Abstract
Aging and oxidative stress seem to be the most important factors in the pathogenesis of age-related macular degeneration (AMD), a condition affecting many elderly people in the developed world. However, aging is associated with the accumulation of oxidative damage in many biomolecules, including DNA. Furthermore, mitochondria may be especially important in this process because the reactive oxygen species produced in their electron transport chain can damage cellular components. Therefore, the cellular response to DNA damage, expressed mainly through DNA repair, may play an important role in AMD etiology. In several studies the increase in mitochondrial DNA (mtDNA) damage and mutations, and the decrease in the efficacy of DNA repair have been correlated with the occurrence and the stage of AMD. It has also been shown that mitochondrial DNA accumulates more DNA lesions than nuclear DNA in AMD. However, the DNA damage response in mitochondria is executed by nucleus-encoded proteins, and thus mutagenesis in nuclear DNA (nDNA) may affect the ability to respond to mutagenesis in its mitochondrial counterpart. We reported that lymphocytes from AMD patients displayed a higher amount of total endogenous basal and oxidative DNA damage, exhibited a higher sensitivity to hydrogen peroxide and UV radiation, and repaired the lesions induced by these factors less effectively than did cells from control individuals. We postulate that poor efficacy of DNA repair (i.e., is impaired above average for a particular age) when combined with the enhanced sensitivity of retinal pigment epithelium cells to environmental stress factors, contributes to the pathogenesis of AMD. Collectively, these data suggest that the cellular response to both mitochondrial and nuclear DNA damage may play an important role in AMD pathogenesis.
Highlights
Reactive oxygen species (ROS) and oxidative changes in biomolecules including DNA, have been observed in many diseases, such as cancer, atherosclerosis, diabetes, Alzheimer’s disease, and are believed to be important etiologic factors in these diseases [1]
age-related macular degeneration (AMD) seems to be of special interest, since aging is a primary factor in its etiology, and oxidative DNA damage may be involved in premature aging [4]
This study showed that AMD subjects had a high level of large retinal mitochondrial DNA (mtDNA) deletions and rearrangements in both the coding and non-coding D-loops, and it was speculated that this could have affected the energy production of mitochondria, and the replication and transcription of the mitochondrial genome
Summary
Reactive oxygen species (ROS) and oxidative changes in biomolecules including DNA, have been observed in many diseases, such as cancer, atherosclerosis, diabetes, Alzheimer’s disease, and are believed to be important etiologic factors in these diseases [1]. ROS-related changes to biomolecules are important in the pathogenesis of many serious chronic diseases including ocular disorders such as cataract, glaucoma and age-related macular degeneration (AMD) [3] In this respect, AMD seems to be of special interest, since aging is a primary factor in its etiology, and oxidative DNA damage may be involved in premature aging [4]. It has been hypothesized that the DNA damage accumulating during aging contributes to vascular dysfunctions [7], which is reflected in changes in the architecture of the retina and choroids, another anatomical hallmark of AMD [8] This supports the proposal of a link between the age-related variability in DNA repair genes and vascular stiffness [7]. The association between mitochondrial mutagenesis and AMD, as an age-related disease, is in accordance with the Harman mitochondrial theory of aging [14]
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