TY - JOUR
T1 - Mitochondrial targeting of electron scavenging antioxidants
T2 - Regulation of selective oxidation vs random chain reactions
AU - Kagan, Valerian E.
AU - Wipf, Peter
AU - Stoyanovsky, Detcho
AU - Greenberger, Joel S.
AU - Borisenko, Grigory
AU - Belikova, Natalia A.
AU - Yanamala, Naveena
AU - Samhan Arias, Alejandro K.
AU - Tungekar, Muhammad A.
AU - Jiang, Jianfei
AU - Tyurina, Yulia Y.
AU - Ji, Jing
AU - Klein-Seetharaman, Judith
AU - Pitt, Bruce R.
AU - Shvedova, Anna A.
AU - Bayir, Hülya
N1 - Funding Information:
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 ).
PY - 2009/11/30
Y1 - 2009/11/30
N2 - 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.
AB - 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.
KW - Apoptosis
KW - Cardiolipin
KW - Cytochrome c
KW - Gramicidin S-conjugates
KW - Mitochondria
KW - MnSOD
KW - Nitroxides
KW - Peroxidation
KW - Triphenylphosphonium
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U2 - 10.1016/j.addr.2009.06.008
DO - 10.1016/j.addr.2009.06.008
M3 - Review article
C2 - 19716396
AN - SCOPUS:71549116694
SN - 0169-409X
VL - 61
SP - 1375
EP - 1385
JO - Advanced Drug Delivery Reviews
JF - Advanced Drug Delivery Reviews
IS - 14
ER -