Ceramide and Apoptosis: Exploring the Enigmatic Connections between Sphingolipid Metabolism and Programmed Cell Death

Programmed cell death, or apoptosis, is a complex process whereby eukaryotic cells react to physiologic or pathophysiologic stimuli by undergoing genetically programmed suicide. Programmed cell death involves many well-characterized signaling pathways including permeabilization of the mitochondrial outer membrane and activation of caspases. Other pathways, such as pro-apoptotic lipid signaling, are less understood despite many years of study. The sphingolipid ceramide has received considerable attention as a key regulator of programmed cell death, yet the mechanisms of its up-regulation and ability to control cell fate remain ill-defined. In this review, we will examine the connections between sphingolipid metabolism and programmed cell death with a focus on the role of de novo sphingolipid synthesis and sphingosine salvage in producing pro-apoptotic ceramide. We will also highlight the evidence supporting an increasingly complex role for ceramide in regulating apoptosis and provide a framework in which to ask new questions about the functions of this enigmatic lipid.