L 17 Lens Metabolism and Cataracts

What process drives lens circulation?

water/ion flow through lens which is dependent on NKA concentrated in cells near the equator, gap junctions, and aquaporins

How is glucose supplied to the lens?

glucose must be acquired from the surrounding aqueous humor

glucose is supplied to the aqueous humor by transport through the ciliary body

What glucose transporter is primarily found in the lens epithelium?

GLUT1

What glucose transporter is primarily found in cortical lens fibers and decreases towards the center of the lens?

GLUT3

Does glucose have a higher affinity for GLUT1 or GLUT3?

glucose has a higher affinity for GLUT3

Which glucose transporter is found in deep lens fiber cells?

SGLT

What are the general complications of diabetes on the lens?

lens is damaged by high levels of glucose, it facilitates cataract formation

sorbitol causes osmotic damage

Which enzyme mediates lens damage from high glucose levels?

aldose reductase

What are the long term effects of diabetes on the lens?

variable refractive changes and opacities

increases lens size (thicker lens and increase in curvature)

*could be due to changes in lens growth rate/fiber length/water

What are the short term effects of diabetes on the lens?

variable refractive changes that are caused by fluctuations in glucose levels affects osmolarity of the lens

fluctuations in osmolarity is caused by sorbitol formation

galactosemia

defect in, or absence of , galactose-metabolizing enzymes that causes osmotic swelling of the lens epithelial cells

causes lens opacity (cataracts)

What are the two main oxygen sources of the lens?

1. diffusion across the cornea (MAJOR)

2. retinal vasculature (minor)

*small contribution from ciliary body vasculature, but most O2 is utilized by ciliary body epithelia

What is the gradient of pO2 in the lens tissue?

highest in the lens epithelium and peripheral lens fibers

lowest in the lens nucleus

What are the effects of low pO2 in the lens?

1. protects lens proteins and lipids from oxidative damage

2. linked to rate of growth: more oxygen = more growth, less oxygen = less growth

What is the difference in pO2 of aqueous humor in the anterior chamber vs posterior chamber?

anterior aqueous humor has higher pO2 than posterior aqueous humor near the lens

What is the type of lens metabolism dependent on?

oxygen content and mitochondria number

Which part of the lens has the highest number of mitochondria?

lens epithelium

How does the number of mitochondria change as you go from superficial lens fibers to central nuclear fibers?

number of mitochondria decreases in lens fibers from superficial fiber to the central nucleus

What type of metabolism do the lens epithelial cells undergo?

cells undergo both aerobic and anaerobic metabolism

What type of metabolism do the lens fiber cells undergo?

almost entirely anaerobic

Where is the majority of the lens ATP derived from?

anaerobic glycolysis

What are the two main functions of the hexose monophosphate pathway in the lens cells?

1. produces NADPH used in the synthesis of lipids and to limit reactive oxygen species generated by aerobic glycolysis

2. produces ribose-phosphate, needed for nucleic acid synthesis

What accumulates in the lens due to anaerobic glycolysis?

lactate/lactic acid

causes intracellular pH to drop significantly from peripheral to deeper fiber cells

T/F: hyperbaric oxygen can cause nuclear cataract formation

true

How does increased oxygen levels cause cataracts?

1. oxidative phosphorylation generates free radicals in cortical lens fibers/epithelium

2. UV light absorbed by lens fiber proteins/DNA can produce free-radicals

How does a vitrectomy cause cataracts?

removes the barrier of the vitreous between the lens and retina

increased O2 from the retinal vasculature increases oxidative stress of the lens

What are the minor and major lens oxidants?

minor = lens mitochondria act on superoxide anion with superoxide dismutase

major = oxidation of ascorbic acid

glutathione

mitigates oxidation of lens proteins by becoming oxidized itself

generated by lens epithelial cells, superficial lens fibers and gap junctions allow passage between cells

What are the steps of glutathione production?

1. amino acid transporters bring precursors into the lens epithelial/cortical lens fiber cells

2. assembly in part through the enzyme glutathione synthase

3. transported through sodium dependent transporter and gap junctions

How does glutathione reduce ROS?

forms disulfide bonds with oxidized sulfhydryl groups of damaged proteins

Which protein reduces mixed disulfide and produces a "fixed" protein and oxidized glutathione?

thioltransferase

What enzymes are used to refresh glutathione?

glutathione reductase

*utililizes NADPH in the process, NADPH from hexose monophosphate shunt

How is the rate of infusion of reduced glutathione change with age and what is the effect of the changed diffusion rate?

rate of diffusion diminishes with age

older lenses are therefore more susceptible to oxidative damage than younger lenses

What is H2O2 produced by in the eye and how is it mitigated?

H2O2 is produced via ascorbic acid oxidation/oxidative phosphorylation and it is mitigated by glutathione peroxidase and catalase

cataract

opacification of the lens

What can cataracts be caused by?

1. increases in light scattering by:

disruption of lens structure

increase in protein aggregation

cytoplasmic phase separation

2. increase in light absorption by brunescent

What is bruncescence of the lens caused by?

buildup of chromophores

kynureine

normally provides UV filtration of UVB/UVA light

prone to deamination/oxidation and becomes a chromophore

age-related nuclear cataracts

associated with increased oxidative damage to the lens proteins and lipids:

1. disulfide bond formation between protein subunits aggregates proteins

2. crystalline protein-lipid membrane interactions occur

3. an increase in oxidized glutathione in lens nucleus occurs

What is the most common type of age-related nuclear cataracts?

age-related nuclear cataracts

What is the function of alpha crystallin proteins?

have chaperone-like activity

prevents protein unfolding

promotes protein solubility

What is the role of alpha crystallin proteins in maintaining solubility of proteins and how does this relate to age-related cataracts?

soluble alpha crystallin proteins decrease with age in the lens nucleus further decreasing its ability to maintain the solubility of other proteins

Where do age-related cataracts most often occur?

inferior/nasal quadrant of the lens

What type of cataracts can be caused by disruptions to adherents junctions?

cortical cataracts

posterior sub capsular cataract

light scattering in a cluster of swollen cells at he posterior pole just beneath the capsule, forms in light path making it more likely to reduce vision

What are the two causes of sub capsular cataracts?

1. aberrant migration or differentiation of lens epithelial cells: can be cause by radiation or intravitreal steroids

2. can occur due to swelling of posterior ends of fibers along suture planes

anterior polar cataract

formation of an opaque plaque near center of lens epithelium

inherited or sporadic

due to abberant lens epithelial cell differentiation and growth

secondary cataracts

frequent complication of extra capsular cataract surgery