Tissue specific distribution of the 3243A→G mtDNA mutation

Background: The 3243A -> RG is a common pathogenic mitochondrial DNA (mtDNA) point mutation causing a variety of different phenotypes. Segregation of this mutation to different tissues during embryonic life and postnatally is still enigmatic. Objective: To investigate the tissue distribution of this mutation. Methods: In 65 individuals from nine families segregating the 3243A -> G mutation, the mutation load (% mutated mtDNA) was determined in various tissues. Mutation load was measured in two to four cell types-blood leucocytes, buccal cells, skeletal muscle cells, and urine epithelial cells (UEC)-derived from all three embryogenic germ layers. Results: There was a significant correlation among mutation loads in the four tissues (r = 0.80-0.89, p < 0.0001). With blood serving as reference, the mutation load was increased by 16% in buccal mucosa, by 31% in UEC, and by 37% in muscle. There were significant differences between the mitotic tissues blood, buccal mucosa, and UEC (p < 0.0001), but no difference between UEC and muscle. Using the present data as a cross sectional investigation, a negative correlation of age with the mutation load was found in blood, while the mutation load in muscle did not change with time; 75% of the children presented with higher mutation loads than their mothers in mitotic tissues but not in the post-mitotic muscle. Conclusions: There appears to be a uniform distribution of mutant mtDNA throughout the three germ layers in embryogenesis. The significant differences between mutation loads of the individual tissue types indicate tissue specific segregation of the 3243A -> G mtDNA later in embryogenesis.