As a key regulatory site for mtDNA expression, the D-loop region harbors the leading strand for origin of replication and the major transcriptional promoters for both heavy and light strands of mtDNA. Despite the fact that D-loop mutations do not necessarily lead to changes in the coding sequence and directly induce major impairments of mitochondrial function, such alterations within this transcriptionally-active region may interfere with the
V5 Epitope sequence and modify the binding affinity for some essential transactivating inducers and modulators, ultimately altering the rate of mtDNA transcription and replication [19]. Indeed, quantitative changes in mtDNA levels have been reported in several human cancers [20], as either an increase in head and neck cancers or a decrease in hepatocellular carcinoma, advanced gastric cancer, breast cancer and lung cancer. More importantly, it has been proposed that somatic D-loop mutation is among the key contributing factors leading to decreased mtDNA copy number in breast cancer and hepatocellular carcinoma [21] and [22]. Furthermore, mtDNA D-loop mutations may positively contribute to the promotion of cancer by enhancing the production of reactive oxygen species (ROS). While it is assumed that sequence alterations in the D-loop only have subtle effects on mitochondrial respiratory chain activity, long-term accumulation of many subtle changes could trigger
cells to release abnormally high levels of ROS or free radicals into the cytosol. As a consequence, exposure of the nucleus and other organelles of the cell to these cytotoxic compounds will result in nDNA damage and facilitate neoplastic transformation [15], [23] and [24]. Nonetheless, whether some of the identified sequence variants, if not all, favor the carcinogenesis of EWS still need to be defined.
