ROS and UV Induced Mitochondria DNA Mutation and Common Deletion In Skin

Mitochondria are cellular organelles that produce energy (ATP) by consuming oxygen. In the chronological aging process, mitochondria not only produce less ATP, but they also increase the production of reactive oxygen species (ROS) as by-products of aerobic metabolism, particularly during the last step of ADP conversion to ATP. Age-related respiratory function decline can result in enhanced production of ROS in mitochondria. Moreover, the activities of free radical-scavenging enzymes are altered in the aging process. The concurrent age-related changes of these two systems result in the accumulation of endogenous source of ROS in aging tissues. UV irradiation induce an immediate production and accumulation of excess ROS in the skin. The exposure of skin to UV is known to stimulate the intracellular production of ROS (e.g. superoxide and hydrogen peroxide) and reactive nitrogen species (RNS; e.g. nitric oxide). In vitro, ex vivo studies have found that ROS such as oxygen radical, hydrogen peroxide (H2O2), superoxide anion and nitric oxide radical are generated after absorption of UV radiation by chromophores that are also found in keratinocytes (urocanic acid, riboflavin, reduced form of nicotinamide adenine dinucleotide–reduced nicotinamide adenine dinucleotide phosphate [NADH/NADPH], tryptophan). ROS are known to damage proteins, membranes and DNA by oxidation. Continuous generation and accumulation of endogenous and UV induced ROS damages mitochondrial DNA (mtDNA) – deletions, (point) mutations, tandem duplications of mtDNA, recombination. Although UVA penetrates skin more deeply, UVB is more mutagenic. UVA induced DNA mutation is mainly mediated through ROS oxidation. UVB can be absorbed by DNA bases and can induce DNA mutation without ROS; the most common UVB-induced DNA modification is the formation of dimeric photoproducts between adjacent pyrimidines on the same strand of DNA.

The accumulation of mitochondrial DNA (mtDNA) mutations and deletion in intrinsic and extrinsic skin aging is one of the main causes of aging and skin aging. mtDNA is a circular double-stranded DNA 16 559 bp in length. Typically, there are 100–1000 mitochondria per cell and each mitochondrion carries 1–10 copies of the mtDNA. Part of the cellular respiratory electron transport chain membrane bound protein and protein complexes genes are encoded by mitochondria DNA instead of nuclear DNA genome. mtDNA mutation and deletion disrupts the cellular energy production function of the mitochondria. Continuous generation and accumulation of endogenous and UV induced ROS damages mitochondrial DNA (mtDNA) more severely than that of genomic DNA primarily because mitochondria is the cellular organelle where respiratory electron transport chain is located and where free radicals are generated. Mitochondria do not contain any repair mechanism for DNA mutations and deletion except the base excision mechanism; and mtDNA has a lack of association with protective histones protein, making mtDNA more vulnerable to ROS than that of nuclear genome. In fact, the mutation frequency of mtDNA is approximately 50-times of nuclear DNA. Because mtDNA does not contain introns, with coding sequences (genes) being continuous or having very few bases between them; 95% of mtDNA is encoding (functional genes) in comparison to 3% of nuclear DNA, and so any mutagenesis to mtDNA will disrupt a coding gene sequence. The only non-coding region is the ∼1-kb D-loop (displacement loop) which functions as the major regulatory region for both replication and transcription of the genome.

Mutations of mtDNA and the decline of mitochondrial functions, particularly the energy production, is one of the significant causative factor in the chronological, photo aging and age-related disease process. In contrast to nuclear genes, mtDNA is present in multiple copies,each coding genes may exist thousands of copies per cell. Mutant mtDNA and wild-type mtDNA coexist in a cell, a a phenomenon known as heteroplasmy. mtDNA mutations are functionally recessive, cellular dysfunction only occurs when the ratio of mutated to wild-type mtDNA exceeds certain threshold level. A mitochondrial genome harboring a sequence mutation may be replicated allowing its level in cells to increase by intracellular drift. In this way, mtDNA mutations can accumulate during aging

Photoaged skin is characterized by increased mutations of the mitochondrial genome. Of the spectrum of mtDNA deletions identified in the sun-exposed skin, the major deletion have been the 4977 bp common deletion and a 3895 bp deletion. These mtDNA deletions can be also be induced in human skin and cultured skin cells by sub-lethal repetitive doses of UV. It has been shown that a 4977-bp portion of mtDNA containing coding sequences of elements that participate in the respiratory chain is consistently deleted in many different tissues with increasing age and in many age-related diseases. Studies have revealed that the so-called common deletion, a 4,977 base pair deletion of mtDNA, is increased about ten times in photoaged skin compared to that of sun-protected skin of the same individual. Apart from deletions, more tandem mtDNA duplications has been observed in sun-exposed human skin. Large amount of accumulation of mtDNA point mutations in the non-coding regulatory region was also observed in skin. The accumulation of a most common regulatory region point mutation (T414G) in aging skin is shown to be accelerated by UV exposure in human skin.

It was shown that UV-induced mutations of mtDNA in cultured dermal fibroblasts correlates with the amount of ROS production. ROS generated damage of respiratory genes, causing a defective cellular respiratory chain, in a vicious cycle, inducing even more ROS and subsequently allowing mtDNA mutation without the inducing agents which further accelerate the rate of mtDNA damage. In vivo evidence revealed the magnified increase of mtDNA common deletion after the UV irradiation.

Induction of the common deletion in human skin fibroblasts is paralleled by a measurable decrease of oxygen consumption, mitochondrial membrane potential, and ATP content, as well as an increase of matrix metalloproteinase MMP-1, while TIMP remains, suggesting a causative role of mtDNA mutagenesis in photo skin aging. These observations suggest a link not only between mutations of mtDNA and cellular energy metabolism, but also between mtDNA mutagenesis, energy metabolism, and nuclear encoded gene regulation/activation of the skin fibroblast such as increased skin matrix degradation enzyme MMPs. A number of genes may be activated in response to mtDNA damage signal i.e. DNA damage response genes, although ROS also acts as a signal to regulate and activate genes responsible for the aging signs of the skin. Studies indicate that the mtDNA common deletions in human dermal fibroblasts is causally related to photo skin aging phenotypes because it leads to an altered gene profile in these cells and subsequently to structural and functional alterations of the human dermis which are characteristic of photo skin aging.

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