Ceramide channels: Influence of molecular structure on channel formation in membranes

Perera, Meenu N.; Ganesan, Vidyaramanan; Siskind, Leah J.; Szulc, Zdzislaw M.; Bielawski, Jacek; Bielawska, Alicja; Bittman, Robert; Colombini, Marco

doi:10.1016/j.bbamem.2012.02.010

Cited by 42 publications

(26 citation statements)

References 43 publications

(58 reference statements)

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“…The mechanism by which MOMP occurs is still under study but, among other possibilities, has been attributed to the formation of pores in the outer mitochondrial membrane by Bax and Bak. More recently, formation of ceramide channels has been proposed as another mechanism mediating the release of pro-apoptotic proteins from mitochondria during the induction phase of apoptosis [49], [50]. Studies using yeast mitochondria and planar phospholipid membranes have shown that activated Bax interacts synergistically with ceramide channels promoting MOMP [51].…”

Section: Discussionmentioning

confidence: 99%

Modulation of Mitochondrial Outer Membrane Permeabilization and Apoptosis by Ceramide Metabolism

et al. 2012

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The yeast Saccharomyces cerevisiae undergoes a mitochondrial-dependent programmed cell death in response to different stimuli, such as acetic acid, with features similar to those of mammalian apoptosis. However, the upstream signaling events in this process, including those leading to mitochondrial membrane permeabilization, are still poorly characterized. Changes in sphingolipid metabolism have been linked to modulation of apoptosis in both yeast and mammalian cells, and ceramides have been detected in mitochondria upon apoptotic stimuli. In this study, we aimed to characterize the contribution of enzymes involved in ceramide metabolism to apoptotic cell death induced by acetic acid. We show that isc1Δ and lag1Δ mutants, lacking inositol phosphosphingolipid phospholipase C and ceramide synthase, respectively, exhibited a higher resistance to acetic acid that was associated with lower levels of some phytoceramide species. Consistently, these mutant cells displayed lower levels of ROS production and reduced mitochondrial alterations, such as mitochondrial fragmentation and degradation, and decreased translocation of cytochrome c into the cytosol in response to acetic acid. These results suggest that ceramide production contributes to cell death induced by acetic acid, especially through hydrolysis of complex sphingolipids catalyzed by Isc1p and de novo synthesis catalyzed by Lag1p, and provide the first in vivo indication of its involvement in mitochondrial outer membrane permeabilization in yeast.

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Section: Discussionmentioning

confidence: 99%

Modulation of Mitochondrial Outer Membrane Permeabilization and Apoptosis by Ceramide Metabolism

et al. 2012

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“…It is also evident that many enzymes that metabolize ceramide do not recognize C 2 -Cers [53,54], thus allowing these molecules to act over a longer time scale. Interestingly, the ability of short-and long-chain ceramides to form channels is about the same, and mixtures of long-and short-chain ceramides are actually more potent [55]. Thus it is possible that these short-chain ceramides may be more effective than long-chain ceramides therapeutically in promoting apoptosis because Bcl-xL is unable to recognize or regulate these species, while Bax retains the ability to promote channel formation by these ceramides.…”

Section: The Importance Of Tail Length and Apolar Bulkmentioning

confidence: 93%

Bax and Bcl-xL exert their regulation on different sites of the ceramide channel

Perera

Lin

Peterson

et al. 2012

Biochemical Journal

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The present study demonstrates the important structural features of ceramide required for proper regulation, binding and identification by both pro-apoptotic and anti-apoptotic Bcl-2 family proteins. The C-4=C-5 trans-double bond has little influence on the ability of Bax and Bcl-xL to identify and bind to these channels. The stereochemistry of the headgroup and access to the amide group of ceramide is indispensible for Bax binding, indicating that Bax may interact with the polar portion of the ceramide channel facing the bulk phase. In contrast, Bcl-xL binding to ceramide channels is tolerant of stereochemical changes in the headgroup. The present study also revealed that Bcl-xL has an optimal interaction with long-chain ceramides that are elevated early in apoptosis, whereas short-chain ceramides are not well regulated. Inhibitors specific for the hydrophobic groove of Bcl-xL, including 2-methoxyantimycin A3, ABT-737 and ABT-263 provide insights into the region of Bcl-xL involved in binding to ceramide channels. Molecular docking simulations of the lowest-energy binding poses of ceramides and Bcl-xL inhibitors to Bcl-xL were consistent with the results of our functional studies and propose potential binding modes.

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“…= 0.31), indicating that as long as the analog can produce any level of permeability the erythrocyte will lyse. The analogs unable to permeabilize either membrane ( #7 and #9 ) or barely able to do so ( #6 ) are simply very poor channel formers (Perera et al, 2012). What's left is C 16 -ceramide ( #1 ).…”

Section: Resultsmentioning

confidence: 99%

Ceramide channel: Structural basis for selective membrane targeting

Perera

Ganesan

Siskind

et al. 2016

Chemistry and Physics of Lipids

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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.

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Ceramide channels: Influence of molecular structure on channel formation in membranes

Cited by 42 publications

References 43 publications

Modulation of Mitochondrial Outer Membrane Permeabilization and Apoptosis by Ceramide Metabolism

Modulation of Mitochondrial Outer Membrane Permeabilization and Apoptosis by Ceramide Metabolism

Bax and Bcl-xL exert their regulation on different sites of the ceramide channel

Ceramide channel: Structural basis for selective membrane targeting

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