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Mitochondrial targeting of electron scavenging antioxidants: Regulation of selective oxidation vs random chain reactions

Journal

ADVANCED DRUG DELIVERY REVIEWS
Volume 61, Issue 14, Pages 1375-1385

Publisher

ELSEVIER
DOI: 10.1016/j.addr.2009.06.008

Keywords

Cytochrome c; Cardiolipin; Mitochondria; Apoptosis; Triphenylphosphonium; MnSOD; Peroxidation; Nitroxides; Gramicidin; S-conjugates

Funding

  1. NIH [U19 AIO68021, HL70755, HD057587, NS061817, NORA 927Z1LU]
  2. la junta de Extremadura Consejeria de Infraestructuras y Desarrollo Tecnologico- y el Fondo Social Europeo [2008050288]

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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. (C) 2009 Elsevier B.V. All rights reserved.

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