Mitochondrial DNA damage as a biomarker for ultraviolet radiation exposure and oxidative stress

Birch‐Machin, Mark A.; Russell, Elena; Latimer, Jennifer

doi:10.1111/bjd.12207

Cited by 87 publications

(82 citation statements)

References 54 publications

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“…Endogenous ROS can be generated during normal cellular metabolism, immune reactions, or under pathological conditions, whereas exogenous ROS may originate from the exposure to air pollution, UV irradiation, microorganisms, viruses, and xenobiotics. Skin is the first defensive barrier for the body and is thus susceptible to both endogenous and exogenous ROS (3).…”

Section: Introductionmentioning

confidence: 99%

Blocking of JB6 Cell Transformation by Tanshinone IIA: Epigenetic Reactivation of Nrf2 Antioxidative Stress Pathway

Wang

Zhang

Guo

et al. 2014

AAPS J

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Abstract. Increasing numbers of natural products have been found to possess anticancer effects. Nuclear factor erythroid-2-related factor-2 (Nrf2) is a master regulator of the antioxidative stress response, and our previous studies found that epigenetic modification of the Nrf2 gene appears to be a critical mechanism. Salvia miltiorrhiza, a Chinese herbal medicine widely used in Asian countries, has been shown to possess anticancer and antioxidant effects. Tanshinone IIA (TIIA), an active component in S. miltiorrhiza, has been reported to activate Nrf2 pathway. The objective of this study was to investigate the epigenetic regulation of Nrf2 by TIIA in mouse skin epidermal JB6 cells and the functional consequences for cell transformation. TIIA was found to induce antioxidant response element-luciferase and upregulate the mRNA and protein levels of Nrf2 and Nrf2 downstream target genes HO-1 and NQO-1. TIIA decreased the colony formation of JB6 cells by approximately 80%. TIIA decreased the protein levels of DNMT1, DNMT3a, DNMT3b, and HDAC3 and inhibited the enzymatic activity of HDACs. Bisulfite genomic sequencing indicated that TIIA demethylated the first five CpGs in the promoter region of the Nrf2 gene. Chromatin immunoprecipitation assays showed that TIIA treatment increased the recruitment of RNA polymerase II at Nrf2 transcription start site but had limited effects on enrichment of Ac-H3 in Nrf2 promoter. Taken together, our results show that TIIA activates the Nrf2 signaling pathway and induces epigenetic demethylation of the CpGs of Nrf2. The epigenetic reactivation of the Nrf2 signaling pathway by TIIA could potentially contribute to the attenuation of JB6 cellular transformation and anticancer effects.

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Section: Introductionmentioning

confidence: 99%

Blocking of JB6 Cell Transformation by Tanshinone IIA: Epigenetic Reactivation of Nrf2 Antioxidative Stress Pathway

Wang

Zhang

Guo

et al. 2014

AAPS J

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“…Mitochondrial dysfunction has been suggested to play a major role in intrinsic aging (8). Furthermore, mitochondrial damage is associated with extrinsic aging, particularly ultraviolet (UV) radiation-induced photoaging in the skin (9). Thus, mitochondrial damage may be a common link between intrinsic and extrinsic aging.…”

mentioning

confidence: 99%

Pleiotropic age-dependent effects of mitochondrial dysfunction on epidermal stem cells

Velarde

Demaria

Melov

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Tissue homeostasis declines with age partly because stem/progenitor cells fail to self-renew or differentiate. Because mitochondrial damage can accelerate aging, we tested the hypothesis that mitochondrial dysfunction impairs stem cell renewal or function. We developed a mouse model, Tg(KRT14-cre/Esr1) 20Efu/J × Sod2 tm1Smel , that generates mitochondrial oxidative stress in keratin 14-expressing epidermal stem/progenitor cells in a temporally controlled manner owing to deletion of Sod2, a nuclear gene that encodes the mitochondrial antioxidant enzyme superoxide dismutase 2 (Sod2). Epidermal Sod2 loss induced cellular senescence, which irreversibly arrested proliferation in a fraction of keratinocytes. Surprisingly, in young mice, Sod2 deficiency accelerated wound closure, increasing epidermal differentiation and reepithelialization, despite the reduced proliferation. In contrast, at older ages, Sod2 deficiency delayed wound closure and reduced epidermal thickness, accompanied by epidermal stem cell exhaustion. In young mice, Sod2 deficiency accelerated epidermal thinning in response to the tumor promoter 12-O-tetradecanoylphorbol-13-acetate, phenocopying the reduced regeneration of older Sod2-deficient skin. Our results show a surprising beneficial effect of mitochondrial dysfunction at young ages, provide a potential mechanism for the decline in epidermal regeneration at older ages, and identify a previously unidentified age-dependent role for mitochondria in skin quality and wound closure.

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“…The skin is equipped with a DNA repair system such as the Base Excision Repair and Nucleotide Excision Repair [36]. Mitochondrial DNA is more vulnerable than nucleus DNA to oxidative stress due to a limited and less efficient DNA repair system [40]. Activity of Nucleotide Excision Repair system has been enhanced to be increased in keratinocytes exposed to low-dose UVB [41].…”

Section: Endogenous Cellular Defense Systems In the Skinmentioning

confidence: 99%

Skin Redox Balance Maintenance: The Need for an Nrf2-Activator Delivery System

et al. 2016

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Abstract:The skin, being the largest organ of the body, functions as a barrier between our body and the environment. It is consistently exposed to various exogenous and endogenous stressors (e.g., air pollutants, ionizing and non-ionizing irradiation, toxins, mitochondrial metabolism, enzyme activity, inflammatory process, etc.) producing reactive oxygen species (ROS) and physical damage (e.g., wounds, sunburns) also resulting in reactive oxygen species production. Although skin is equipped with an array of defense mechanisms to counteract reactive oxygen species, augmented exposure and continued reactive oxygen species might result in excessive oxidative stress leading to many skin disorders including inflammatory diseases, pigmenting disorders and some types of cutaneous malignancy. The nuclear factor erythroid 2-related factor 2 (Nrf2) is an emerging regulator of cellular resistance and of defensive enzymes such as the phase II enzymes. Induction of the Keap1-Nrf2 pathway may have a beneficial effect in the treatment of a large number of skin disorders by stimulating an endogenous defense mechanism. However, prolonged and enhanced activation of this pathway is detrimental and, thus, limits the therapeutic potential of Keap1-Nrf2 modulators. Here, we review the consequences of oxidative stress to the skin, and the defense mechanisms that skin is equipped with. We describe the challenges of maintaining skin redox balance and its impact on skin status and function. Finally, we suggest a novel strategy for maintenance of skin redox homeostasis by modulating the Keap1-Nrf2 pathway using nanotechnology-based delivery systems.

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Mitochondrial DNA damage as a biomarker for ultraviolet radiation exposure and oxidative stress

Cited by 87 publications

References 54 publications

Blocking of JB6 Cell Transformation by Tanshinone IIA: Epigenetic Reactivation of Nrf2 Antioxidative Stress Pathway

Blocking of JB6 Cell Transformation by Tanshinone IIA: Epigenetic Reactivation of Nrf2 Antioxidative Stress Pathway

Pleiotropic age-dependent effects of mitochondrial dysfunction on epidermal stem cells

Skin Redox Balance Maintenance: The Need for an Nrf2-Activator Delivery System

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