Mitochondrial DNA Mutations in Aging
Human aging is characterized by the progressive decline in function at the levels of cells, tissues and organs. Various proposals have been put forward to explain the basis of aging, but the different processes envisaged should not be considered as mutual
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Mitochondrial DNA Mutations in Aging Phillip Nagley and Chunfang Zhang
Introduction
H
uman aging is characterized bythe progressive decline in function at the levels of cells, tissues and organs. Various proposals have been put forward to explain the basis of aging, but the different processes envisaged should not be considered as mutually exclusive. The most prominent mechanisms proposed include genetic programming of senescence, damage to macromolecules by free radicals, molecular crosslinking, changes in immunological function, telomere shortening and somatic genetic changes in DNAY Among these mechanisms, the contribution of mitochondrial DNA (mtDNA) mutations to the aging process, with consequential changes in cellular bioenergetic functions, has attracted wide attention in recent years (for reviews, see refs. 3-8). The circular human mitochondrial genome is very small (16,569 bp) and economically packed. 9 Cells contain about 400-8000 molecules of mtDNA, depending upon the tissue. The mtDNA encodes only genes directly concerned with energy production. lO These comprise the structural genes for 13 of the protein subunits of three enzyme complexes of the mitochondrial respiratory chain (complexes I, III and IV) and ATP synthase (complex V), and genes specifying the two organellar rRNAs and 22 tRNAs that are components of the mitochondrial pro tein synthesizing system. The D-loop region of mtDNA contains the site of initiation of heavystrand DNA replication (OH}j the site of initiation of light-strand replication (Ot> lies some 5 kb from OH' Given the paucity of spacer regions between human mitochondrial genes, a mutation of the mtDNA will almost certainly involve a functionally important region of the genome. Although many base substitution mutations will affect the third base of a codon and may thus not alter amino acids in a pro tein gene product, many other substitutions will have effects on polypeptide sequences or on tRNA or rRNA gene products. The mutation rate of mtDNA is estimated to be 10 to 100 times greater than that of nuclear DNA. lO ,ll This is generally accepted to be associated with the oxidative stress that is prevalent in mitochondria, due to the organelle's function in oxygen metabolism. There was early recognition that this oxidative stress in mitochondria throughout life could be an important factor in the aging process of complex organisms. 12- 14 Mitochondrial DNA Mutations in Aging, Disease and Cancer, edited by Keshav K. Singh. © 1998 Springer-Verlag and R.G. Landes Company.
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Mitochondrial DNA Mutations in Aging, Disease and Cancer
A specific formulation of an aging hypothesis involving mtDNA was made by Linnane et al. 3 In considering that the occurrence of somatic mutations in mtDNA and their accumulation during the life span would make a significant contribution to the aging process, Linnane et aP made the following proposals. Random mtDNA mutations occur in somatic tissues and progressively accumulate throughout human life. The particular metabolism of cells of differe
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