactive oxygen species and peroxidation reactions in mitochondria requires targeting of small molecule antioxidants and antioxidant enzymes into the organelles. This review describes recently developed approaches to mitochondrial targeting of small biologically active molecules based on: (i) preferential accumulation in mitochondria because of their hydrophobicity and positive charge (hydrophobic cations), (ii) binding with high affinity to an intra-mitochondrial constituent, and (iii) metabolic conversions by specific mitochondrial enzymes to reveal an active entity. In addition, targeted delivery of antioxidant enzymes via expression of leader sequences directing the proteins into mitochondria is considered. Examples of successful antioxidant and anti-apoptotic protection based on the ability of targeted cargoes to inhibit cytochrome c-catalyzed peroxidation of a mitochondria-specific phospholipid cardiolipin, in vitro and in vivo are presented. Particular emphasis is placed on the employment of triphenylphosphonium- and hemi-gramicidin S-moieties as two effective vehicles for mitochondrial delivery of antioxidants.

Keyword(s): Animals (MeSH) ; Antioxidants: pharmacology (MeSH) ; Apoptosis: drug effects (MeSH) ; Drug Delivery Systems: methods (MeSH) ; Electron Transport Complex I: metabolism (MeSH) ; Free Radical Scavengers: chemistry (MeSH) ; Free Radical Scavengers: pharmacokinetics (MeSH) ; Humans (MeSH) ; Mitochondria: drug effects (MeSH) ; Mitochondria: metabolism (MeSH) ; Models, Biological (MeSH) ; Molecular Structure (MeSH) ; Oxidation-Reduction: drug effects (MeSH) ; Oxidative Stress: drug effects (MeSH) ; Reactive Oxygen Species: metabolism (MeSH) ; Antioxidants ; Free Radical Scavengers ; Reactive Oxygen Species ; Electron Transport Complex I ; J ; Cytochrome c (auto) ; Cardiolipin (auto) ; Mitochondria (auto) ; Apoptosis (auto) ; Triphenylphosphonium (auto) ; MnSOD (auto) ; Peroxidation (auto) ; Nitroxides (auto) ; Gramicidin (auto) ; S-conjugates (auto)

Note: This work was supported by NIH Grants U19 AIO68021, HL70755, HD057587, NS061817, NORA 927Z1LU, PittGrid (http://www.pittgrid. pitt.edu) and la junta de Extremadura -Consejeria de Infraestructuras y Desarrollo Tecnologico- y el Fondo Social Europeo (Orden 2008050288).

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Contributing Institute(s):

1. Molekulare Biophysik (ISB-2)

Research Program(s):

1. Programm Biosoft (N03)

Appears in the scientific report 2009

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