Regulation of tissue oxygen levels in the mammalian lens

Abstract

Opacification of the lens nucleus is a major cause of blindness and is thought to result from oxidation of key cellular components. Thus, long-term preservation of lens clarity may depend on the maintenance of hypoxia in the lens nucleus. We mapped the distribution of dissolved oxygen within isolated bovine lenses and also measured the rate of oxygen consumption (Q O 2 ) by lenses, or parts thereof. To assess the contribution of mitochondrial metabolism to the lens oxygen budget, we tested the effect of mitochondrial inhibitors onQ O 2 and partial pressure of oxygen (P O 2 ). The distribution of mitochondria was mapped in living lenses by 2-photon microscopy. We found that a steep gradient of P O 2 was maintained within the tissue, leading to P O 2 < 2 mmHg in the core. Mitochondrial respiration accounted for approximately 90% of the oxygen consumed by the lens; however, P O 2 gradients extended beyond the boundaries of the mitochondria-containing cell layer, indicating the presence of non-mitochondrial oxygen consumers. Time constants for oxygen consumption in various regions of the lens and an effective oxygen diffusion coefficient were calculated from a diffusion-consumption model. Typical values were 3 × 10 −5 cm 2 s −1 for the effective diffusion coefficient and a 5 min time constant for oxygen consumption. Surprisingly, the calculated time constants did not differ between differentiating fibres (DF) that contained mitochondria and mature fibres (MF) that did not. Based on these parameters, DF cells were responsible for approximately 88% of lens oxygen consumption. A modest reduction in tissue temperature resulted in a marked decrease inQ O 2 and the subsequent flooding of the lens core with oxygen. This phenomenon may be of clinical relevance because cold, oxygen-rich solutions are often infused into the eye during intraocular surgery. Such procedures are associated with a strikingly high incidence of postsurgical nuclear cataract.

Measurement of PO2 during vitrectomy for central retinal vein occlusion, a pilot study

“…The objective to increase oxygenation of the vitreous chamber should be offset by the caveat that increased PO 2 is implicated in the generation of nuclear sclerotic cataracts 10,28 . Therefore, a balance between maintaining sufficient oxygenation to support the viability of surrounding tissues but preventing the development of unwanted side-effects needs to be established.…”

Vitreoretinal influences on lens function and cataract

“…In the vitreous near the posterior of the human lens, the pO 2 drops to approximately 7 mmHg (approx.1% O 2 ) [21] and our recent measurements in human patients revealed that the pO 2 near the anterior and lateral surfaces of the lens is typically about 3 mmHg (less than 0.4%) [22]. The low oxygen near the surfaces of the lens and the consumption of oxygen by lens cells results in even lower pO 2 in the lens nucleus [23,24]. Therefore, cells in the eye are exposed to conditions that, for typical cells, would range from hyperoxic to severely hypoxic.…”

“…These cells have no mitochondria, peroxisomes, endoplasmic reticulum, or other organelles known to generate ROS. They are also in a very low-oxygen environment [24,27]. With their high levels of glutathione, superficial fibre cells are probably the least likely cells in the body to suffer oxidative damage.…”

Wild-type Human γD-crystallin Promotes Aggregation of Its Oxidation-mimicking, Misfolding-prone W42Q Mutant

“…Perhaps because of its low glutathione concentrations, the lens core is maintained at a very low partial pressure of oxygen (45). Our aggregation reactions were carried out under ambient atmosphere.…”