April 2010
Volume 51, Issue 13
Free
ARVO Annual Meeting Abstract  |   April 2010
Heterozygous Mouse Model of Opa1 Dominant Optic Atrophy Displays Increased Mitochondrial Fragmentation but No Significant Increase in Retinal Apoptosis
Author Affiliations & Notes
  • M. Votruba
    School of Optometry & Vision Sciences, Cardiff University, Cardiff, United Kingdom
    University Hospital Wales, Cardiff, United Kingdom
  • M. Piechota
    School of Optometry & Vision Sciences, Cardiff University, Cardiff, United Kingdom
  • E. Taylor
    School of Optometry & Vision Sciences, Cardiff University, Cardiff, United Kingdom
  • J. R. Davies
    School of Optometry & Vision Sciences, Cardiff University, Cardiff, United Kingdom
  • M. E. Boulton
    Anatomy and Cell Biology, University of Florida, Gainesville, Florida
  • V. J. Davies
    School of Optometry & Vision Sciences, Cardiff University, Cardiff, United Kingdom
    Cardiff Neuroscience Centre, Cardiff University, Cardiff, United Kingdom
  • Footnotes
    Commercial Relationships  M. Votruba, None; M. Piechota, None; E. Taylor, None; J.R. Davies, None; M.E. Boulton, None; V.J. Davies, None.
  • Footnotes
    Support  MRC Project Grant G0700949
Investigative Ophthalmology & Visual Science April 2010, Vol.51, 1001. doi:
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      M. Votruba, M. Piechota, E. Taylor, J. R. Davies, M. E. Boulton, V. J. Davies; Heterozygous Mouse Model of Opa1 Dominant Optic Atrophy Displays Increased Mitochondrial Fragmentation but No Significant Increase in Retinal Apoptosis. Invest. Ophthalmol. Vis. Sci. 2010;51(13):1001.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: : Autosomal dominant optic atrophy (ADOA) due to mutations in OPA1 is a slowly progressive optic neuropathy. OPA1 is ubiquitously expressed and plays a key role in mitochondrial fusion. Heterozygous Opa1 mutant mice (B6;C3-Opa1Q285STOP), with previously reported visual defects and optic nerve changes on EM, were assessed for evidence of cellular effects and retinal sequelae.

Methods: : The level and processing of Opa1 were studied by Western blot. Membrane potential was assessed by JC-1 in isolated mitochondria. Mitochondrial morphology was investigated using Mitotracker staining on E13.5 mouse embryonic fibroblasts (MEFS). MEFS were treated with H2O2 (1mM: 1hr and 2hr) and blue light (irradiance 2.3 mW/cm2 for up to 24hr), and analysed by MTT assay to assess vulnerability to oxidative stress. End-organ evidence for apoptosis was explored on TUNEL stained retinal sections.

Results: : The heterozygous mutation leads to ca. 50% reduction in Opa1 protein in mitochondria. Despite this there is no statistically significant reduction in the average mitochondrial membrane potential in the retina and brain by 5 months of age. Although Opa1 +/- MEFS demonstrate a 15% increase in the number of cells showing mitochondrial fragmentation their growth and survival characteristics after oxidative stress were not significantly affected. There was no increased apoptosis in retinal sections from mutant animals.

Conclusions: : A 50% reduction in Opa1 protein, capable of causing a defect in mitochondrial morphology in MEFS, in the presence of visual dysfunction and morphological changes on electron microscopy in the optic nerve, nevertheless does not appear to lead to a significant increase in apoptosis in retina. This suggests that the protein truncating mutation in this model may lead to an alternative putative mechanism for RGC dysfunction and long-term removal.

Keywords: proteins encoded by disease genes • mitochondria • gene/expression 
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