Innovita Research Foundation

I.R.F. / Aging news / General / 03031701

mtDNA Change During Aging
Posted on: March 17, 2003

Fig. 1.

Recently a large aging-dependent accumulation of tissue-specific point mutations at critical control sites for mtDNA replication in human skin fibroblasts and skeletal muscle was reported. Such mutations increasing with age could influence proper organism's functionality. The T414G transversion within the promoter for light (L)-strand transcription and for synthesis of the RNA primer of heavy (H)-strand synthesis was found in a generally high proportion (up to 50%) of mtDNA molecules in skin fibroblast cultures from 8 of 14 normal individuals above 65 years of age, but was absent in fibroblast cultures from 13 younger individuals. The age distribution and the results of two longitudinal studies indicated clearly that the T414G mutation was not inherited. A search for possible point mutations in the main mtDNA control region of skeletal muscle revealed, surprisingly, the presence of two mutations that had not been observed in fibroblast mtDNA. In particular, an A189G transition, very close to the main origin of H-strand synthesis (position 191), in 11-64% of the mtDNA and a T408A transversion, within the promoter for the RNA primer of H-strand synthesis, in 2-16% of the mtDNA were found in the muscle from the majority of 27 normal individuals above 53 years old, while being absent or marginally present in the muscle from 19 individuals younger than 34 years. Both the fibroblast T414G mtDNA mutation and the muscle A189G and T408A mutations showed striking tissue specificity, being absent in heart, liver, lymph nodes, and spleen. The occurrence of the fibroblast-specific T414G transversion in four of six centenarians raised the question of whether aging-dependent mutations may play a role in longevity. The availability of leukocytes from a large group of centenarians and control subjects of an Italian population offered scientists the opportunity of testing this possibility. Recently it was reported that a homoplasmic C150T transition, very close to a replication origin in the main mtDNA control region, occurs at a much higher frequency in leukocytes from centenarians and from twins than in leukocytes from the rest of the population. Evidence was obtained that this mutation causes a remodeling of the replication origin at position 151, and that both maternal inheritance and somatic events play a role in this phenomenon. Furthermore, the aging-dependent somatic accumulation of the same mutation in skin fibroblasts was also demonstrated.

In conclusion, the data obtained in this recent study on the C150T mutation in both leukocytes and fibroblasts have indicated that this mutation can be inherited or can arise de novo during life, its level changing with age to a different extent in different individuals, most probably under genetic control.

Source: Jin Zhang, Jordi Asin-Cayuela, Jennifer Fish, Yuichi Michikawa, Massimiliano Bonafe?, Fabiola Olivieri, Giuseppe Passarino, Giovanna De Benedictis, Claudio Franceschi, and Giuseppe Attardi; Strikingly higher frequency in centenarians and twins of mtDNA mutation causing remodeling of replication origin in leukocytes; 1116-1121 PNAS February 4, 2003 vol. 100 no.3;
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