Cellular DNA effects of radiation and cancer risk assessment in cells with mitochondrial defects

Abstract

Mitochondria play a key role in mediating non-targeted effects (NTE) post-radiation exposure. Mitochondrial DNA (mtDNA), due to its less efficient repair as compared to nuclear DNA, is more severely affected by radiation exposure and mutations in essential mtDNA genes can further exacerbate oxidative stress. Our objective was to evaluate the impact of mitochondrial defects on radiation-induced DDR and genomic instability, biomarkers that can foreshadow cancer development. To better understand this relationship, we used commercially available lymphoblastoid cell lines containing characterized mitochondrial mutations and studied the kinetics of DNA damage and relative telomere length (RTL) changes over time post 0.5 Gy X-ray exposure. Our work suggests that cells containing different mitochondrial mutations exhibit unique DNA damage and telomere length effects following radiation exposure. For example, a cell line containing a mitochondrial mutation in the ND4 subunit of complex 1 showed decreased growth rate, higher levels of persistent DNA damage, and telomere instability as compared to wild type. In contrast, a cell line with a mutation in the ATPase 6 mitochondrial protein showed more subtle negative alterations. These findings suggest mitochondrial integrity may play an important role in cellular changes that promote cancer. In total results indicate mitochondrial mutations can influence DNA damage kinetics and genomic instability and have long-term consequences in the ability to regain homeostasis following radiation exposure. These results may help explain, at least in part, the rationale for the persistent genomic instability often observed following a low dose of radiation and how it may promote cancer.