Mitochondrial Biogenesis, Autophagy and Mitochondrial UPR Co-operate in Modulating Ionizing Radiation Induced Cellular Damage

This study aims to understand the important role of mitochondria in relaying ionizing radiation induced cellular insult. We exposed normal human dermal fibroblast cells to X-rays and investigated the changes in mitochondrial structure/function and related cellular parameters. We show that X-rays mediated oxidative outburst majorly contribute for mitochondrial fission, augmented mitochondrial DNA damage and lowered OXPHOS activity and ATP levels. We also demonstrate that irradiated cells exhibit a G2/M arrest with a modest percentage of cells undergoing cell death. In fact, our data show the activation of cytoprotective autophagy (observed by elevated levels of Beclin-1, LC3b, Atg5/16 L proteins) as a protecting mechanism against X-ray mediated cellular insults, blocking which (using chloroquine/3-methyladenine) led to activation of caspase-3 mediated apoptosis. Upregulation of mitochondrial biogenesis factors Nrf1/ PGC-1α was observed post irradiation. Apart from mitochondrial biogenesis, Nrf1 also forms an integral component of mitochondrial unfolded protein response. Hence, we infer that autophagy, mitochondrial biogenesis and mitochondrialUPR co-operate in order to maintain cellular integrity and impede radiation induced cell damage.