Professor Noah Malmstadt of the University of Southern California

Tuesday, September 22, 2020 - 10:45am

"How Oxidation Changes Cell Membrane Function: Distortion of Mechanics, Permeability, and Protein Activity"

Many biological processes produce reactive oxygen species (ROS); ROS production is intrinsic to metabolism and there are many routes by which biological antioxidative systems can fail, leading to oxidative stress. ROS are also generated upon interaction of cells with ambient light, as part of photodynamic therapies, and in hyperbaric environments. A key site of ROS-mediated chemical transformation is the cell plasma membrane, which is composed in part of oxygen-reactive polyunsaturated lipids.

Over the past decade, we have developed a set of systems for investigating how oxidative damage to lipids changes the fundamental properties of the plasma membrane. We construct giant unilammelar vesicles (GUVs)—cell-sized biomimetic membrane models—with either controlled chemical composition that mimics the oxidation process or light-reactive lipids that generate ROS in situ. Combining video microscopy with reaction kinetics modeling allows us to observe in real time how ROS attacks on saturated lipids change membrane mechanics and morphology, revealing in part that oxidized membranes form unusually large and stable pores. This violation of the integrity of membrane barrier properties is also borne out by microfluidic permeability experiments, which show a radical increase in lipid bilayer permeability to drug- and toxin-like molecules upon oxidation. More recently, we have investigated how membrane oxidation can alter the behavior of integral membrane proteins, particularly G protein-coupled receptors (GPCRs) involved in CNS function. As an example, the activity of the 1A serotonin receptor increases by a factor of two in oxidized membranes, suggesting that plasma membrane oxidation could be coupled to increased neuronal excitability.