Abstract
It has recently been suggested that mitochondrial DNA (mtDNA) mutations are important contributors to human ageing and degenerative diseases. Using PCR techniques, we demonstrated three types of mtDNA length mutations, a 4977 bp deletion, a 7436 bp deletion and tandem duplications, in normal human skin tissues. We found that these mutations started to appear in the third decade of life, and the age at which the mutations could be detected in sun-exposed skin was usually younger than in non-exposed skin. Moreover, the incidences of these deletions and tandem duplications of mtDNA in sun-exposed skin were all significantly higher than those in non-exposed skin (P<0.05). The 4977 bp deletion was the most prevalant mtDNA mutation in human skin, and the 7436 bp deletion was the least frequent among the three types of mtDNA mutations examined. We first demonstrated the existence of tandem duplications with sizes of about 260 bp, 200 bp and 150 bp in the D-loop region of mtDNA in the skin of elderly individuals. Among the three tandem duplications, the 200-bp duplication was found to occur most frequently in ageing skin. The tandem duplications were found to coexist with either or both of the deletions in some elderly individuals. The frequency of occurrence of mtDNA deletions and tandem duplications in skin was found to increase in an age-dependent manner. However, the incidence of tandem duplications was not well correlated with the age of the subject. Using a semiquantitative PCR method, we found that the proportion of the 4977 bp-deleted mtDNA in the skin was significantly increased with advancing age (regression analysis: r=0.4, P<0.05). In the same individual, exposed skin harboured the 4977 bp-deleted mtDNA more frequently and usually more abundantly than non-exposed skin. Taken together, these findings demonstrate that deletions and/ or tandem duplications of mtDNA occur, alone or in combination, in human skin tissues with increasing frequency during ageing. Moreover, the incidence and proportion of mtDNA deletions and tandem duplications in exposed skin were usually higher than in non-exposed skin. We therefore suggest that the stochastic induction and accumulation of these mtDNA mutations may be greatly enhanced by light exposure and that photoageing plays a dominant role in human skin ageing.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Ledo A (1993) Clinical aspects of intrinsic ageing and associated dermatoses. In: Burgdorf WHC, Katz SI (eds) Dermatology: progress and perspective, proceedings of the 18th World Congress of Dermatology. Parthenon Publishing, New York, pp 823–824
Lavker RM (1993) Structural aspects of intrinsic vs photoageing. In: Burgdorf WHC, Katz SI (eds) Dermatology: progress and perspective, proceedings of the 18th World Congress of Dermatology. Parthenon Publishing, New York, pp 825–827
Gilchrest BA (1989) Skin ageing and photoageing: an overview. J Am Acad Dermatol 21: 610–613
Yen TC, Chen YS, King KL, Yeh SH, Wei YH (1989) Liver mitochondrial respiratory functions decline with age. Biochem Biophys Res Commun 65: 994–1003
Trounce I, Byrne E, Marzuki S (1989) Decline in skeletal muscle mitochondrial respiratory chain function: possible factor in ageing. Lancet I: 637–639
Poulton J (1992) Mitochondrial DNA and genetic disease. Bioessays 14: 763–768
Wallace DC (1992) Diseases of the mitochondrial DNA. Annu Rev Biochem 61: 1175–1212
Wei YH (1992) Mitochondrial DNA alterations as ageing-associated molecular events. Mutat Res 275: 145–155
Linnane AW, Marzuki S, Ozawa T, Tanaka M (1989) Mitochondrial DNA mutations as an important contributor to ageing and degenerative diseases. Lancet I: 642–645
Linnane AW, Baumer A, Maxwell RJ, Preston H, Zhang C, Marzuki S (1990) Mitochondrial gene mutation: the ageing process and degenerative diseases. Biochem Int 22: 1067–1076
Wallace DC (1992) Mitochondrial genetics: a paradigm for ageing and degenerative disease? Science 256: 628–632
Cortopassi GA, Shibata D, Soong NW, Arnheim N (1992) A pattern of accumulation of a somatic deletion of mitochondrial DNA in ageing human tissues. Proc Natl Acad Sci USA 89: 7370–7374
Johns DR, Rutledge SL, Stine OC, Hurko O (1989) Directly repeated sequences associated with pathogenic mitochondrial DNA deletions. Proc Natl Acad Sci USA 86: 8059–8062
Yang JH, Lee HC, Lin KJ, Wei YH (1994) A specific 4,977 bp deletion of mitochondrial DNA in human ageing skin. Arch Dermatol Res 286: 386–390
Pang CY, Lee HC, Yang JH, Wei YH (1994) Human skin mitochondrial DNA deletions associated with light exposure. Arch Biochem Biophys 312: 534–538
Brockington M, Sweeney MG, Hammans SR, Morgan-Hughes JA, Harding AE (1993) A tandem duplication in the D-loop of human mitochondrial DNA is associated with deletions in mitochondrial myopathies. Nat Genet 4: 67–71
Lee HC, Pang CY, Hsu HS, Wei YH (1994) Ageing-associated tandem duplications in the D-loop of mitochondrial DNA of human muscle. FEBS Lett 354: 79–83
Lee HC, Pang CY, Hsu HS, Wei YH (1994) Differential accumulations of 4,977 bp deletion in mitochondrial DNA of various tissues in human ageing. Biochim Biophys Acta 1226: 37–43
Corral-Debrinski M, Horton T, Lott MT, Shoffner JM, Beal MF, Wallace DC (1992) Mitochondrial DNA deletions in human brain: regional variability and increase with advanced age. Nat Genet 2: 324–329
Anderson S, Bankier AT, Barrel BG, de Bruijn MHL, Coulson AR, Drouin J, et al (1981) Sequence and organization of the human mitochondrial genome. Nature 290: 457–465
Tanaka M, Ozawa T (1992) Analysis of mitochondrial DNA mutations. In: Longstaff A, Revest P (eds) Methods in molecular biology. Humana Press, Totowa, pp 1–28
Harman D (1956) Ageing: a theory based on free radical and radiation chemistry. J Gerontol 11: 298–300
Celleno L, Serri F (1987) The pathogenetic role of free radicals in cutaneous ageing and skin cancer. G Ital Chir Dermatol 2: 264–266
Ames BN, Shigenaga MK, Hagen TM (1993) Oxidants, antioxidants and the degenerative diseases of ageing. Proc Natl Acad Sci USA 90: 7915–7922
Darr D, Fridovich I (1994) Free radicals in cutaneous biology. J Invest Dermatol 102: 671–675
Clayton DA, Doda JN, Friedberg EC (1974) The absence of a pyrimidine dimer repair mechanism in mammalian mitochondria. Proc Natl Acad Sci USA 71: 2777–2781
Tomkinson AE, Bonk RT, Linn S (1990) Mammalian mitochondrial endonuclease activities specific for ultraviolet-irradiated DNA. Nucleic Acids Res 18: 929–935
Richter C, Park JW, Ames BN (1988) Normal oxidative damage to mitochondrial and nuclear DNA is extensive. Proc Natl Acad Sci USA 85: 6465–6467
Fuchs J, Huflejt ME, Laurie MS, Rothfuss LM, David AB, Wilson DS, et al (1989) Impairment of enzymic and nonenzymic antioxidants in skin by UVB irradiation. J Invest Dermatol 93: 769–773
Shindo T, Witte E, Packer L (1993) Antioxidant defense mechanisms in murine epidermis and dermis and their responses to ultraviolet light. J Invest Dermatol 100: 260–265
Roza L, De Gruijl FR, Bergen Henegouwen JBA, Guikers K, Van Weelden H, Van der Schans GP, Bann RA (1991) Detection of photorepair of UV-induced thymine dimers in human epidermis by immunofluorescence microscopy. J Invest Dermatol 96: 903–907
Poulton J, Deadman ME, Bindoff L, Morten K, Land J, Brown G (1993) Families of mtDNA re-arrangments can be detected in patients with mtDNA deletions: duplications may be a transient intermediate form. Hum Mol Genet 2: 23–30
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Lee, HC., Wei, YH. & Yang, JH. Photoageing-associated mitochondrial DNA length mutations in human skin. Arch Dermatol Res 287, 641–648 (1995). https://doi.org/10.1007/BF00371736
Received:
Issue Date:
DOI: https://doi.org/10.1007/BF00371736