Lipid Oxidation: Role of Membrane Phase-Separated Domains

Abstract

Lipid oxidation is associated with several inflammatory and neurodegenerative diseases, but many questions to unravel its effects on biomembranes are still open due to the complexity of the topic. For instance, recent studies indicated that phase-separated domains can have a significant effect on membrane function. It is reported that domain interfaces are “hot spots” for pore formation, but the underlying mechanisms and the effect of oxidation-induced phase separation on membranes remain elusive. Thus, to evaluate the permeability of the membrane coexisting of liquid-ordered (Lo) and liquid-disordered (Ld) domains, we performed atomistic molecular dynamics simulations. Specifically, we studied the membrane permeability of nonoxidized or oxidized homogeneous membranes (single-phase) and at the Lo/Ld domain interfaces of heterogeneous membranes, where the Ld domain is composed of either oxidized or nonoxidized lipids. Our simulation results reveal that the addition of only 1.5% of lipid aldehyde molecules at the Lo/Ld domain interfaces of heterogeneous membranes increases the membrane permeability, whereas their addition at homogeneous membranes does not have any effect. This study is of interest for a better understanding of cancer treatment methods based on oxidative stress (causing among others lipid oxidation), such as plasma medicine and photodynamic therapy.

Fluorescence lifetime imaging of lipid heterogeneity in the inner mitochondrial membrane

“…4a and 4f), indicating an increase in the membrane order. This stands in contrast to our assumption that lipid peroxidation would shorten the fluorescence lifetime, given that a geometrically disordered bilayer causes an increase in water permeability, and thus, an increase in membrane polarity [34][35][36][37] . To deeply understand how the mitochondria were damaged, the light-induced lipid oxidation process was then recorded using FLIM in time-lapse mode.…”

Melatonin: Regulation of Prion Protein Phase Separation in Cancer Multidrug Resistance

“…Lipid peroxidation is a cascading event initiated by ROS attacking anionic headgroups at membrane interfaces [ 804 ] where oxidized moieties residing close to lipid headgroups perturb membrane bilayer structures, modifying membrane properties including increasing membrane permeability [ 805 ], decreasing membrane fluidity [ 806 , 807 ], and increasing line tension, which can transform nanometer-scale lipid rafts into larger, micron-sized domains [ 776 , 808 , 809 ] that carry pro-inflammatory molecules often associated with cancer cell signaling pathways [ 328 , 777 , 780 ]. Experimental results using giant membrane vesicle model systems showed that lipid peroxidation induced significant changes in membrane phase behavior, causing a dramatic escalation of phase separation at room temperature, which increased the non-raft phase while decreasing affinity of tested raft proteins for raft domains [ 810 ].…”

Oxidation of Membrane Lipids Alters the Activity of the Human Serotonin 1A Receptor

“…27−29 Such changes in the membrane may lead to an increase in permeability for polar molecules like water. 27,30,31 Increased plasma membrane permeability can make a cell more susceptible to spontaneous pore formation, leading to solute imbalance and cell death. 7,32 While there has been significant study on how phospholipid oxidation can alter the material properties of the lipid bilayer, little is known about how changes in these properties are connected to the behavior of integral membrane proteins.…”

“…For instance, one possible result of a free-radical chain reaction in the lipid bilayer is the scission of a fragment of a phospholipid tail, resulting in the altered lipid molecular area and potential removal of the cleaved tail from the bilayer . Lipid oxidation causes a decrease in membrane thickness and a drastic change in area per lipid depending on the degree of oxidation. , Changes to lipid conformation are due to the tendency of the cleaved tail to be in the proximity of the headgroup region, forming hydrogen bonds with water molecules. − Such changes in the membrane may lead to an increase in permeability for polar molecules like water. ,, Increased plasma membrane permeability can make a cell more susceptible to spontaneous pore formation, leading to solute imbalance and cell death. , …”