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Ionizing Radiation-induced, Mitochondria-dependent Generation of Reactive Oxygen/Nitrogen¹

Departments of Radiation Oncology [J. K. L., P-S. L., R. S-U., R. B. M.] and Biochemistry [G. V. T.], Virginia Commonwealth University, Richmond, Virginia 23298

Transient generation of reactive oxygen or nitrogen (ROS/RNS), detected with dihydrodichlorofluoroscein by fluorescence microscopy, occurs within minutes of exposing cells to ionizing radiation. In the 1–10 Gy dose range, the amount of ROS/RNS produced/cell is constant, but the percentage of producing cells increases with dose (20 to 80%). Reversible depolarization of the mitochondrial membrane potential () and decrease in fluorescence of a mitochondria-entrapped dye, calcein, are observed coincidentally. Radiation-induced ROS/RNS, depolarization, and calcein fluorescence decrease are inhibited by the mitochondrial permeability transition inhibitor, cyclosporin A, but not the structural analogue, cyclosporin H. Radiation-stimulated ROS/RNS is also inhibited by overexpressing the Ca²⁺-binding protein, calbindin 28K, or treating cells with an intracellular Ca²⁺ chelator. Radiation-induced ROS/RNS is observed in several cell types with the exception of ^o cells deficient in mitochondrial electron transport. ^o cells show neither radiation-induced ROS/RNS production nor depolarization. We propose that radiation damage in a few mitochondria is transmitted via a reversible, Ca²⁺-dependent mitochondrial permeability transition to adjacent mitochondria with resulting enhanced ROS/RNS generation. Measurements of radiation-induced mitogen-activated protein kinase activity indicate that this sensing/amplification mechanism is necessary for activation of some cytoplasmic signaling pathways by low doses of radiation.

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