Abstract
Purpose :
The mitochondrial respiratory chain (RC) is the site of cellular energy production. The mitochondrial gene cytochrome c oxidase 1 (CO1) encodes a crucial subunit of the RC Complex IV. A CO1 missense mutation (V421A) generated on a C57BL/6 background demonstrated decreased Complex IV activity, decreased visual function, and increased oxidative stress in the retinas of both sexes (IVOS 2019;#665-B0143). Male mutants also demonstrated reduced number of retinal ganglion cells (RGCs) and decreased RGC-specific gene expression suggestive of RGC death. We characterized the ocular phenotype of CO1 mutant mice in the setting of induced ocular hypertension.
Methods :
The microbead occlusion model was used to induce ocular hypertension as previously described (PMID:27077732). Briefly, 18-month-old mice (14 mutants and 8 WT controls) received injections of magnetic microbeads in the anterior chamber of the left eye (OS) while the right eye (OD) received concurrent injections of sterile BSS. Mice were injected on day 0 and again 2 weeks later. Intraocular pressures (IOPs) were measured immediately prior to the first injection and then weekly using the Icare® TONOLAB tonometer. After 8 weeks, RGCs were labeled with Brn3a and rbpms on retina flat mounts of mutants and WT controls and cellular density was assessed in 6 40x images. The number of RGC axons were counted in optic nerve cross sections obtained 1.5mm posterior to the globe.
Results :
Following microbead injections, IOP remained elevated for > 8 weeks in both CO1 mutants (10.3±0.7 OD vs. 19.0±3.34 mmHg OS [Mean±SE]) and WT controls (11.3±0.5 vs. 23.4±4.8). Following 8 weeks of sustained ocular hypertension, averaged RGC density decreased by ~17% in CO1 mutants (170.5±4.0 OD vs. 142.3±13.7 OS) and by ~11% in WT controls (203.1±7.2 OD vs. 179.5±18.9 OS). Assessment of RGC axon counts in the optic nerves are pending.
Conclusions :
Results suggest increased susceptibility to glaucomatous optic neuropathy in CO1 mutants of both sexes. Interestingly, while RGC loss was present only in male mutants at baseline, female mutants also proved susceptible to RGC loss following the additional perturbation of induced ocular hypertension.
This is a 2020 ARVO Annual Meeting abstract.