New insights into the metabolic consequences of large-scale mtDNA deletions: A quantitative analysis of biochemical, morphological, and genetic findings in human skeletal muscle

In order to study putative genotype phenotype correlations in mitochondrial disorders due to large-scale mtDNA deletions we performed a quantitative a nalysis of biochemical, morphological, and genetic findings in 20 patients. The size of the mtDNA deletions varied from 2 to 7.5 kb with a degree of h eteroplasmy ranging from 16% to 78%. Applying improved methods for measurin g respiratory chain enzyme activities, we found highly significant inverse correlations between the percentage of cytochrome c oxidase (COX)- negative fibers and citrate synthase (CS) normalized COX ratios. Significant correl ations were also established between CS normalized complex I and complex IV ratios as well as between the degree of heteroplasmy of mtDNA deletions an d the percentage of ragged red fibers, COX-negative fibers, and CS normaliz ed complex I and complex IV ratios. Our results indicate that the degree of heteroplasmy of mtDNA deletions is mirrored on the histological as well as the biochemical level. Furthermore, our findings suggest that single large -scale deletions equally influence the activities of all mitochondrially en coded respiratory chain enzymes. Even low degrees of heteroplasmy of mtDNA deletions were found to result in biochemical abnormalities indicating the absence of any well-defined mtDNA deletion threshold in skeletal muscle.