Abstract
A variety of endogenous and exogenous factors induce chemical and structural alterations to cellular DNA, as well as errors occurring throughout DNA synthesis. These DNA damages are cytotoxic, miscoding, or both, and are believed to be at the origin of cancer and other age related diseases. A human cell, in addition to nuclear DNA, contains thousands copies of mitochondrial DNA (mtDNA), a double-stranded, circular molecule of 16,569 bp. It was proposed that mtDNA is a critical target for reactive oxygen species (ROS), by-products of the oxidative phosphorylation (OXPHOS), generated in the organelle during aerobic respiration. Indeed, oxidative damage to mtDNA are more extensive and persistent as compared to that of nuclear DNA. Although, transversions are the hallmarks of mutations induced by ROS, paradoxically, the majority of mtDNA mutations that occurred during ageing and cancer are transitions. Furthermore, these mutations exhibit a striking strand orientation bias: T→C/G→A transitions preferentially occur on the Light strand, whereas C→T/A→G on the Heavy strand of mtDNA. Here, we propose that the majority of mtDNA progenies, created after multiple rounds of DNA replication, are derived from the Heavy strand only, due to asymmetric replication of the DNA strand anchored to inner membrane via D-loop structure.