OXIDATIVE-PHOSPHORYLATION DYSFUNCTION DOES NOT INCREASE THE RATE OF ACCUMULATION OF AGE-RELATED MTDNA DELETIONS IN SKELETAL-MUSCLE

Several reports described an age-related accumulation of a particular mitochondrial DNA (mtDNA) deletion ('common deletion') in post-mitotic tissues. These findings led to the hypothesis that free radicals gene rated inside the mitochondria could damage mtDNA during a normal life span. The impaired electron transfer function resulting from mtDNA dam age would increase the production of free radicals creating a vicious cycle. If this vicious cycle is an important player in the somatic acc umulation of mtDNA deletions, patients with impaired oxidative phospho rylation (regardless of the primary defect) should have an accelerated accumulation of mtDNA deletions. We tested this hypothesis by perform ing three analyses: (a) comparing the amounts of the mtDNA 'common del etion' in normal controls and patients with genetically characterized mitochondrial disorders associated with pathogenic mtDNA point mutatio ns or deletions other than the common deletion; (b) analyzing the co-s egregation of the age-related mtDNA common deletion with a pathogenic mtDNA point mutation; and (c) by the detection of multiple mtDNA delet ions by long PCR in controls and patients with mitochondrial disorders . We observed a positive correlation between age and common deletion l evels in controls (r = 0.80) and patients (r = 0.69). The slopes of th e curves were similar, suggesting that the rate of accumulation of the age-related common deletion was the same in both groups. We could not find a co-segregation of the pathogenic point mutated mtDNA molecules with the common deletion nor increased number of age-related deletion s in patients. Our data do not support the hypothesis that a vicious c ycle (damage to mtDNA would affect the respiratory function, leading t o the generation of more free radicals, which in turn would provoke ad ditional mtDNA damage) is an important factor in the accumulation of a ge-related mtDNA deletions. (C) 1997 Elsevier Science B.V.