Evidence of severe mitochondrial oxidative stress and a protective effect of low oxygen in mouse models of inherited photoreceptor degeneration.

TitleEvidence of severe mitochondrial oxidative stress and a protective effect of low oxygen in mouse models of inherited photoreceptor degeneration.
Publication TypeJournal Article
Year of Publication2011
AuthorsVlachantoni, D, Bramall, AN, Murphy, MP, Taylor, RW, Shu, X, Tulloch, B, Van Veen, T, Turnbull, DM, McInnes, RR, Wright, AF
JournalHum Mol Genet
Volume20
Issue2
Pagination322-35
Date Published2011 Jan 15
ISSN1460-2083
KeywordsAnimals, Antioxidants, Cell Hypoxia, Cell Survival, Disease Models, Animal, Electron Transport Complex I, Glutathione, Mice, Mice, Inbred C3H, Mice, Inbred C57BL, Mice, Inbred DBA, Mitochondria, Organophosphorus Compounds, Oxidative Stress, Photoreceptor Cells, Retinal Degeneration, Superoxide Dismutase, Ubiquinone
Abstract

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.

DOI10.1093/hmg/ddq467
Alternate JournalHum. Mol. Genet.
Citation Key10.1093/hmg/ddq467
PubMed ID21051333
Grant ListMC_U105663142 / / Medical Research Council / United Kingdom
MOP-7315 / / Canadian Institutes of Health Research / Canada
IOP 54037 / / Canadian Institutes of Health Research / Canada
074454 / / Wellcome Trust / United Kingdom
MC_U127584475 / / Medical Research Council / United Kingdom
G0601943 / / Medical Research Council / United Kingdom