Evidence of severe mitochondrial oxidative stress and a protective effect of low oxygen in mouse models of inherited photoreceptor degeneration.
The role of oxidative stress within photoreceptors (PRs) in inherited photoreceptor degeneration (IPD) is unclear. We investigated this question using four IPD mouse models (Pde6b(rd1/rd1), Pde6b(atrd1/atrd1), Rho(-/-) and Prph2(rds/rds)) and compared the abundance of reduced glutathione (GSH) and the activity of mitochondrial NADH:ubiquinone oxidoreductase (complex I), which is oxidative stress sensitive, as indirect measures of redox status, in the retinas of wild type and IPD mice. All four IPD mutants had significantly reduced retinal complex I activities (14-29% of wild type) and two showed reduced GSH, at a stage prior to the occurrence of significant cell death, whereas mitochondrial citrate synthase, which is oxidative stress insensitive, was unchanged. We orally administered the mitochondrially targeted anti oxidant MitoQ in order to reduce oxidative stress but without any improvement in retinal complex I activity, GSH or rates of PR degeneration. One possible source of oxidative stress in IPDs is oxygen toxicity in the outer retina due to reduced consumption by PR mitochondria. We therefore asked whether a reduction in the ambient O(2) concentration might improve PR survival in Pde6b(rd1/rd1) retinal explants either directly, by reducing reactive oxygen species formation, or indirectly by a neuroprotective mechanism. Pde6b(rd1/rd1) retinal explants cultured in 6% O(2) showed 31% less PR death than normoxic explants. We conclude that (i) mitochondrial oxidative stress is a significant early feature of IPDs; (ii) the ineffectiveness of MitoQ may indicate its inability to reduce some mediators of oxidative stress, such as hydrogen peroxide; and (iii) elucidation of the mechanisms by which hypoxia protects mutant PRs may identify novel neuroprotective pathways in the retina.
MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Edinburgh, UK.
Dafni
D
Vlachantoni
Alexa N
AN
Bramall
Michael P
MP
Murphy
Robert W
RW
Taylor
Xinhua
X
Shu
Brian
B
Tulloch
Theo
T
Van Veen
Douglass M
DM
Turnbull
Roderick R
RR
McInnes
Alan F
AF
Wright
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D015687:Cell Hypoxia; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D042967:Electron Transport Complex I / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008928:Mitochondria / Q000378:metabolism*; D009943:Organophosphorus Compounds / Q000494:pharmacology; D018384:Oxidative Stress / Q000502:physiology*; D010786:Photoreceptor Cells / Q000187:drug effects / Q000473:pathology*; D012162:Retinal Degeneration / Q000503:physiopathology*; D013482:Superoxide Dismutase / Q000378:metabolism; D014451:Ubiquinone / Q000031:analogs & derivatives / Q000494:pharmacology; D000099156:Superoxide Dismutase 2
D000975:Antioxidants; D042967:Electron Transport Complex I; D005978:Glutathione; D009943:Organophosphorus Compounds; D013482:Superoxide Dismutase; D014451:Ubiquinone; D000099156:Superoxide Dismutase 2; C429014:mitoquinone