Age-related increase in mitochondrial DNA damage and loss of DNA repair capacity in the neural retina.
With age, there is increased mitochondrial DNA (mtDNA) damage in the central nervous system (CNS) that may underlie, contribute or increase the susceptibility to certain neurodegenerative diseases. We examined retinas from the eyes of young and old rodents for mtDNA damage and for changes in selected DNA repair enzymes. We found increased levels of 8-hydroxy-2'-deoxy-guanosine (8-OHdG) by immunohistochemical labeling for the oxidative DNA damage marker in aged rodent retinas, which was confirmed by quantitative ELISA. 8-OHdG co-localized with the mitochondrial enzyme superoxide dismutase (MnSOD), suggesting damage to mtDNA. Most of the damaged mtDNA was in the photoreceptors and retinal ganglion cells. Measurements of nuclear DNA (nDNA) and mtDNA lesions indicated that DNA damage was primarily in mtDNA in aged retinas. The increased damage to mtDNA may be due to decreased levels of DNA repair enzymes in the aged retina. Using qPCR, Western blots and immunohistochemistry, we determined the levels of DNA repair enzymes for oxidative damage. In retinas from old eyes compared to retinas from young eyes, we found decreased levels of poly (ADP-ribose) polymerase 1 (PARP1), mutY homolog (MYH) and endonuclease III homologue 1 (NTH1). Our results suggest that normal, age-related, increased mtDNA damage, likely due to decreased repair capacity in aged retinas, may be a susceptibility factor that underlies age-related retinal diseases.
Wang
Ai Ling
AL
Forsythe Laboratory for the Investigation of the Aging Retina, Department of Ophthalmology, Northwestern University School of Medicine, Tarry 13-762, 303 E. Chicago Avenue, Chicago, IL 60611, USA. a-wang@northwestern.edu
Lukas
Thomas J
TJ
Yuan
Ming
M
Neufeld
Arthur H
AH
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000375:Aging / Q000378:metabolism*; D000818:Animals; D004249:DNA Damage; D045647:DNA Glycosylases / Q000378:metabolism; D004260:DNA Repair / Q000502:physiology; D045643:DNA Repair Enzymes / Q000378:metabolism*; D004272:DNA, Mitochondrial / Q000378:metabolism*; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D043224:Deoxyribonuclease (Pyrimidine Dimer) / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000201:enzymology; D020419:Photoreceptor Cells, Vertebrate / Q000201:enzymology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051381:Rats; D011914:Rats, Inbred BN; D012160:Retina / Q000166:cytology / Q000201:enzymology; D012165:Retinal Ganglion Cells / Q000201:enzymology*; D013482:Superoxide Dismutase / Q000378:metabolism
D004272:DNA, Mitochondrial; D000080242:8-Hydroxy-2'-Deoxyguanosine; D013482:Superoxide Dismutase; D011065:Poly(ADP-ribose) Polymerases; D043224:Deoxyribonuclease (Pyrimidine Dimer); C470703:Nthl1 protein, mouse; D045647:DNA Glycosylases; C061738:mutY adenine glycosylase; D045643:DNA Repair Enzymes; D003849:Deoxyguanosine