Mitochondrial DNA damage as a potential mechanism for age-related macular degeneration
Pabalu P Karunadharma1, Curtis L Nordgaard, Timothy W Olsen
1Department of Ophthalmology, University of Minnesota Twin Cities, Minneapolis, Minnesota 55455, USA.
Purpose:
Increasing evidence suggests a central role for mitochondrial (mt) dysfunction in age-related macular degeneration (AMD). Previous proteomic data from the retinal pigment epithelium (RPE) revealed significant changes to mt proteins, suggesting potential functional defects and damage to mitochondrial DNA (mtDNA) with AMD progression. The present study tests the hypothesis that mtDNA damage increases with aging and AMD.
Methods:
Genomic DNA was isolated from the macular region of human donor RPE graded for stages of AMD (Minnesota Grading System [MGS] 1-4). Region-specific mtDNA damage with normal aging was evaluated in 45 control subjects (ages 34-88 years, MGS 1) and AMD-associated damage in diseased subjects (n = 46), compared with that in age-matched control subjects (n = 26). Lesions per 10 kb per genome in the mtDNA and nuclear DNA were measured with long-extension polymerase chain reaction (LX PCR). The level of deleted mtDNA in each donor was measured with quantitative real-time PCR (qPCR).
Results:
With aging, an increase in mtDNA damage was observed only in the common deletion region of the mt genome. In contrast, with AMD, mtDNA lesions increased significantly in all regions of the mt genome beyond levels found in age-matched control subjects. mtDNA accumulated more lesions than did two nuclear genes, with total damage of the mt genome estimated to be eight times higher.
Conclusions:
Collectively, the data indicate that mtDNA is preferentially damaged with AMD progression. These results suggest a potential link between mt dysfunction due to increased mtDNA lesions and AMD.
Insights
Mitochondrial DNA (mtDNA) damage significantly increases in age-related macular degeneration (AMD), suggesting a link between mtDNA lesions and AMD progression. This study quanties mtDNA damage in aging and AMD.
Area of Science:
- Ophthalmology
- Genetics
- Cell Biology
Background:
- Mitochondrial dysfunction is implicated in age-related macular degeneration (AMD).
- Previous studies show altered mitochondrial proteins in the retinal pigment epithelium (RPE) of AMD patients.
- Mitochondrial DNA (mtDNA) damage is a potential contributor to AMD pathogenesis.
Purpose of the Study:
- To investigate whether mtDNA damage increases with normal aging and AMD.
- To compare mtDNA damage levels in control subjects and AMD patients.
Main Methods:
- Genomic DNA was isolated from human RPE samples graded for AMD severity.
- Long-extension polymerase chain reaction (LX PCR) measured mtDNA and nuclear DNA lesions.
- Quantitative real-time PCR (qPCR) assessed the level of deleted mtDNA.
Main Results:
- mtDNA damage increased in the common deletion region with aging.
- AMD significantly elevated mtDNA lesions across all regions of the mitochondrial genome.
- mtDNA sustained approximately eight times more damage than nuclear DNA.
Conclusions:
- mtDNA is preferentially damaged in AMD progression.
- Increased mtDNA lesions and subsequent mitochondrial dysfunction may contribute to AMD.
- These findings highlight mtDNA damage as a potential therapeutic target for AMD.
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