Oxidative Damage Elicited by Imbalance of Free Radical Scavenging Enzymes Is Associated with Large-Scale MtDNA Deletions in Aging Human Skin
Abstract
Mitochondrial DNA (mtDNA) mutations and impaired respiratory function have been demonstrated in various tissues of aged individuals. We hypothesized that age-dependent increase of ROS and free radicals production in mitochondria is associated with the accumulation of large-scale mtDNA deletions. In this study, we first confirmed that the proportion of mtDNA with the 4977 bp deletion in human skin tissues increases with age. We then investigated the 8-hydroxy-2'-deoxyguanosine (8-OH-dG) content in skin tissues and lipid peroxides content of the skin fibroblasts from subjects of different ages. The results showed an age-dependent increase of 8-OH-dG level in the total DNA of skin tissues of the subjects above the age of 60 years. The specific content of malondialdehyde, an end product of lipid peroxidation, was also found to increase with age. On the other hand, we examined the enzyme activities of Cu, Zn-superoxide dismutase (Cu,Zn-SOD), Mn-superoxide dismutase (Mn-SOD), catalase, and glutathione peroxidase (GPx) in the skin fibroblasts. The activities of Cu,Zn-SOD, catalase and glutathione peroxidase were found to decrease with age. However, the activity of Mn-SOD was increased with age before 60 years but was decreased thereafter. Moreover, the activity ratios of Mn-SOD/catalase and Mn-SOD/GPx exhibited the same pattern of change with age. This indicates that free radical scavenging enzymes can effectively dispose of ROS and free radicals before 60 years of age. However, elevated oxidative stress caused by an imbalance between the production and removal of ROS and free radicals occurred in skin fibroblasts after 60 years of age. Taken together, we suggest that the functional decline of free radical scavenging enzymes and the elevation of oxidative stress may play an important role in eliciting oxidative damage and mutation of mtDNA during the human aging process.
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Senescent fibroblasts rapidly develop growth arrest, changes in morphology and function, increased ROS production with marked up-regulation of SOD2 in transcripts and proteomics.
“These senescent fibroblasts rapidly develop a growth arrest, changes in morphology and function, increased ROS production with a marked up-regulation of SOD2 in terms of both transcripts and proteomics [36,37,38].”
From The Role of Antioxidants in the Interplay between Oxidative Stress and Senescence (2022) · cites this paper as [38]
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- Authors
- Lu, C.-Y., Lee, H.-C., Fahn, H.-J., & Wei, Y.-H.
- Affiliations
- National Yang Ming University (TW)
- Corresponding author
- Wei, Yau-Huei
- Venue
- Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis
- Publisher
- Elsevier BV
- Published
- 1999-01
- Volume
- 423
- Issue
- 1-2
- Pages
- 11-21
- ISSN
- 0027-5107 (ISSN-L)
- 1386-1964
- OpenAlex
- W2083326631
- Cited by
- 186
- References
- 41
- Citations by year
- 2025: 3 · 2024: 6 · 2023: 2 · 2022: 6 · 2021: 7 · 2020: 1 · 2019: 3 · 2018: 1 · 2017: 6 · 2016: 6 · 2015: 7 · 2014: 7 · 2013: 8 · 2012: 9
- FWCI
- 2.99
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Mutation research. Fundamental and molecular mechanisms of mutagenesis (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Science Council
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Biochemistry › Antioxidant Activity and Oxidative Stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- mitochondrial DNA deletions, 4977 bp deletion, skin aging, oxidative stress, reactive oxygen species, free radical scavenging enzymes, superoxide dismutase, catalase, glutathione peroxidase, 8-hydroxy-2'-deoxyguanosine, lipid peroxidation, malondialdehyde, dermal fibroblasts, mitochondrial DNA mutations
- MeSH terms
- 8-Hydroxy-2'-Deoxyguanosine, Adolescent, Adult, Age Factors, Aged, Aged, 80 and over, Child, Deoxyguanosine, DNA, Mitochondrial, Fibroblasts, Humans, Lipid Peroxides, Middle Aged, Mutation, Skin, Skin Aging, Free Radical Scavengers, Sequence Deletion, Oxidative Stress
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