Aging-dependent large accumulation of muscle-specific point mutations in the transcription/replication control region of human mitochondrial DNA

The aging-dependent large accumulation of specific point mutations, especially the most frequent mutation T414G, in the cultured human skin fibroblast mtDNA transcription/replication regulatory region raised the question of their occurrence in post-mitotic tissues. In the present work, analysis of biopsied or autopsied human skeletal muscle from variously aged individuals revealed the absence or only minimal presence of those skin fibroblast mutations. By contrast, surprisingly, most of 26 individuals 53 to 92 years old, without a known history of neuromuscular disease, exhibited at the same region of human mtDNA in muscle an accumulation of two new point mutations, i.e., A189G and T408A, which were absent or marginally present in the muscle of 19 individuals younger than 34 years. These two mutations were not found in the skin fibroblasts from 22 subjects 64 to 101 years of age (T408A), or were present only in three subjects in very low amounts (A189G). Furthermore, in several older individuals exhibiting an accumulation in muscle of one or both of these mutations, they were nearly absent in other post-mitotic tissues, whereas the most frequent fibroblast-specific mutation (T414G) was present in skin autopsy, but not in muscle. The striking tissue specificity of the aging-dependent mtDNA point mutations and their mapping at critical sites for mtDNA transcription/replication strongly point to the involvement of a specific mutagenic machinery or a specific advantage for the mtDNA replication/transmission and to the functional relevance of these mutations during human aging processes