Mitochondrial Ceramide in Stroke

Abstract

Sphingolipids are essential structural components of cellular membranes, playing prominent roles in signal transduction that governs cell proliferation, differentiation, migration, and apoptosis. Most sphingolipids are ubiquitous, but complex sphingolipids, including sphingomyelin (SM) and glycosphingolipids (GSLs), are more abundant in the brain and are particularly abundant in myelin. Sphingolipids are defined by the presence of a long-chain sphingoid backbone, generally sphingosine. Acylation of the sphingoid base, i.e. addition of a C14–C26 fatty acid to the amino group, yields ceramide, a building block for more complex sphingolipids. Neural cells are particularly enriched in GSLs and SM which is also a major lipid component of myelin. Sphingolipids are abundant in the plasma membranes and have unique molecular structures and conformational properties that cause them to form segregated compositional lipid domains in phospholipid bilayers (Sonnino et al., 2006). Membrane lipid domains, zones of the membrane with reduced fluidity, contain complex lipids of the cell, but are highly enriched in cholesterol and sphingolipids. Importantly, the proteins involved in signal transduction appear to segregate also in the lipid domains where they can exert their functions. Experimental evidence indicating that sphingolipids function through membrane reorganization and formation of lipid domains is summarized in a recent review by Kolesnick and Stancevic (Stancevic and Kolesnick, 2010). In addition to their role as building blocks of cellular membranes, sphingolipids have been reported to be pleotropic modulators of numerous enzymes in intracellular signaling pathways. Basic organization and specific principles of sphingolipid-mediated cell regulation have been reviewed by Hannun and Obeid (Hannun and Obeid, 2008, 2011). After more than a decade of extensive investigations, it has become clear that ceramide is a key sphingolipid messenger regulating a diverse range of cell-stress responses, including apoptosis, cell senescence, and autophagy. Ceramide is tightly regulated in cells, and its participation in cell death signaling pathways is controlled by rapid conversion of ceramide into less deleterious sphingolipids (Scheme 1). Thus, ceramide can be metabolized into complex sphingolipids by glucosylceramide synthase or into SM by SM synthase, or into ceramide-1-phosphate by ceramide kinase (Hannun and Obeid, 2002; Ogretmen and Hannun, 2004), or into sphingosine-1-phosphate by ceramidase and sphingosine kinase (Hannun and Obeid, 2008). However, pathological conditions, including cerebral ischemia/reperfusion, could disturb ceramide metabolism resulting in ceramide accumulation that ultimately leads to cell death.