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The skin is regularly exposed to the harmful effects of sunlight, such as ultraviolet radiation (UVR), which leads to ageing effects as well as clinical precancerous lesions and skin cancer. The accumulation of mitochondrial DNA (mtDNA) damage has been strongly associated as an underlying cause of the general ageing process in tissues and mtDNA damage has been associated with cancer development in many tissues including human skin. This scenario is linked to the key roles of mitochondrial function and mtDNA both in terms of energy production and also oxidative stress production as well as a mediator of apoptosis. We and others have pioneered the use of mtDNA damage as a highly sensitive biomarker of UVR exposure and oxidative stress in human skin; furthermore, ageing-dependent mtDNA mutations can be accelerated by exposure to sunlight. In addition, this review will also highlight useful applications of mtDNA as a biomarker of UVR-induced oxidative stress including effects of antioxidants.

Previous epidemiological, animal and human data report that lycopene has a protective effect against ultraviolet radiation (UVR)-induced erythema.We examined whether tomato paste--rich in lycopene, a powerful antioxidant--can protect human skin against UVR-induced effects partially mediated by oxidative stress, i.e. erythema, matrix changes and mitochondrial DNA (mtDNA) damage.In a randomized controlled study, 20 healthy women (median age 33 years, range 21-47; phototype I/II) ingested 55 g tomato paste (16 mg lycopene) in olive oil, or olive oil alone, daily for 12 weeks. Pre- and postsupplementation, UVR erythemal sensitivity was assessed visually as the minimal erythema dose (MED) and quantified with a reflectance instrument. Biopsies were taken from unexposed and UVR-exposed (3 × MED 24 h earlier) buttock skin pre- and postsupplementation, and analysed immunohistochemically for procollagen (pC) I, fibrillin-1 and matrix metalloproteinase (MMP)-1, and by quantitative polymerase chain reaction for mtDNA 3895-bp deletion.Mean ± SD erythemal D(30) was significantly higher following tomato paste vs. control (baseline, 26·5 ± 7·5 mJ cm(-2); control, 23 ± 6·6 mJ cm(-2); tomato paste, 36·6 ± 14·7 mJ cm(-2); P = 0·03), while the MED was not significantly different between groups (baseline, 35·1 ± 9·9 mJ cm(-2); control, 32·6 ± 9·6 mJ cm(-2); tomato paste, 42·2 ± 11·3 mJ cm(-2)). Presupplementation, UVR induced an increase in MMP-1 (P = 0·01) and a reduction in fibrillin-1 (P = 0·03). Postsupplementation, UVR-induced MMP-1 was reduced in the tomato paste vs. control group (P = 0·04), while the UVR-induced reduction in fibrillin-1 was similarly abrogated in both groups, and an increase in pCI deposition was seen following tomato paste (P = 0·05). mtDNA 3895-bp deletion following 3 × MED UVR was significantly reduced postsupplementation with tomato paste (P = 0·01).Tomato paste containing lycopene provides protection against acute and potentially longer-term aspects of photodamage.

The use of mitochondrial DNA (mtDNA) damage as a reliable and highly sensitive biomarker of ultraviolet (UV) radiation exposure in both the dermis and epidermis has now been well developed by our group and others. We have previously identified a 3895-bp mtDNA deletion which occurred more frequently and to a higher level in usually sun-exposed skin as opposed to occasionally sun-exposed skin. This work focused on older-aged individuals and, in particular, perilesional, histologically normal skin biopsies taken from patients with skin cancer.To develop novel, less-invasive methods of obtaining skin samples (i.e. epidermis) from volunteers covering a much wider age range and larger number of individuals (n = 239).The 3895-bp deletion was quantified by a specific real-time polymerase chain reaction assay in normal human epidermis samples taken from three body sites with differing sun exposure.The results show a statistical increase of the level of the 3895-bp deletion with increasing sun exposure in the epidermal swabs of human skin (P0·001) and with increasing age of the donor in the needle biopsy samples.These data suggest that the upper layers of the epidermis are an accessible and reliable site for assessing mtDNA damage caused by UV exposure.

Field cancerization was first described in 1953 as histologically altered mucosa surrounding tumours removed from the upper gastro-intestinal tract. Over the years the definition has changed to include an area which is clinically occult but has multifocal preneoplastic changes, showing genetic mutations and which precedes the development of second primary tumours and local recurrences. Field cancerization has been described in the oropharynx, oesophagus, stomach, lung, colon, anus, cervix, bladder and skin. Various molecular techniques have been developed to look for genetic mutations and clonality in areas of field change. These studies have highlighted the need for early detection and treatment in order to prevent the development of tumours and local recurrences. In this article we examine the concept of field cancerization and treatments available to manage field change.

Genetic defects affecting the mitochondrial respiratory chain are an important cause of neurological disease. Previously, we identified a family with complex II deficiency and late-onset neurodegenerative disease with progressive optic atrophy, ataxia, and myopathy. The affected family members are now shown to carry a C-to-T transition in one allele of the nuclear gene encoding the flavoprotein subunit of complex II. Mutation of the equivalent base in Escherichia coli generates an inactive enzyme unable to bind flavin adenine dinucleotide covalently. Compatible with these findings, our patients have an approximate 50% decrease in complex II and succinate dehydrogenase activity. These results suggest that genetic defects of nuclear-encoded subunits of the mitochondrial respiratory chain can result in late-onset neurodegenerative disease.

In addition to the 3 billion base pair nuclear genome, each human cell contains thousands of copies of a small, 16.5 kb circular molecule of double stranded DNA: mitochondria have their own DNA (mtDNA) which generally accounts for only 1% of the total cellular nucleic acid content. Therefore why should anyone, particularly in the field of dermatology, have an interest in this cytoplasmic organelle and its DNA? This review will address this question; there are three principle reasons: (i) mitochondria have a crucial role both in energy production and the viability of the cell and recently mitochondria have been implicated in programmed cell death (apoptosis). Although much smaller than the nuclear genome, mtDNA is equally important. MtDNA defects and the resulting mitochondrial dysfunction is an important contributor to human degenerative diseases, ageing and cancer; (ii) mtDNA is a significant target of ultraviolet radiation and current work shows that it may be useful as a candidate biomarker of cumulative exposure in skin; and (iii) there is a broad spectrum of skin manifestations that are signs of mitochondrial disorders; in addition, the frequency of skin findings in these syndromes is probably under-reported.

Monilethrix is an autosomal dominant disorder chiefly affecting hair. The degree of hair dystrophy is highly variable, as is the presence of additional features, such as follicular keratoses. In three British families of monilethrix, linkage has recently been reported to the type II keratin gene cluster at chromosome 12q13, and it has been suggested that the disease is due to a defect in the hard keratins of hair and nail. If monilethrix is a keratin disorder, we would predict that some pedigrees might map to the type I keratin gene cluster on 17q where hard keratin genes are also found. We have now studied clinically and by linkage analysis three new and unrelated pedigrees from England, Scotland and Spain, the first of which showed a variant phenotype. In this family the disease was expressed in four of 12 cases only as a follicular-keratosis of the neck, elbows and knees, and without clinical or historical evidence of hair anomalies; non-penetrance in an obligate carrier was also observed. In all three families, we have established linkage to a series of microsatellite markers at the type II locus at 12q13 (Zmax = 6.34 at theta = 0.00 for D12S368) and have excluded linkage from the type I keratin gene cluster on 17q. It remains probable that monilethrix is a disorder of hard keratins, but at present there is no evidence that it is due to defects in type I keratins.

We have studied the control by complex III of both succinate-cytochrome c reductase and of oxidative flux measured polarographically in rat muscle and liver mitochondria using the specific inhibitor, myxothiazol, to induce partial inhibitions of complex III activity. Complex III exerted a low degree of control on electron flux through succinate-cytochrome c reductase, and a 30-50% decrease in complex III activity remained undetected by this assay. However, when overall oxidative flux was measured polarographically there was a considerable difference in the effect of lowered complex III activity on this pathway between rat muscle and liver mitochondria. Small changes in complex III activity (approximately 5% inhibition) in muscle mitochondria caused marked changes in succinate-stimulated respiration, whereas in liver mitochondria complex III had to be inhibited by about 45% before changes in maximum oxidation rates could be detected. These differences between muscle and liver mitochondria occurred despite rat liver mitochondria having at least a 4-fold lower complex III activity. This suggests that when considering the biochemical consequences of defects of the respiratory chain an important factor is the degree to which an individual complex can be lowered before major changes in overall flux occur. In addition, since many patients with respiratory chain disease present with predominantly muscle symptoms, this latter finding suggests that an understanding of the control of mitochondrial oxidations by different tissues may be important when considering the tissue-specific nature of defects of the respiratory chain.

A one-year-old boy suffering from intermittent lactic acidosis, muscular hypotonia, horizontal gaze paralysis and spasticity in both legs had low activity of the pyruvate dehydrogenase complex associated with low amounts of immunoreactive E 1 alpha and E 1 beta. Leigh syndrome was diagnosed on the basis of the clinical and biochemical abnormalities and the typical lesions observed on MRI of the brain. Treatment with a ketogenic diet was associated with clinical and biochemical amelioration. A striking improvement of the cerebral lesions was observed by neuro-imaging.