The Eye: Metabolism and Vision

The Eye: Metabolism and Vision

• Light passes through the cornea, aqueous humor, lens, vitreous body, and focuses on the retina.
• Tears bathe the cornea's exterior; aqueous humor bathes the interior.
• Aqueous humor is isoosmotic, containing salts, albumin, globulins, glucose, and other components.
• It delivers nutrients to the cornea and lens, and removes metabolic waste.
• The vitreous humor is a gel that maintains the eye's shape and pliability.

Cornea Derives ATP from Aerobic Metabolism

• The eye, like the nervous system, primarily uses glucose for metabolism.
• The cornea, like the lens, diffracts light. Its clarity comes from the arrangement of collagen in the stroma.
• The cornea is permeable to water and oxygen.
• The cornea's water content is regulated by an ATP-driven water pump.
• The lack of blood vessels in the epithelial layer contributes to clarity.
• VEGFR-3, a protein in the anterior epithelial layer, prevents blood vessel growth.
• ATP is generated through aerobic glucose metabolism (glycolysis and the TCA cycle).
• Lactate doesn't significantly accumulate due to efficient metabolic pathways.
• 30% of glucose metabolism is via glycolysis, 65% via the hexose monophosphate pathway.
• The cornea has high hexose monophosphate pathway activity compared to other tissues.
• The cornea also has high glutathione reductase activity, which uses NADPH.

The Pentose Phosphate Pathway

• The nonoxidative reactions facilitate reversible conversion between intermediates of glycolysis and five-carbon sugars (e.g., ribose-5-P).
• Cell needs dictate the pathway's direction. If the cell needs ribose 5-P for nucleotides, it goes towards ribose 5-P. If it needs NADPH, it may convert ribose 5-P back to glucose 6-phosphate.
• NADPH is critical (made in the pentose phosphate pathway).
• Oxygen reactions can form harmful active oxygen species that damage lipids and proteins.
• Reduced glutathione (GSH) converts oxidized glutathione (GSSG) back to its reduced state; NADPH supports this process.

Glutathione

• Glutathione is a tripeptide (glutamate, cysteine, and glycine).
• It's found in the cell's millimolar range (1-10 mM).
• Reduced glutathione (GSH) maintains the cellular reduced state.
• Glutathione reductase utilizes NADPH to convert GSSG back to 2GSH.

Glucose 6-Phosphate Dehydrogenase Deficiency

• Deficiency impairs NADPH production.
• Inadequate NADPH leads to insufficient cellular glutathione reduction.

Glutathione Peroxidases

• Glutathione peroxidases are selenium enzymes that remove hydrogen peroxide (H₂O₂).
• These enzymes and the glutathione reductase cycle play a crucial role in protecting against free radical injury.
• NADPH is essential for the glutathione reductase cycle.

Cornea Active Oxygen and Lipids

• Pentose phosphate pathway and glutathione reductase protect the cornea by neutralizing active oxygen species.
• Peroxidized lipids may form active aldehydes.
• ALDH3A1, an aldehyde dehydrogenase isoform, inactivates active aldehydes.

Lens Function

• Lenses primarily consist of water and proteins (α-, β-, γ-crystallins).
• They obtain nutrients and eliminate waste through the aqueous humor.
• No blood vessels exist within the lens.
• They have specific protein requirements to maintain a clear, crystalline structural state.
• The lens is sensitive to osmolarity changes, oxidation-reduction imbalances, metabolite concentrations.

Lens Structural Integrity

• Maintaining osmotic balance is crucial; the Na+/K+ ATPase helps with salt concentration.
• The glutathione reductase cycle safeguards against redox state imbalances.
• Protein synthesis and other metabolic processes sustain growth and integrity in the lens periphery.
• α- and β-Crystallins (small heat shock proteins) maintain lens protein structure in their native state.
• Mutations in crystallins can lead to cataract formation and potential muscular issues.

Lens Metabolism

• About 85% of glucose metabolism in the lens occurs through glycolysis, with 3% utilizing the TCA cycle, and the remaining using the pentose phosphate pathway.
• The lens nucleus remains from birth, growing in size and thickness with age.
• This growth pattern affects the lens's elasticity which results in presbyopia (loss of near vision).
• A threefold increase in lens size and a 12-fold increase in thickness from birth to 80 years are observed.

Cataract

• Cataracts are lens opacities stemming from varied conditions.
• The two most common are senile and diabetic cataracts.
• Senile cataracts correlate to age-related changes in lens crystallins and protein molecules (e.g., breakdown at C-terminal ends, deamidation, and racemization).

Diabetic Cataracts

• Increased aldose reductase activity, alongside polyol dehydrogenase activity, leads to osmotic imbalances in the lens.
• Elevated glucose levels increase sorbitol accumulation; it cannot be effectively metabolized by the lens.
• This accumulation leads to structural changes and impairment within the lens proteins, and increase in the rate of protein aggregation and denaturation
• The higher glucose concentration in diabetic individuals leads to more visible light scatter, characteristic of cataract formation.

Retinal Metabolism

• The retina heavily relies on anaerobic glycolysis for ATP.
• Unlike the lens, the retina is vascularized.
• The fovea centralis, the central region of the macula (a region in the retina), is rich in cones. This is the area of greatest visual activity.
• Mitochondria are present in connecting retinal rods and cones, but not in the outer segments containing visual pigments.

Glucose Conversion to Fructose via Sorbitol

• Most sugars are phosphorylated upon entering cells, trapping them within the cells; this prevents them from freely entering the cytoplasm
• Sugar alcohols, like sorbitol, are formed via the reduction of an aldehyde group in a monosaccharide, producing an extra hydroxyl group.

Sorbitol Synthesis

• Aldose reductase synthesizes sorbitol. Its activity is high in the retina, lens, kidneys, and peripheral nerves.
• Sorbitol dehydrogenase converts sorbitol to fructose (primarily in the liver, ovaries, and seminal vesicles).
• This pathway helps fructose become available to cells for glycolytic metabolism.