Mitochondrial DNA polymorphism in disease: a possible contributor to respiratory dysfunction

Abstract

Intergenomic variation in the human mitochondrial genome was examined in 27 mtDNA sequences using a pairwise analysis technique. Analysis of 16 of these mtDNA sequences from patients with mitochondrial cytopathies indicated a wide range between different mitochondrial genes in the degree of nucleotide variation from the standard Cambridge sequence. Mean complex I polymorphic frequencies in cytopathic (CPEO, MERRF, MELAS and LHON collectively) patients and in LHON patients differed significantly from controls (P < or = 0.05, t). Total mean sequence divergence (mean number of diverging nucleotides between two sequences per 100 bp) over the entire mtDNA coding region was 0.21% for cytopathies (n = 16) as opposed to 0.18% for a control group (n = 4). Within the cytopathy group, the greatest pairwise divergence was observed in ND3 and ND6 subunits of complex I (0.46 and 0.70% respectively) and the magnitude of specific gene divergences differed considerably from those observed for the corresponding genes in the control population. The extent to which the increased variation in ND3 and ND6 is a general phenomenon applicable to all subjects rather than a finding specific to cytopathies cannot be stated with certainty given the small control group. Regardless as to which of these suggestions is correct, the possibility exists that increased nucleotide variation in certain mitochondrial ND subunits may contribute to respiratory inefficiency through a cumulative effect of a series of polymorphisms of minor individual mutagenic potential.

Involvement of Mitochondrial DNA Sequence Variations and Respiratory Activity in Late Complications following Radiotherapy

“…MRA was significantly lower in the radiosensitive group (P = 0.001). Therefore, it is possible that increased nucleotide variation in mtDNA may contribute to respiratory inefficiency through a cumulative effect of a series of polymorphisms of minor individual mutagenic potential (22). These results are encouraging and suggest that mtDNA variations can influence radiosensitivity and can contribute to late complications to radiotherapy in cancer patients.…”

Increased variation in mtDNA in patients with familial sensorineural hearing impairment

“…A previous study has suggested that the mean pairwise sequence divergence is higher in patients with mitochondrial disorders than among controls (Lertrit et al 1994). This study nevertheless included only four controls and was ethnically diverse, in that the controls consisted only of Caucasian samples, whereas the patients with mitochondrial disorders were of Caucasian, African and Japanese origin.…”

Mitochondrial DNA in Stroke and Migraine with Aura

“…Evidence for increased nucleotide variation in mitochondrial cytopathies in general suggests that cumulative mutagenesis involving a series of mutations with a lesser pathogenic significance, rather than a single central mutation, is a possible mechanism in mitochondrial disease [19]. The studies presented in this paper, while preliminary, are significant and suggest that if respiratory chain impairment consequent upon mitochondrial DNA mutagenesis is a factor in some patients with complicated migraine or young stroke, then it seems likely to involve an accumulation of lesser mutations.…”