Mitochondrial targeting of electron scavenging antioxidants: Regulation of selective oxidation vs random chain reactions.
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.
Kagan
Valerian E
VE
Center for Free Radical and Antioxidant Health, University of Pittsburgh, PA 15219, USA. kagan@pitt.edu
Wipf
Peter
P
Stoyanovsky
Detcho
D
Greenberger
Joel S
JS
Borisenko
Grigory
G
Belikova
Natalia A
NA
Yanamala
Naveena
N
Samhan Arias
Alejandro K
AK
Tungekar
Muhammad A
MA
Jiang
Jianfei
J
Tyurina
Yulia Y
YY
Ji
Jing
J
Klein-Seetharaman
Judith
J
Pitt
Bruce R
BR
Shvedova
Anna A
AA
Bayir
Hülya
H
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
D000975:Antioxidants; D016166:Free Radical Scavengers; D017382:Reactive Oxygen Species; D042967:Electron Transport Complex I