Membrane Channels Formed by Ceramide

Abstract

The sphingolipid, ceramide, forms channels in the mitochondrial outer membrane and in lipid membranes composed of only phospholipid/cholesterol, using lipids typically found in the natural membrane. These channels are large, allowing proteins to cross membranes. Experimental results are consistent with ceramide forming barrel-stave channels that are rigid and highly organized. Bcl-2 family proteins control these channels in a manner expected from their physiological function: anti-apoptotic proteins destabilize the channels whereas pro-apoptotic proteins act synergistically with ceramide to increase membrane permeability. The use of ceramide analogs has allowed one to gain insight into the features of the molecule that are most important for channel formation. These analogs have also been useful in identifying the sites of interaction between ceramide and both Bax and Bcl-xL. The pores formed in phospholipid membranes by ceramide were visualized by electron microscopy. The most common pore size was 10 nm in diameter, consistent with results obtained from electrophysiological recordings. All indications point to a role for ceramide channels in the release of proteins from mitochondria, a key decision-making step in the apoptotic process.