Mitochondria and ceramide: intertwined roles in regulation of apoptosis
Introduction
Many extracellular agents and inducers of cell injury activate sphingomyelinases which cause the hydrolysis of sphingomyelin (SM), activate de novo synthesis of sphingolipids, and/or regulate other changes in sphingolipid metabolism that result in the accumulation of ceramide (Hannun, 1996). In many cell types, ceramide modulates a number of biochemical and cellular responses to stress, including cell cycle arrest, cell senescence and apoptosis. In particular, ample evidence has now clearly implicated sphingolipids, particularly ceramide, in the cell death pathway.
Interestingly, very recent studies are beginning to disclose the presence of ceramide metabolism in mitochondria and the possibility that ceramide may exert at least part of its actions in mitochondria. This review will focus on the emerging links between mitochondria and ceramide, especially in the context of regulation of apoptosis.
Section snippets
Sphingolipid metabolism
Ceramide is a central molecule in sphingolipid metabolism. Sphingolipid biosynthesis begins in the endoplasmic reticulum (ER) with the condensation of serine and palmitoyl CoA, followed by reduction to dihydrosphingosine. By the action of a ceramide (dihydroceramide) synthase, the N-acylation of dihydrosphingosine produces dihydroceramide which is then desaturated to give ceramide (Merrill and Wang, 1992; Michel and van Echten-Deckert, 1997). Ceramide can then serve as a precursor for the
Biological effects and cell signaling pathways induced by sphingolipids
The last 15 years have witnessed an accelerating growth in the identification of biologically active sphingolipids with special emphasis on their roles in signal transduction and cell regulation. Initially, sphingolipids were thought to play predominantly a structural role as components of lipid bilayers. It has now become apparent that sphingolipid metabolites, including ceramide, sphingosine, and sphingosine-1-phosphate, play essential roles in cell growth, survival and death (Spiegel and
Mitochondria and apoptosis
Another line of investigation has implicated mitochondria as a converging point upon which apoptotic signals occur and by which apoptosis is initiated. Mitochondria play a major role in apoptosis triggered by many stimuli. In fact, the mitochondrion is the target of numerous pro-apoptotic signal transducing molecules such as ceramide, ganglioside GD3, fatty acids (e.g. palmitate) and their oxidation products (e.g. 4-hydroxynonenal), reactive oxygen species, nitric oxide, and calcium. These
Sphingolipids in mitochondria
A small, but significant, body of work is beginning to identify a role for sphingolipids and their targets in mitochondria and apoptosis (Fig. 2). For example, (i) treatment of isolated mitochondria with ceramide leads to the inhibition of mitochondrial respiratory chain complex III (Gudz et al., 1997), (ii) a ceramide synthase has been partially purified from bovine liver mitochondria (Shimeno et al., 1998), (iii) mitochondrial fractions that were confirmed to have monoamine oxidase and
Conclusions
Mitochondria have a central role in the control of cell survival and cell death. Most apoptotic signaling processes converge on the mitochondria, which release cytochrome c and other proteins leading to the activation of effector caspases. The response of mitochondria to upstream pro-apototic signals is a critical control point for the regulation of cell death. A growing body of research also supports key roles for sphingolipids, and especially ceramide in the regulation of apoptosis. The
Summary
The role of mitochondria as crucial participants in the cell death program is now becoming established. A growing body of work has also implicated sphingolipids, particularly ceramide, in apoptosis; however, the exact mechanism of how ceramide regulates the apoptotic pathway and its relationship to the mitochondrial role are still unanswered. Recently, our group has identified a mitochondrial ceramidase and we have shown that ceramide generation especially in mitochondria is able to induce
Acknowledgements
This work was supported by the National Institutes of Health grants AG16583 (Lina M. Obeid) and GM43825 DK59340 (project 3) (Yusuf A. Hannun).
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Current address: Diabetic Microangiopathy Research Unit, MERCK-LIPHA/INSERM U352, INSA-Lyon, 11 Av. J. Capelle, 69621, Villeurbanne, France.