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W. D. Ferrell, F. R. Vazquez-Chona, Y. Lin, B. W. Jones, R. E. Marc; Metabolic Biomarkers of Early Retinal Oxidative Stress. Invest. Ophthalmol. Vis. Sci. 2009;50(13):4478.
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We are interested in discovering initiators of retinal remodeling through exploration of characteristic proteomic and small molecular stress signatures in photoreceptors after acute oxidative insult. Our hypothesis is that oxidative stress induces metabolic changes in photoreceptors that can be identified, tracked and predicted.
We explored the acute phase of induced phototoxic oxidative stress in Balb/c albino mice. Retinas were harvested during light exposure (0h-24h) and immediately after light exposure (0d-4d). Mice were euthanized, eyes enucleated and fixed for visualization by computational small-molecular phenotyping (Marc and Jones, J Neurosci 22:413-427) or proteomic profiling. Cell death rates were assessed with Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL).
Oxidative stress induces dynamic changes in arginine, aspartate and glutamate levels. The earliest changes observed are the transient upregulation of arginine in virtually every photoreceptor nuclei. In areas of known photoreceptor vulnerability to light damage, abnormal spikes of glutamate and aspartate occur. In areas of traditionally defined cell death (TUNEL staining) rod aspartate and glutamate decrease dramatically, falling to undetectable levels indicating a complete dialysis of both aspartate and glutamate in those cell classes.
Enhanced rod aspartate, glutamate, and arginine are novel markers of oxidative stress in photoreceptors. Arginine upregulation in the nucleus could reveal a role in DNA repair while elevated levels of aspartate and glutamate suggest potential mitochondrial damage. Depletion of aspartate and glutamate reveals more acute metabolic indicators of cell death than traditional proteomic measures. Ongoing work aims to understand how these metabolic changes reveal which metabolic pathways photoreceptors undergo in survival or cell death.
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