ミトコンドリア遺伝子変異の蓄積と老化 : 第12回公開シンポジウム : 活性酸素の分子病態学

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All of the genes in mitochondrial DNA (mtDNA) are fully expressed in cells, whereas only 1.5% of the nuclear DNA (nDNA) is functionally expressed. Assuming that the copy number of mtDNA is 2000 per cell, the total functioning mtDNA is 3×10^7 bp, which is 1/3 of the functioning nDNA. Because the evolutionary rate of mtDNA is 5-10 times higher than that of nDNA, the functional significance of the single nucleotide polymorphisms (SNPs) in mtDNA is comparable to those in nDNA. Thus, SNPs in mtDNA are expected to influence the susceptibility of individuals to various diseases in combination with SNPs in nDNA. First, we analyzed synonymous mutations in mtDNA to understand the mutational mechanisms. Replication of mtDNA is highly asymmetric between the heavy (H) and light (L) strands. The parental H strand is displaced by the daughter H strand and remains in a single-stranded state until the daughter L strand is synthesized. Occurrence of nucleotide substitutions was distinctly asymmetric between the two strands ; G→A and T→C transitions were 9-fold and 1.8-fold more frequent on the L strand than on the H strand, respectively. This nucleotide substitution bias is consistent with the T- and G-abundance of the H strand as well as the A- and C-abundance of the L strand. Deamination of cytosine to uracil or adenine to hypoxanthine in the single-stranded state of the parental H strand seems to contribute to the mutagenesis in mtDNA. Second, we examined the effect of mitochondrial genotypes on the predisposition to longevity or various diseases. Mt5178A, causing a Leu→Met replacement in the ND2 gene, was more frequently observed in centenarians than in controls. The longevity-associated genotype Mt5178A predisposes resistance to adult-onset diseases. We have confirmed that Mt5178A exhibits an anti-arteriosclerotic effect at least in diabetic patients. Genotyping of patients with mitochondrial diseases has revealed that the Mt5178A genotype suppresses the occurrence of mtDNA mutations, especially the Mt8993 T→G transversion. Because T→G transversion can be induced by oxidative damage to DNA, the difference in the occurrence of this mutation may be relevant to the functional differences between genotypes Mt5178A and Mt5178C. We can also speculate that the rates of age-associated accumulation of mitochondrial mutations in somatic cells are different between these mitochondrial genotypes.
日本環境変異原学会の論文
2001-12-22

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