Mitochondrial targeting of electron scavenging antioxidants: regulation of selective oxidation vs random chain reactions.
Kagan-VE; Wipf-P; Stoyanovsky-D; Greenberger-JS; Borisenko-G; Belikova-NA; Yanamala-N; Arias-AKS; Tungekar-MA; Jiang-JF; Tyurina-YY; Ji-J; Klein-Seetharaman-J; Pitt-BR; Shvedova-AA; Bayir-H
Adv Drug Deliv Rev 2009 Nov; 61(14)(SI):1375-1385
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.
Biological-agents; Biological-effects; Cellular-transport-mechanism Cytotoxic-effects; Molecular-biology; Molecular-structure; Oxidative-metabolism; Oxidative-processes; Phospholipids;
Author Keywords: Cytochrome c; Cardiolipin; Mitochondria; Apoptosis; Triphenylphosphonium; MnSOD; Peroxidation; Nitroxides; Gramicidin; S-conjugates
Valerian E. Kagan, Univ Pittsburgh, Dept Environm & Occupat Hlth, Ctr Free Radical & Antioxidant Hlth, BRIDG, 100 Technol Dr, Room 330, Pittsburgh, PA 15219
Advanced Drug Delivery Reviews