title: Predicted ionisation in mitochondria and observed acute changes in the mitochondrial transcriptome after gamma irradiation: a Monte Carlo simulation and quantitative PCR study.
abstract: It is a widely accepted that the cell nucleus is the primary site of radiation damage while extra-nuclear radiation effects are not yet systematically included into models of radiation damage. We performed Monte Carlo simulations assuming a spherical cell (diameter 11.5 μm) modelled after JURKAT cells with the inclusion of realistic elemental composition data based on published literature. The cell model consists of cytoplasm (density 1g/cm(3)), nucleus (diameter 8.5 μm; 40% of cell volume) as well as cylindrical mitochondria (diameter 1 μm; volume 0.5 μm(3)) of three different densities (1, 2 and 10 g/cm(3)) and total mitochondrial volume relative to the cell volume (10, 20, 30%). Our simulation predicts that if mitochondria take up more than 20% of a cell's volume, ionisation events will be the preferentially located in mitochondria rather than in the cell nucleus. Using quantitative polymerase chain reaction, we substantiate in JURKAT cells that human mitochondria respond to gamma radiation with early (within 30 min) differential changes in the expression levels of 18 mitochondrially encoded genes, whereby the number of regulated genes varies in a dose-dependent but non-linear pattern (10 Gy: 1 gene; 50 Gy: 5 genes; 100 Gy: 12 genes). The simulation data as well as the experimental observations suggest that current models of acute radiation effects, which largely focus on nuclear effects, might benefit from more systematic considerations of the early mitochondrial responses and how these may subsequently determine cell response to ionising radiation.
authors.affiliation: Australian Nuclear Science and Technology Organisation, Lucas Heights, Sydney, New South Wales 2234, Australia; Medical Radiation Sciences, Faculty of Health Sciences, University of Sydney, Cumberland, Sydney, New South Wales 2141, Australia. Electronic address: wik@ansto.gov.au.
authors.forename: Winnie Wai-Ying
authors.initials: WW
authors.lastname: Kam
authors.forename: Aimee L
authors.initials: AL
authors.lastname: McNamara
authors.forename: Vanessa
authors.initials: V
authors.lastname: Lake
authors.forename: Connie
authors.initials: C
authors.lastname: Banos
authors.forename: Justin B
authors.initials: JB
authors.lastname: Davies
authors.forename: Zdenka
authors.initials: Z
authors.lastname: Kuncic
authors.forename: Richard B
authors.initials: RB
authors.lastname: Banati
mesh_terms: D005720:Gamma Rays; D006801:Humans; D007477:Ions; D019169:Jurkat Cells; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism* / Q000528:radiation effects; D009010:Monte Carlo Method; D016133:Polymerase Chain Reaction; D059467:Transcriptome
chemical_list: D007477:Ions
keywords: Ionising radiation; Mitochondria; Monte Carlo radiation transport; Quantitative polymerase chain reaction (qPCR); RNA