Sphingolipids and mitochondrial apoptosis

Abstract

The sphingolipid family of lipids modulate several cellular processes, including proliferation, cell cycle regulation, inflammatory signaling pathways, and cell death. Several members of the sphingolipid pathway have opposing functions and thus imbalances in sphingolipid metabolism result in deregulated cellular processes, which cause or contribute to diseases and disorders in humans. A key cellular process regulated by sphingolipids is apoptosis, or programmed cell death. Sphingolipids play an important role in both extrinsic and intrinsic apoptotic pathways depending on the stimuli, cell type and cellular response to the stress. During mitochondrial-mediated apoptosis, multiple pathways converge on mitochondria and induce mitochondrial outer membrane permeabilization (MOMP). MOMP results in the release of intermembrane space proteins such as cytochrome c and Apaf1 into the cytosol where they activate the caspases and DNases that execute cell death. The precise molecular components of the pore(s) responsible for MOMP are unknown, but sphingolipids are thought to play a role. Here, we review evidence for a role of sphingolipids in the induction of mitochondrial-mediated apoptosis with a focus on potential underlying molecular mechanisms by which altered sphingolipid metabolism indirectly or directly induce MOMP. Data available on these mechanisms is reviewed, and the focus and limitations of previous and current studies are discussed to present important unanswered questions and potential future directions.

Keywords: Apoptosis; Bcl-2 proteins; Cancer; Ceramide; Mitochondria; Sphingolipid.

Figure 1

Basic structure of a sphingolipid. Sphingolipid family members generally contain a common sphingoid base backbone, which can be altered in a number of ways including the introduction of a double bond(s), differing length (sphingoid base backbones of 16 and 18 carbons are possible), addition of a N-linked fatty acyl chain, and additions to the terminal hydroxyl group. The length of the N-linked fatty acyl chain varies as well as its degree of saturation and hydroxylation. Groups that can be added to the C1- hydroxyl group of the sphingoid base backbone include a phosphate, carbohydrates, and phosphorylcholine moieties, giving rise to thousands of different sphingolipid species.

Figure 2

Schematic of sphingolipid metabolism. Ceramide is the center of sphingolipid metabolism and can be synthesized de novo from serine and palmitoyl CoA, the hydrolysis of sphingomyelin, breakdown of glycosphingolipids, or via salvaging free sphingosine. Once synthesized, ceramides can be utilized to form glycosphingolipids, ceramide-1-phosphate, or sphingomyelin. Alternatively, the N-linked fatty acyl chain can be cleaved off of ceramide to generate sphingosine that can be utilized to form sphingosine-1-phosphate. Sphingosine-1-phosphate can be turned back into sphingosine or can broken down to form hexadecenal and phosphoethanolamine (ethanolamine-1-phosphate).

Figure 3

Diagram illustrating the proposed mechanisms by which sphingolipids alter mitochondrial structure and function to induce mitochondrial outer membrane permeabilization (MOMP) and apoptosis.