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Dongfeng Cao, Jeffrey D Messinger, Deepayan Kar, Thomas Ach, Christine A Curcio; Human photoreceptor mitochondria (PR-Mit) are molecularly unique in healthy aged retina and outer retinal tubulation (ORT) of age-related macular degeneration (AMD). Invest. Ophthalmol. Vis. Sci. 2022;63(7):2584 – F0467.
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Mit in inner segments (IS) of photoreceptors (PR) have optical as well as energy-generating and calcium-buffering functions. They guide light to outer segments (OS). PR Mit are the hypothesized reflectivity source for the border of ORT, a scrolling of photoreceptors by Müller glia in advanced AMD, seen in optical coherence tomography (OCT). We immuno-stained Mit in aged-normal and advanced AMD retinas for cytochrome oxidase 4 (COX4), the terminal oxidase of the electron transport chain, and transmembrane protein 119 (TMEM119), a microglia cell-surface marker.
Twelve μm-thick sections of maculae from 20 eyes including 4 normal, 7 early-or-intermediate (e-i) AMD, 9 advanced AMD (6 atrophic (a), 3 neovascular (nv)) of white donors >80 years were immuno-stained with COX4 (Invitrogen, #459600) and TMEM119 (Abcam, #ab185333) using red-substrate enzymatic detection and scanned with a 40x objective. Positive controls were surgically excised human liver tissue. Negative control experiments used mouse IgG isotope (COX4) and omitted primary antibody (TMEM119).
In neurosensory retina of normal and e-iAMD eyes, punctate COX4 immunoreactivity localized to inner limiting membrane, ganglion cell layer, PR IS, retinal pigment epithelium and cone pedicles/rod spherules in outer plexiform layer. Staining was moderate in other retinal layers and undetectable in PR OS, Bruch’s membrane, and sclera. Of these locations, PR IS was also labeled with anti-TMEM119, in fovea and non-fovea regions, indicating labeling in both cones and rods. In advanced AMD eyes with ORT, both COX4 and TMEM119 specifically labeled PR IS in ORT open and closed configurations. In ORT, immunoreactivity in individual IS of PR lacking OS progressively approached and crossed the external limiting membrane.
Data suggest that PR MIT have a unique molecular composition possibly important for optical properties in health and AMD. The hypothesis that mitochondria are reflectivity sources in OCT, initially shown for ORT using electron microscopy of advanced AMD eyes (PMID 25635579), is further supported by the current demonstration of immunoreactivity for TMEM119 and COX4 at all stages of photoreceptor degeneration. Direct contributions of COX4 and TMEM119 to light transmission and reflectance remain to be determined experimentally.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.
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