Genotypic and phenotypic changes in exhaustively grown cell lines from mitochondrial cytopathy patients

Understanding the pathobiology of mitochondrial (mt) DNA diseases involves both characterization of the effects of individual mutations on respiratory function and elucidation of the changes in mutation load and distribution (energy mosaicism) over serial cell generations. Whether a given mutation is stably maintained, or increases or decreases with cell growth, is one of the determinants as to whether a particular tissue will be affected by oxidative phosphorylation failure. In this study, we correlated mt genotype with biochemical phenotype in myoblasts from patients with pathogenic mtDNA mutations. The dominant process detected was a progressive elimination of mutant mtDNA genomes concomitant with an improvement in respiratory chain activity, suggesting that energetically normal cells have a growth advantage over those with a high mutation load. We propose that this elimination is by biased distribution of wild-type mtDNA to daughter cells, and that a similar mechanism could operate in vivo and contribute to both the clinical expression of mt disease and the maintenance of a predominantly wild-type mt genome pool across generations.