title: Mitochondria regulate DNA damage and genomic instability induced by high LET radiation.
abstract: High linear energy transfer (LET) radiation including α particles and heavy ions is the major type of radiation find in space and is considered a potential health risk for astronauts. Even though the chance that these high LET particles traversing through the cytoplasm of cells is higher than that through the nuclei, the contribution of targeted cytoplasmic irradiation, to the induction of genomic instability and other chromosomal damages induced by high LET radiation is not known. In the present study, we investigated whether mitochondria are the potential cytoplasmic target of high LET radiation in mediating cellular damage using a mitochondrial DNA (mtDNA) depleted (ρ0) human small airway epithelial (SAE) cell model and a precision charged particle microbeam with a beam width of merely one micron. Targeted cytoplasmic irradiation by high LET α particles induced DNA oxidative damage and double strand breaks in wild type ρ+SAE cells. Furthermore, there was a significant increase in autophagy, micronuclei, which is an indication of genomic instability, together with the activation of nuclear factor kappa-B (NF-κB) and mitochondrial inducible nitric oxide synthase (iNOS) signaling pathways in ρ+SAE cells. In contrast, ρ0SAE cells exhibited a significantly lower response to these same endpoints examined after cytoplasmic irradiation with high LET α particles. The results indicate that mitochondria are essential in mediating cytoplasmic radiation induced genotoxic damage in mammalian cells. Furthermore, the findings may shed some light in the design of countermeasures for space radiation.
authors: Center for Radiological Research, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, VC 11-205/218, New York, N.Y. 10032.
authors: Bo
authors: B
authors: Zhang
authors: Department of Radiation Oncology, Columbia University, 630 West 168th Street, P&S 11-451, New York, N.Y. 10032.
authors: Mercy M
authors: MM
authors: Davidson
authors: Center for Radiological Research, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, VC 11-205/218, New York, N.Y. 10032.
authors: Tom K
authors: TK
authors: Hei
keywords: Mitochondria; ROS; autophagy; genomic instability