Influence of Cholesterol on the Oxygen Permeability of Membranes: Insight from Atomistic Simulations

Abstract

Cholesterol is widely known to alter the physical properties and permeability of membranes. Several prior works have implicated cell membrane cholesterol as a barrier to tissue oxygenation, yet a good deal remains to be explained with regard to the mechanism and magnitude of the effect. We use molecular dynamics simulations to provide atomic-resolution insight into the influence of cholesterol on oxygen diffusion across and within the membrane. Our simulations show strong overall agreement with published experimental data, reproducing the shapes of experimental oximetry curves with high accuracy. We calculate the upper-limit transmembrane oxygen permeability of a 1-palmitoyl,2-oleoylphosphatidylcholine phospholipid bilayer to be 52 ± 2 cm/s, close to the permeability of a water layer of the same thickness. With addition of cholesterol, the permeability decreases somewhat, reaching 40 ± 2 cm/s at the near-saturating level of 62.5 mol % cholesterol and 10 ± 2 cm/s in a 100% cholesterol mimic of the experimentally observed noncrystalline cholesterol bilayer domain. These reductions in permeability can only be biologically consequential in contexts where the diffusional path of oxygen is not water dominated. In our simulations, cholesterol reduces the overall solubility of oxygen within the membrane but enhances the oxygen transport parameter (solubility-diffusion product) near the membrane center. Given relatively low barriers to passing from membrane to membrane, our findings support hydrophobic channeling within membranes as a means of cellular and tissue-level oxygen transport. In such a membrane-dominated diffusional scheme, the influence of cholesterol on oxygen permeability is large enough to warrant further attention.

Oxygen Transport to Tissue XL

“…The rafts are believed to function together with integral and peripheral proteins and could play a role in signal transduction, intracellular transport, and protein sorting in these membranes [1,2]. Both experimental [3] and computational [4] work have demonstrated that addition of cholesterol reduces the permeability of POPC phospholipid bilayers, and experimental work [5] confirms this trend for DOPC. Another characteristic of rafts is the richness in saturated lipids.…”

Supramolecular Crowding Can Avoid Oxygen Quenching of Photon Upconversion in Water

“…This loosens the molecular alignment, and, consequently, the spacer methylene groups connected to the highly hydrated ammonium groups exhibit enhanced micropolarity near the aggregate surface. A larger partition coefficient of oxygen to these molecular voids is expected, with a diffusion path possibly dominated by water …”

“…Indeed, studies on oxygen transport across model and plasma membranes showed that membranes are in general not barriers to oxygen transport into the cell . Meanwhile, oxygen concentration is known to be low in some tissues, notably fiber cells of the eye lens, in which the lens nuclei are protected from oxidative damage and cataracts . The plasma membranes of these fiber cells show extremely high cholesterol content, which is considered to ensure the rigidity of the membrane that contributes to reducing its oxygen permeability .…”

“…Meanwhile, oxygen concentration is known to be low in some tissues, notably fiber cells of the eye lens, in which the lens nuclei are protected from oxidative damage and cataracts . The plasma membranes of these fiber cells show extremely high cholesterol content, which is considered to ensure the rigidity of the membrane that contributes to reducing its oxygen permeability . Recent atomic‐scale molecular dynamics investigations suggest that the close packing of cholesterol molecules and phospholipids generates a physical barrier to oxygen diffusion at the membrane interfaces …”

Non-Canonical Mechanisms Regulating Hypoxia-Inducible Factor 1 Alpha in Cancer

“…Therefore, OXPHOS damage does not seem to irreversibly prevent, but may rather attenuate HIF-1α stabilization, suggesting that the increased intracellular oxygen concentrations, caused by the lower oxygen consumption, may rapidly equilibrate with the extracellular tensions. Such equilibration probably depends on the cellular membrane permeability to molecular oxygen, which among other is influenced by cholesterol levels and, therefore, lipid metabolism, which is conditioned by the OXPHOS status ( 44 ).…”