title: Mitochondrial targeting of electron scavenging antioxidants: Regulation of selective oxidation vs random chain reactions.
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.
authors.affiliation: Center for Free Radical and Antioxidant Health, University of Pittsburgh, PA 15219, USA. kagan@pitt.edu
authors.forename: Valerian E
authors.initials: VE
authors.lastname: Kagan
authors.forename: Peter
authors.initials: P
authors.lastname: Wipf
authors.forename: Detcho
authors.initials: D
authors.lastname: Stoyanovsky
authors.forename: Joel S
authors.initials: JS
authors.lastname: Greenberger
authors.forename: Grigory
authors.initials: G
authors.lastname: Borisenko
authors.forename: Natalia A
authors.initials: NA
authors.lastname: Belikova
authors.forename: Naveena
authors.initials: N
authors.lastname: Yanamala
authors.forename: Alejandro K
authors.initials: AK
authors.lastname: Samhan Arias
authors.forename: Muhammad A
authors.initials: MA
authors.lastname: Tungekar
authors.forename: Jianfei
authors.initials: J
authors.lastname: Jiang
authors.forename: Yulia Y
authors.initials: YY
authors.lastname: Tyurina
authors.forename: Jing
authors.initials: J
authors.lastname: Ji
authors.forename: Judith
authors.initials: J
authors.lastname: Klein-Seetharaman
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Pitt
authors.forename: Anna A
authors.initials: AA
authors.lastname: Shvedova
authors.forename: Hülya
authors.initials: H
authors.lastname: Bayir
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D016503:Drug Delivery Systems / Q000379:methods*; D042967:Electron Transport Complex I / Q000378:metabolism; D016166:Free Radical Scavengers / Q000737:chemistry* / Q000493:pharmacokinetics; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D008954:Models, Biological; D015394:Molecular Structure; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000975:Antioxidants; D016166:Free Radical Scavengers; D017382:Reactive Oxygen Species; D042967:Electron Transport Complex I