Journal
RADIATION RESEARCH
Volume 172, Issue 6, Pages 706-717Publisher
RADIATION RESEARCH SOC
DOI: 10.1667/RR1729.1
Keywords
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Funding
- NHLBI NIH HHS [R01 HL070755-06, R01 HL070755-04, HL-70755, R01 HL070755-05, R01 HL070755-01, R01 HL070755, R01 HL070755-02, R01 HL070755-03] Funding Source: Medline
- NIAID NIH HHS [U19 AI068021, U19 AI068021-030001, U19 AI068021-019006, U19 AI068021-050001, U19 AI068021-03, U19 AI068021-059007, U19 AI068021-049007, U19 AI068021-039007, U19 AI068021-015637, U19 AI068021-019007, U19 AI068021-020001, U19 AI068021-05S1, U19 AI068021-039006, U19 AI068021-01, U19 AI068021-040001, U19 AI068021-049006, U19 AI068021-059006, U19 AI068021-029007, U19 AI068021-05, U19 AI068021-05S17864, U19 AI 068021, U19 AI068021-04, U19 AI068021-029006, U19 AI068021-010001, U19 AI068021-02] Funding Source: Medline
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Jiang, J., Stoyanovsky, D. A., Belikova, N. A., Tyurina, Y. Y., Zhao, Q., Tungekar, M. A., Kapralova, V., Huang, Z., Mintz, A. H., Greenberger, J. S. and Kagan, V. E. A Mitochondria-Targeted Triphenylphosphonium-Conjugated Nitroxide Functions as a Radioprotector/Mitigator. Radiat. Res. 172, 706-717 (2009). Removal of excessive mitochondrial reactive oxygen species by electron scavengers and antioxidants is a promising therapeutic strategy to reduce the detrimental effects of radiation exposure. Here we exploited triphenylphosphonium (TPP) cation as a means to target nitroxide radicals to mitochondria. We synthesized a library of TPP-conjugated nitroxides and tested their radioprotective effects in gamma-irradiated mouse embryo cells and human epithelial BEAS-2B cells. Cells were incubated with conjugates either before or after irradiation. We found that [2-(1-oxyl-2,2,6,6-tetramethyl-piperidin-4-ylimino)-ethyl]-triphenyl-phosphonium (TPEY-Tempo) significantly blocked radiation-induced apoptosis as revealed by externalization of phosphatidylserine on the cell surface and inhibition of cytochrome c release from mitochondria. Using electron paramagnetic resonance, we showed that TPEY-Tempo was integrated into cells and mitochondria, where it underwent one-electron reduction to hydroxylamine. TPEY-Tempo acted as an electron scavenger that prevented superoxide generation and cardiolipin oxidation in mitochondria. Finally, TPEY-Tempo increased the clonogenic survival rate of irradiated cells. The cellular integration efficiencies of nonradioprotective TPP conjugates, including Mito-Tempo (Alexis, San Diego, CA), were markedly lower, although these homologues were integrated into isolated succinate-energized mitochondria to a similar extent as TPEY-Tempo. We conclude that mitochondrial targeting of TPP-conjugated nitroxides represents a promising approach for the development of novel radioprotectors. (C) 2009 by Radiation Research Society
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