Modelling initial radiation-induced damage to mitochondrial DNA by PARTRAC

Alterations to mitochondria as the sites of energy production in human cells have been identified in a number of severe diseases. Mitochondria may initiate and/or amplify bystander signalling [1]. Mitochondrial alterations have been implicated in radiation-induced cardiovascular effects, too [2]. To extend the applicability of PARTRAC biophysical tool [3] towards effects on mitochondria, the nuclear DNA and chromatin as the primary target of radiation has been complemented by a model of mitochondrial DNA (mtDNA). Following experimental information [4], the mtDNA model consists of a circular 16.6 kbp double-helix with U-turns every about 20 bp, with compact higher-order structure so that the whole molecule packs into a 100 nm nucleoid. 10 such nucleoids have been placed within a mitochondrion, and a model heart cell has been populated with 1000 mitochondria placed randomly in the cytoplasm. This model of mitochondria and their DNA has been overlaid with tracks of 60Co photons and 5 MeV α-particles. The event-by-event simulation includes ionizations and excitations in liquid water by both primary and all secondary particles, as well as production of radicals, their diffusion, mutual reactions, and attacks to mtDNA, as described for nuclear DNA previously [3]. Single- and double-strand breaks have been scored, assuming alternative radical scavenging capacities within the mitochondria. While direct radiation effects in mtDNA are identical to nuclear DNA, indirect effects in mtDNA are in general larger due to lesser scavenging and the lack of DNA-protecting histones. The predicted fragmentation patterns in mtDNA reflect the frequent U-turns of the molecule. Detailed results will be presented at the meeting. The simulations complement the scarce experimental data on radiation-induced mtDNA damage [5] and help elucidate the relative roles of initial mtDNA vs nuclear DNA damage and of pathways that amplify their respective effects.