Ceramide channel: Structural basis for selective membrane targeting

Abstract

A ceramide commonly found in mammalian cells, C16-ceramide (N-palmitoyl-D-erythrosphingosine), is capable of forming large, protein-permeable channels in the mitochondrial outer membrane (MOM). However, C16-ceramide is unable to permeabilize the plasma membrane of erythrocytes. This specificity is unexpected considering that ceramide forms channels in simple phosphoglycerolipid membranes. Synthetic analogs of C16-ceramide with targeted changes at each of the functional regions of the molecule including methylation, altered hydrocarbon chain length, and changes in the stereochemistry, were tested to probe the role of ceramide's molecular features on its ability to form channels in these two different membrane types. The ability to permeabilize the MOM was relatively insensitive to modifications of the various functional groups of ceramide whereas the same modifications resulted in plasma membrane permeabilization (a gain of function rather than a loss of function). Some analogs (ceramine, NBD-labeled ceramide, C18,1 ceramide) gained another function, the ability to inhibit cytochrome oxidase. The gain of deleterious functions indicates that constraints on the structure of ceramide that is formed by the cell's synthetic machinery includes the avoidance of deleterious interactions. We propose that the specific structure of ceramide limits the size of its interactome (both proteins and lipids) thus reducing the likelihood of unwanted side effects.

Sphingolipids and lipid rafts: Novel concepts and methods of analysis

“…These studies found that mixtures of cholesterol and ceramide may increase permeability of cellular membranes including those of mitochondria (Goni et al, 2005). The mechanism is related but not identical to ceramide pores described by Marco Colombini’s group (Perera et al, 2016; Siskind et al, 2002). They form at a certain concentration in isolated mitochondria and may induce apoptosis, an alternative (or complementary) mechanism to death receptor clustering previously described for ceramide rafts.…”

“…Our study showed that ceramide enrichment in MAMs and its interaction with tubulin promotes closure of VDAC1 and impairs ATP generation when ceramide levels increase (Kong et al, 2018). It should be noted that the function of ceramide in or at mitochondria has gained growing attention in many recent studies ranging from inducing mitophagy to forming pro-apoptotic pores (Dany and Ogretmen, 2015; Hernandez-Corbacho et al, 2017; Law et al, 2017; Novgorodov et al, 2011; Novgorodov and Gudz, 2011; Novgorodov et al, 2018; Patwardhan et al, 2016; Perera et al, 2016; Schwartz et al, 2018; Siskind et al, 2002, 2006), which may involve processes such as lipid raft speciation for membrane remodeling. Regulation of ceramide levels to modify the lipid composition and function of lipid rafts in MAMs or mitochondria is mainly achieved by ER-resident enzymes such as ceramide synthases (CerSs) or membrane-associated SMases such as nSMase2 and potentially, a recently discovered mitochondrial neutral SMase (Kong et al, 2018; Novgorodov et al, 2018; Rajagopalan et al, 2015; Wu et al, 2010).…”

The leptin receptor mutation of the obese Zucker rat causes sciatic nerve demyelination with a centripetal pattern defect

“…The demyelination changes of the obese nerve myelin, observed at first as narrow spaces or nicks to channel-like into cones with electron dense contrast, could originate from the overloads of ceramides as sphingomyelin precursors in the Cajal bands. Ceramide channels have been illustrated in model membranes and other cells 229,230 and correspond with ceramidase inactivity in obese rats. 231 It can be hypothesized that the maintenance of myelin layers by the high need of ceramides to form sphingomyelins produces sorts of molecular trans-and, then, intermembranous throughs or channels that could widen toward the adaxonal myelin zones.…”

Novel function of ceramide for regulation of mitochondrial ATP release in astrocytes

“…MAMs are a subcompartment of the ER that forms contact sites with mitochondria and takes part in the crosstalk between mitochondria and microtubules. While CerSs and nSMases have been shown to generate ceramide in mitochondria involved in inducing apoptosis (59)(60)(61)(62), it is not known if ceramide regulates the function of MAMs and whether this involves ceramide-associated tubulin (CAT) and its effect on VDAC1.…”