Mitochondrial DNA damage and its potential role in retinal degeneration.
Mitochondria are central to retinal cell function and survival. There is increasing evidence to support an association between mitochondrial dysfunction and a number of retinal pathologies including age-related macular degeneration (AMD), diabetic retinopathy and glaucoma. The past decade has highlighted mitochondrial genomic instability as an important factor in mitochondrial impairment culminating in age-related changes and age-related pathology. This represents a combination of the susceptibility of mitochondrial DNA (mtDNA) to oxidative damage and a limited base excision repair pathway. This random cumulative mtDNA damage leads to cellular heteroplasmy and, if the damage affects a sufficient proportion of mitochondria within a given cell, results in loss of cell function and greater susceptibility to stress. mtDNA damage is increased in the neural retina and RPE with ageing and appears to be greatest in AMD. It thus appears that the mitochondrial genome is a weak link in the antioxidant defenses of retinal cells and that deficits in mitochondrial DNA (mtDNA) repair pathways are important contributors to the pathogenesis of retinal degeneration. Specifically targeting mitochondria with pharmacological agents able to protect against oxidative stress or promote repair of mtDNA damage may offer potential alternatives for the treatment of retinal degenerations such as AMD.
Department of Molecular and Biomedical Pharmacology, College of Medicine, University of Kentucky, Lexington, KY, USA.
Stuart G
SG
Jarrett
Haijiang
H
Lin
Bernard F
BF
Godley
Michael E
ME
Boulton
D000818:Animals; D004249:DNA Damage; D004260:DNA Repair; D004272:DNA, Mitochondrial / Q000235:genetics*; D042822:Genomic Instability; D006801:Humans; D018384:Oxidative Stress / Q000235:genetics; D012162:Retinal Degeneration / Q000235:genetics*; D055213:Retinal Pigment Epithelium / Q000473:pathology*
D004272:DNA, Mitochondrial