Fig. 3.

The source and nature of mutations in mtDNA. a Simple schematic of radical oxygen generation by the mitochondrial ETC. Superoxide (O₂^•-), the proximal mitochondria radical oxygen species, is primarily produced at the flavin mononucleotide site of complex I, and the Q_o site of complex III. O₂^•- is rapidly dismutated to hydrogen peroxide (H₂O₂) by mitochondrial superoxide dismutase (SOD2). H₂O₂ may act as a signalling molecule, but can also introduce oxidative lesions to lipid, protein, and nucleic acid. In the presence of O₂^•- and ferric iron, H₂O₂ may also participate in redox cycling Fenton and Haber-Weiss chemistry, producing highly reactive hydroxyl radicals (^•OH) that present a major oxidative stress to biological systems. b Skeletal formula of deoxyguanosine (dG) and its oxidised derivative 8-oxo-guanosine, which can be produced through reaction with either H₂O₂ or ^•OH (phosphates not depicted for clarity). Theoretically, this oxidation should result in G > T mutations following erroneous DNA replication; however, no increase in such mutations is detected in mtDNA following: knockout of individual DNA glycosylases required for repair of this lesion (ΔMUTYH, ΔOGG1), increased oxidative burden (ΔSOD2), or even a double knockout (ΔOGG1, ΔSOD2) in mice [40]. c The nature of mtDNA mutations detected in 527 human tumours of varying pathology. Regions and genes within mtDNA that are mutated with higher than expected occurrence and recurrence are indicated in grey. The distribution of mutations is strand asymmetric, with significantly increased C > T burden (> 10 times expected frequency) on the H-strand, and significantly increased T > C burden (~ 2.5 times expected frequency) on the L-strand. These differences are likely due to differing replicative modes of the two strands (Fig. 2). Mutation distribution is for illustrative purposes only. Based on data from [29]