Mitochondria-targeted (2-hydroxyamino-vinyl)-triphenyl-phosphonium releases NO and protects mouse embryonic cells against irradiation-induced apoptosis

Edited by Vladimir Skulachev

Received 13 March 2009; received in revised form 16 April 2009; accepted 30 April 2009. published online 08 May 2009.

Abstract

Generation of reactive oxygen species by damaged respiratory chain followed by the formation of cytochrome c (cyt c)–cardiolipin (CL) complex with peroxidase activity are early events in apoptosis. By quenching the peroxidase activity of cyt c–CL complexes in mitochondria, nitric oxide can exert anti-apoptotic effects. Therefore, mitochondria-targeted pro-drugs capable of gradual nitric oxide radical (NO) release are promising radioprotectants. Here we demonstrate that (2-hydroxyamino-vinyl)-triphenyl-phosphonium effectively accumulates in mitochondria, releases NO upon mitochondrial peroxidase reaction, protects mouse embryonic cells from irradiation-induced apoptosis and increases their clonogenic survival after irradiation. We conclude that mitochondria-targeted peroxidase-activatable NO-donors represent a new interesting class of radioprotectors.

Keywords: Apoptosis, Cytochrome c, Cardiolipin, Radioprotection, Triphenyl-phosphonium

a Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15219, USA

b Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA 15219, USA

c Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA

d Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA

e Department of Radiation Oncology, University of Pittsburgh, Pittsburgh, PA 15260, USA

Corresponding author. Address: Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15219, USA. Fax: +1 412 624 9361.

PII: S0014-5793(09)00354-8

doi:10.1016/j.febslet.2009.04.050

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