Watching synchronous mitochondrial respiration in the retina and its instability in a mouse model of macular degeneration

Abstract

Mitochondrial function declines with age and in some diseases, but we have been unable to analyze this in vivo. Here, we optically examine retinal mitochondrial function as well as choroidal oxygenation and hemodynamics in aging C57 and complement factor H (CFH−/−) mice, proposed models of macular degeneration which suffer early retinal mitochondrial decline. In young C57s mitochondrial populations respire in coupled oscillatory behavior in cycles of ~ 8 min, which is phase linked to choroidal oscillatory hemodynamics. In aging C57s, the oscillations are less regular being ~ 14 min and more dissociated from choroidal hemodynamics. The mitochondrial oscillatory cycles are extended in CFH−/− mice being ~ 16 min and are further dissociated from choroidal hemodynamics. Mitochondrial decline occurs before age-related changes to choroidal vasculature, hence, is the likely origin of oscillatory disruption in hemodynamics. This technology offers a non-invasive technique to detect early retinal disease and its relationship to blood oxygenation in vivo and in real time.

Watching the human retina breath in real time and the slowing of mitochondrial respiration with age

“…The numerical aperture of both source and detector fibers was 0.37. The miniature system used here has been described previously 16,21 . Briefly, light from a miniature low power broadband light source was filtered (cut off < 710 nm) and dim NIR light was with average power < 6mW across all wavelengths was delivered to the eye through the source fiber.…”

“…bNIRS measures concentration changes in oxidized cytochrome-c-oxidase (Δ[oxCCO]), the terminal enzyme in the mitochondrial electron transport chain (ETC), which catalyses over 95% of oxygen metabolism, simultaneously with blood oxygenation and hemodynamics, through measuring changes in concentration of oxygenated and deoxygenated hemoglobin (Δ[HbO 2 ] and Δ[HHb]) [13][14][15] . We have established this technology examining spectral changes in back reflected light from the retina to measure retinal tissue oxygenation and metabolism in rodents 16,17 .…”

Near infrared spectroscopy reveals instability in retinal mitochondrial metabolism and haemodynamics with blue light exposure at environmental levels

“…The pupils were dilated with 1% Tropicamide (Bausch and Lomb, France) and the cornea lubricated with Viscotears (Novartis, Switzerland). Mice were unrestrained and placed on their sides for real-time measurement of retinal oxygenation and haemodynamics as well as metabolism embedded in light within 780 to 900 nm range using a miniature bNIRS system, miniCYRIL [15].…”

Contribution of animal models to the mechanistic understanding of Alternative Pathway and Amplification Loop (AP/AL)‐driven Complement‐mediated Diseases

“…Analysis of eyes from 2‐year‐old Cfh −/− mice indicated an accumulation of C3 in the neural retinal and a thinning of the Bruch's membrane, associated with disorganization of cellular organelles (mitochondria) in the RPE, providing additional data to support a role for the AP/AL in eye damage in aged mice. 190 Subsequent functional and anatomical analysis of the eye in Cfh −/− mice revealed evidence of retinal damage, 190 , 191 a correlation with changes in oxidative stress, 192 and mitochondrion dysfunction, 193 all factors that are considered to lay the ground for AMD, as well as abnormalities in the retinal vasculature. 192 Increased expression of C1q, C3, and FB but failed upregulation of CD59 were also noted in the eyes of Cfh −/− mice as they age.…”