Ultraviolet radiation exposure accelerates the accumulation of the aging‐dependent T414G mitochondrial DNA mutation in human skin

Abstract

SummaryThe accumulation of mitochondrial DNA (mtDNA) mutations has been proposed as an underlying cause of the aging process. Such mutations are thought to be generated principally through mechanisms involving oxidative stress. Skin is frequently exposed to a potent mutagen in the form of ultraviolet (UV) radiation and mtDNA deletion mutations have previously been shown to accumulate with photoaging. Here we report that the age-related T414G point mutation originally identified in skin fibroblasts from donors over 65 years also accumulates with age in skin tissue. Moreover, there is a significantly greater incidence of this mutation in skin from sun-exposed sites (χ χ χ χ 2 = 6.8, P < 0.01). Identification and quantification of the T414G mutation in dermal skin tissue from 108 donors ranging from 8 to 97 years demonstrated both increased occurrence with photoaging as well as an increase in the proportion of molecules affected. In addition, we have discovered frequent genetic linkage between a common photoaging-associated mtDNA deletion and the T414G mutation. This linkage indicates that mtDNA mutations such as these are unlikely to be distributed equally across the mtDNA population within the skin tissue, increasing their likelihood of exerting focal effects at the cellular level. Taken together, these data significantly contribute to our understanding of the DNA damaging effects of UV exposure and how resultant mutations may ultimately contribute towards premature aging.

Human Mitochondrial DNA Polymerase γ Exhibits Potential for Bypass and Mutagenesis at UV-induced Cyclobutane Thymine Dimers

“…A growing number of epidemiological studies point to correlations between mtDNA damage, UV exposure, and skin disease (37)(38)(39)52). Photoaging of the skin has been closely tied to mtDNA mutations and deletions (36,53,54), and there is recent evidence associating mtDNA damage with several types of skin cancer (55)(56)(57)(58)(59).…”

“…Imbalances in the levels of the 13 proteins encoded by most mitochondrial genomes might lead to mitochondrial dysfunction, reactive oxygen species production, and disruption of normal apoptotic regulation (50,51). Additionally, the accumulation of point mutations in the noncoding control region of mtDNA, which helps control replication and transcription of the mitochondrial genome, has been associated with aging in several human tissues (38,39).…”

Mitochondria and aging: innocent bystanders or guilty parties?

“…This mutation is located in the primer region for the light-strand transcription and was also associated with the level of UV exposure (Birket et al 2007). It has not been detected or observed at extremely low levels in tissues other than skin, which suggests it may be tissue-specific (Murdock et al 2000).…”

The Effects of Aging and Smoking on the Deletions of Mitochondrial DNA in Turkish Population

“…13 İler le yen Eks ter nal Of tal mop le ji (CPE O) ve Ke arn s-Say re Sen dro mu (KSS) gi bi mito kon dri yal mi yo pa ti ler de, önem li de re ce de 4977 bç mtDNA de les yo nu nun bi rik ti ği sap tan mış tır. 14 Yaş lan ma ile bir lik te ar tan ROT 'un oluş tur duğu ok si da tif stre sin ya nı sı ra, 15 si ga ra kul la nı mı -nın, 16 li pid pe rok si das yo nu nun, 17 rad yas yo nun 18 ve ok si dan la rın da, 19 mtDNA' da ki mu tas yon ve de lesyon la rı ar tır dı ğı bir çok do ku da gös te ril miş tir. Saç fo li kül le rin de ki DNA ha sa rı nın, uzun sü re li ma ruzi yet so nu cu si ga ra dan kay nak la nan ge no tok si si tenin iz len me si için iyi bir bi yo gös ter ge ola bi le ce ği ile ri sü rül mek te dir.…”