Sphingolipids and mitochondrial apoptosis

Journal of Bioenergetics and Biomembranes

Volumn 48, Issue 2, 2016, Pages 153-168

  Patwardhan, Gauri A ^a   Beverly, Levi J ^a,b   Siskind, Leah J ^a,b  

^a University of Louisville School of Medicine   (United States)

^b UNIVERSITY OF LOUISVILLE   (United States)

Author keywords

Apoptosis; Bcl 2 proteins; Cancer; Ceramide; Mitochondria; Sphingolipid

Indexed keywords

SPHINGOLIPID; APAF1 PROTEIN, HUMAN; APOPTOTIC PROTEASE ACTIVATING FACTOR 1;

APOPTOSIS; ARTICLE; CELL MEMBRANE PERMEABILITY; CLINICAL TRIAL (TOPIC); ENDOPLASMIC RETICULUM; HUMAN; LIPID ANALYSIS; MITOCHONDRIAL ASSOCIATED MEMBRANE; MITOCHONDRIAL MEMBRANE; MITOCHONDRIAL OUTER MEMBRANE PERMEABILIZATION; MITOCHONDRION; NONHUMAN; SPHINGOLIPID METABOLISM; ANIMAL; GENETICS; METABOLISM; PERMEABILITY; PHYSIOLOGY;

ANIMALS; APOPTOSIS; APOPTOTIC PROTEASE-ACTIVATING FACTOR 1; HUMANS; MITOCHONDRIA; MITOCHONDRIAL MEMBRANES; PERMEABILITY; SPHINGOLIPIDS;

EID: 84921876514     PISSN: 0145479X     EISSN: 15736881     Source Type: Journal    
DOI: 10.1007/s10863-015-9602-3     Document Type: Article

References (215)

1. Abrahan CE, Miranda GE, Agnolazza DL, Politi LE, Rotstein NP (2010) Synthesis of sphingosine is essential for oxidative stress-induced apoptosis of photoreceptors. Invest Ophthalmol Vis Sci 51:1171–1180. doi:10.1167/iovs.09-3909
2. Alphonse G et al (2013) p53-independent early and late apoptosis is mediated by ceramide after exposure of tumor cells to photon or carbon ion irradiation. BMC Cancer 13:151. doi:10.1186/1471-2407-13-151
3. Andrieu-Abadie N, Gouaze V, Salvayre R, Levade T (2001) Ceramide in apoptosis signaling: relationship with oxidative stress. Free Radic Biol Med 31:717–728
4. Annis MG, Zamzami N, Zhu W, Penn LZ, Kroemer G, Leber B, Andrews DW (2001) Endoplasmic reticulum localized Bcl-2 prevents apoptosis when redistribution of cytochrome c is a late event. Oncogene 20:1939–1952
5. Antoon JW et al (2011) Targeting NFkB mediated breast cancer chemoresistance through selective inhibition of sphingosine kinase-2. Cancer Biol Ther 11:678–689
6. Babiychuk EB, Atanassoff AP, Monastyrskaya K, Brandenberger C, Studer D, Allemann C, Draeger A (2011) The targeting of plasmalemmal ceramide to mitochondria during apoptosis. PLoS ONE 6:e23706. doi:10.1371/journal.pone.0023706
7. Baranowski M, Gorski J (2011) Heart sphingolipids in health and disease. Adv Exp Med Biol 721:41–56. doi:10.1007/978-1-4614-0650-1_3
8. Beckham TH et al (2013) LCL124, a cationic analog of ceramide, selectively induces pancreatic cancer cell death by accumulating in mitochondria. J Pharmacol Exp Ther 344:167–178. doi:10.1124/jpet.112.199216
9. Belaud-Rotureau MA et al (2000) Early transitory rise in intracellular pH leads to Bax conformation change during ceramide-induced apoptosis. Apoptosis 5:551–560
10. Bettaieb A, Plo I, Mansat-De Mas V, Quillet-Mary A, Levade T, Laurent G, Jaffrezou JP (1999) Daunorubicin- and mitoxantrone-triggered phosphatidylcholine hydrolysis: implication in drug-induced ceramide generation and apoptosis. Mol Pharmacol 55:118–125
11. Beverly LJ, Howell LA, Hernandez-Corbacho M, Casson L, Chipuk JE, Siskind LJ (2013) BAK activation is necessary and sufficient to drive ceramide synthase-dependent ceramide accumulation following inhibition of BCL2-like proteins. Biochem J 452:111–119. doi:10.1042/BJ20130147
12. Bigi A et al (2010) Human sialidase NEU4 long and short are extrinsic proteins bound to outer mitochondrial membrane and the endoplasmic reticulum, respectively. Glycobiology 20:148–157. doi:10.1093/glycob/cwp156
13. Bionda C, Portoukalian J, Schmitt D, Rodriguez-Lafrasse C, Ardail D (2004) Subcellular compartmentalization of ceramide metabolism: MAM (mitochondria-associated membrane) and/or mitochondria? Biochem J 382:527–533. doi:10.1042/BJ20031819
14. Birbes H, El Bawab S, Hannun YA, Obeid LM (2001) Selective hydrolysis of a mitochondrial pool of sphingomyelin induces apoptosis. FASEB J: Off Publ Fed Am Soc Exp Biol 15:2669–2679
15. Birbes H, El Bawab S, Obeid LM, Hannun YA (2002) Mitochondria and ceramide: intertwined roles in regulation of apoptosis. Adv Enzym Regul 42:113–129
16. Birbes H, Luberto C, Hsu YT, El Bawab S, Hannun YA, Obeid LM (2005) A mitochondrial pool of sphingomyelin is involved in TNFalpha-induced Bax translocation to mitochondria. Biochem J 386:445–451
17. Blaschko H (1975) The first Thudichum lecture, 15 January 1974: biochemical specificity in neuromal function. Biochem Soc Trans 3:27–37
18. Bollinger CR, Teichgraber V, Gulbins E (2005) Ceramide-enriched membrane domains. Biochim Biophys Acta 1746:284–294
19. Bose R, Verheij M, Haimovitz-Friedman A, Scotto K, Fuks Z, Kolesnick R (1995) Ceramide synthase mediates daunorubicin-induced apoptosis: an alternative mechanism for generating death signals. Cell 82:405–414
20. Caricchio R, D’Adamio L, Cohen PL (2002) Fas, ceramide and serum withdrawal induce apoptosis via a common pathway in a type II Jurkat cell line. Cell Death Differ 9:574–580. doi:10.1038/sj/cdd/4400996
21. Cartron PF, Juin P, Oliver L, Martin S, Meflah K, Vallette FM (2003) Nonredundant role of Bax and Bak in Bid-mediated apoptosis. Mol Cell Biol 23:4701–4712
22. Casson L et al (2013) Inhibition of ceramide metabolism sensitizes human leukemia cells to inhibition of BCL2-like proteins. PLoS ONE 8:e54525. doi:10.1371/journal.pone.0054525
23. Charles AG, Han TY, Liu YY, Hansen N, Giuliano AE, Cabot MC (2001) Taxol-induced ceramide generation and apoptosis in human breast cancer cells. Cancer Chemother Pharmacol 47:444–450
24. Charruyer A, Jean C, Colomba A, Jaffrezou JP, Quillet-Mary A, Laurent G, Bezombes C (2007) PKCzeta protects against UV-C-induced apoptosis by inhibiting acid sphingomyelinase-dependent ceramide production. Biochem J 405:77–83. doi:10.1042/BJ20061528
25. Chatterjee M, Wu S (2001) Cell line dependent involvement of ceramide in ultraviolet light-induced apoptosis. Mol Cell Biochem 219:21–27
26. Chen M, Quintans J, Fuks Z, Thompson C, Kufe DW, Weichselbaum RR (1995) Suppression of Bcl-2 messenger RNA production may mediate apoptosis after ionizing radiation, tumor necrosis factor alpha, and ceramide. Cancer Res 55:991–994
27. Chen JS, Chai MQ, Chen HH, Zhao S, Song JG (2000) Regulation of phospholipase D activity and ceramide production in daunorubicin-induced apoptosis in A-431 cells. Biochim Biophys Acta 1488:219–232
28. Chen CL, Lin CF, Chiang CW, Jan MS, Lin YS (2006) Lithium inhibits ceramide- and etoposide-induced protein phosphatase 2A methylation, Bcl-2 dephosphorylation, caspase-2 activation, and apoptosis. Mol Pharmacol 70:510–517. doi:10.1124/mol.106.024059
29. Chipuk JE, Green DR (2004) Cytoplasmic p53: bax and forward. Cell Cycle 3:429–431
30. Chipuk JE, Green DR (2006) Dissecting p53-dependent apoptosis. Cell Death Differ 13:994–1002. doi:10.1038/sj.cdd.4401908
31. Chipuk JE, Green DR (2008) How do BCL-2 proteins induce mitochondrial outer membrane permeabilization? Trends Cell Biol 18:157–164. doi:10.1016/j.tcb.2008.01.007
32. Chipuk JE, Maurer U, Green DR, Schuler M (2003) Pharmacologic activation of p53 elicits Bax-dependent apoptosis in the absence of transcription. Cancer Cell 4:371–381
33. Chipuk JE, Kuwana T, Bouchier-Hayes L, Droin NM, Newmeyer DD, Schuler M, Green DR (2004) Direct activation of Bax by p53 mediates mitochondrial membrane permeabilization and apoptosis. Science 303:1010–1014. doi:10.1126/science.1092734
34. Chipuk JE, Bouchier-Hayes L, Green DR (2006) Mitochondrial outer membrane permeabilization during apoptosis: the innocent bystander scenario. Cell Death Differ 13:1396–1402. doi:10.1038/sj.cdd.4401963
35. Chipuk JE, Moldoveanu T, Llambi F, Parsons MJ, Green DR (2010) The BCL-2 family reunion. Mol Cell 37:299–310. doi:10.1016/j.molcel.2010.01.025
36. Chipuk JE et al (2012) Sphingolipid metabolism cooperates with BAK and BAX to promote the mitochondrial pathway of apoptosis. Cell 148:988–1000. doi:10.1016/j.cell.2012.01.038
37. Chmura SJ, Nodzenski E, Beckett MA, Kufe DW, Quintans J, Weichselbaum RR (1997) Loss of ceramide production confers resistance to radiation-induced apoptosis. Cancer Res 57:1270–1275
38. Ciarlo L et al (2010) Association of fission proteins with mitochondrial raft-like domains. Cell Death Differ 17:1047–1058. doi:10.1038/cdd.2009.208
39. Colombini M (2010) Ceramide channels and their role in mitochondria-mediated apoptosis. Biochim Biophys Acta 1797:1239–1244. doi:10.1016/j.bbabio.2010.01.021
40. Colombini M (2013) Membrane channels formed by ceramide. Handb Exp Pharmacol:109–126 doi:10.1007/978-3-7091-1368-4_6.
41. Come MG, Bettaieb A, Skladanowski A, Larsen AK, Laurent G (1999) Alteration of the daunorubicin-triggered sphingomyelin-ceramide pathway and apoptosis in MDR cells: influence of drug transport abnormalities. Int J Cancer J Int du Cancer 81:580–587
42. Csordas G et al (2006) Structural and functional features and significance of the physical linkage between ER and mitochondria. J Cell Biol 174:915–921. doi:10.1083/jcb.200604016
43. Deng J, Zhang H, Kloosterboer F, Liao Y, Klostergaard J, Levitt ML, Hung MC (2002) Ceramide does not act as a general second messenger for ultraviolet-induced apoptosis. Oncogene 21:44–52. doi:10.1038/sj.onc.1204900
44. Deng X et al (2008) Ceramide biogenesis is required for radiation-induced apoptosis in the germ line of C. elegans. Science 322:110–115. doi:10.1126/science.1158111
45. Don AS, Rosen H (2009) A lipid binding domain in sphingosine kinase 2. Biochem Biophys Res Commun 380:87–92. doi:10.1016/j.bbrc.2009.01.075
46. Ebel P et al (2013) Inactivation of ceramide synthase 6 in mice results in an altered sphingolipid metabolism and behavioral abnormalities. J Biol Chem 288:21433–21447. doi:10.1074/jbc.M113.479907
47. Ebel P et al (2014) Ceramide synthase 4 deficiency in mice causes lipid alterations in sebum and results in alopecia. Biochem J 461:147–158. doi:10.1042/BJ20131242
48. El Bawab S, Roddy P, Qian T, Bielawska A, Lemasters JJ, Hannun YA (2000) Molecular cloning and characterization of a human mitochondrial ceramidase. J Biol Chem 275:21508–21513. doi:10.1074/jbc.M002522200
49. El Bawab S, Birbes H, Roddy P, Szulc ZM, Bielawska A, Hannun YA (2001) Biochemical characterization of the reverse activity of rat brain ceramidase. A CoA-independent and fumonisin B1-insensitive ceramide synthase. J Biol Chem 276:16758–16766. doi:10.1074/jbc.M009331200
50. Elrick MJ, Fluss S, Colombini M (2006) Sphingosine, a product of ceramide hydrolysis, influences the formation of ceramide channels. Biophys J 91:1749–1756. doi:10.1529/biophysj.106.088443
51. Ferlinz K et al (2001) Human acid ceramidase: processing, glycosylation, and lysosomal targeting. J Biol Chem 276:35352–35360. doi:10.1074/jbc.M103066200
52. Fernandez-Ayala DJ et al (2000) Coenzyme Q protects cells against serum withdrawal-induced apoptosis by inhibition of ceramide release and caspase-3 activation. Antioxid Redox Signal 2:263–275
53. Follis AV et al (2013) PUMA binding induces partial unfolding within BCL-xL to disrupt p53 binding and promote apoptosis. Nat Chem Biol 9:163–168. doi:10.1038/nchembio.1166
54. Gagliostro V et al (2012) Dihydroceramide delays cell cycle G1/S transition via activation of ER stress and induction of autophagy. Int J Biochem Cell Biol 44:2135–2143. doi:10.1016/j.biocel.2012.08.025
55. Galluzzi L, Kepp O, Kroemer G (2012) Mitochondria: master regulators of danger signalling. Nat Rev 13:780–788. doi:10.1038/nrm3479
56. Gandy KA, Obeid LM (2013) Regulation of the sphingosine kinase/sphingosine 1-phosphate pathway. Handb Exp Pharmacol:275–303 doi:10.1007/978-3-7091-1511-4_14.
57. Ganesan V, Colombini M (2010) Regulation of ceramide channels by Bcl-2 family proteins. FEBS Lett 584:2128–2134. doi:10.1016/j.febslet.2010.02.032
58. Ganesan V, Perera MN, Colombini D, Datskovskiy D, Chadha K, Colombini M (2010) Ceramide and activated Bax act synergistically to permeabilize the mitochondrial outer membrane. Apoptosis 15:553–562. doi:10.1007/s10495-009-0449-0
59. Garcia-Ruiz C, Colell A, Mari M, Morales A, Fernandez-Checa JC (1997) Direct effect of ceramide on the mitochondrial electron transport chain leads to generation of reactive oxygen species. Role of mitochondrial glutathione. J Biol Chem 272:11369–11377
60. Garcia-Ruiz C, Colell A, Morales A, Calvo M, Enrich C, Fernandez-Checa JC (2002) Trafficking of ganglioside GD3 to mitochondria by tumor necrosis factor-alpha. J Biol Chem 277:36443–36448. doi:10.1074/jbc.M206021200
61. Garofalo T et al (2007) Do mitochondria act as “cargo boats” in the journey of GD3 to the nucleus during apoptosis? FEBS Lett 581:3899–3903. doi:10.1016/j.febslet.2007.07.020
62. Geilen CC, Bektas M, Wieder T, Kodelja V, Goerdt S, Orfanos CE (1997) 1alpha,25-dihydroxyvitamin D3 induces sphingomyelin hydrolysis in HaCaT cells via tumor necrosis factor alpha. J Biol Chem 272:8997–9001
63. Geley S, Hartmann BL, Kofler R (1997) Ceramides induce a form of apoptosis in human acute lymphoblastic leukemia cells that is inhibited by Bcl-2, but not by CrmA. FEBS Lett 400:15–18
64. Gentil B, Grimot F, Riva C (2003) Commitment to apoptosis by ceramides depends on mitochondrial respiratory function, cytochrome c release and caspase-3 activation in Hep-G2 cells. Mol Cell Biochem 254:203–210
65. Ginkel C et al (2012) Ablation of neuronal ceramide synthase 1 in mice decreases ganglioside levels and expression of myelin-associated glycoprotein in oligodendrocytes. J Biol Chem 287:41888–41902. doi:10.1074/jbc.M112.413500
66. Gorria M, Huc L, Sergent O, Rebillard A, Gaboriau F, Dimanche-Boitrel MT, Lagadic-Gossmann D (2006) Protective effect of monosialoganglioside GM1 against chemically induced apoptosis through targeting of mitochondrial function and iron transport. Biochem Pharmacol 72:1343–1353. doi:10.1016/j.bcp.2006.07.014
67. Grassme H et al (2001a) CD95 signaling via ceramide-rich membrane rafts. J Biol Chem 276:20589–20596. doi:10.1074/jbc.M101207200
68. Grassme H, Schwarz H, Gulbins E (2001b) Molecular mechanisms of ceramide-mediated CD95 clustering. Biochem Biophys Res Commun 284:1016–1030. doi:10.1006/bbrc.2001.5045 S0006-291X(01)95045-4
69. Grassme H, Cremesti A, Kolesnick R, Gulbins E (2003) Ceramide-mediated clustering is required for CD95-DISC formation. Oncogene 22:5457–5470. doi:10.1038/sj.onc.1206540
70. Gudz TI, Tserng KY, Hoppel CL (1997) Direct inhibition of mitochondrial respiratory chain complex III by cell-permeable ceramide. J Biol Chem 272:24154–24158
71. Gulbins E, Kolesnick R (2003) Raft ceramide in molecular medicine. Oncogene 22:7070–7077. doi:10.1038/sj.onc.1207146
72. Haimovitz-Friedman A, Kan CC, Ehleiter D, Persaud RS, McLoughlin M, Fuks Z, Kolesnick RN (1994) Ionizing radiation acts on cellular membranes to generate ceramide and initiate apoptosis. J Exp Med 180:525–535
73. Hait NC, Bellamy A, Milstien S, Kordula T, Spiegel S (2007) Sphingosine kinase type 2 activation by ERK-mediated phosphorylation. J Biol Chem 282:12058–12065. doi:10.1074/jbc.M609559200
74. Hanada K (2006) Discovery of the molecular machinery CERT for endoplasmic reticulum-to-Golgi trafficking of ceramide. Mol Cell Biochem 286:23–31. doi:10.1007/s11010-005-9044-z
75. Hanada K, Kumagai K, Tomishige N, Kawano M (2007) CERT and intracellular trafficking of ceramide. Biochim Biophys Acta 1771:644–653. doi:10.1016/j.bbalip.2007.01.009
76. Hannun YA, Obeid LM (2008) Principles of bioactive lipid signalling: lessons from sphingolipids. Nat Rev 9:139–150
77. Hawthorne JN (1975) A note on the life of J.L.W. Thudichum (1829–1901). Biochem Soc Trans 3:591
78. Hearps AC, Burrows J, Connor CE, Woods GM, Lowenthal RM, Ragg SJ (2002) Mitochondrial cytochrome c release precedes transmembrane depolarisation and caspase-3 activation during ceramide-induced apoptosis of Jurkat T cells. Apoptosis 7:387–394
79. Heffernan-Stroud LA, Obeid LM (2013) Sphingosine kinase 1 in cancer. Adv Cancer Res 117:201–235. doi:10.1016/B978-0-12-394274-6.00007-8
80. Heinrich M et al (2000) Ceramide as an activator lipid of cathepsin D. Adv Exp Med Biol 477:305–315
81. Holopainen JM, Angelova MI, Kinnunen PK (2000) Vectorial budding of vesicles by asymmetrical enzymatic formation of ceramide in giant liposomes. Biophys J 78:830–838. doi:10.1016/S0006-3495(00)76640-9
82. Hwang YH, Tani M, Nakagawa T, Okino N, Ito M (2005) Subcellular localization of human neutral ceramidase expressed in HEK293 cells. Biochem Biophys Res Commun 331:37–42. doi:10.1016/j.bbrc.2005.03.134
83. Igarashi N, Okada T, Hayashi S, Fujita T, Jahangeer S, Nakamura S (2003) Sphingosine kinase 2 is a nuclear protein and inhibits DNA synthesis. J Biol Chem 278:46832–46839. doi:10.1074/jbc.M306577200
84. Ikeda M, Kihara A, Igarashi Y (2004) Sphingosine-1-phosphate lyase SPL is an endoplasmic reticulum-resident, integral membrane protein with the pyridoxal 5′-phosphate binding domain exposed to the cytosol. Biochem Biophys Res Commun 325:338–343. doi:10.1016/j.bbrc.2004.10.036
85. Imgrund S et al (2009) Adult ceramide synthase 2 (CERS2)-deficient mice exhibit myelin sheath defects, cerebellar degeneration, and hepatocarcinomas. J Biol Chem 284:33549–33560. doi:10.1074/jbc.M109.031971
86. Ito M, Okino N, Tani M (2014) New insight into the structure, reaction mechanism, and biological functions of neutral ceramidase. Biochim Biophys Acta 1841:682–691. doi:10.1016/j.bbalip.2013.09.008
87. Iwasawa R, Mahul-Mellier AL, Datler C, Pazarentzos E, Grimm S (2011) Fis1 and Bap31 bridge the mitochondria-ER interface to establish a platform for apoptosis induction. EMBO J 30:556–568. doi:10.1038/emboj.2010.346
88. Jaffrezou JP et al (1996) Daunorubicin-induced apoptosis: triggering of ceramide generation through sphingomyelin hydrolysis. EMBO J 15:2417–2424
89. Jenkins RW, Canals D, Hannun YA (2009) Roles and regulation of secretory and lysosomal acid sphingomyelinase. Cell Signal 21:836–846
90. Jennemann R et al (2012) Loss of ceramide synthase 3 causes lethal skin barrier disruption. Hum Mol Genet 21:586–608. doi:10.1093/hmg/ddr494
91. Jensen SA et al (2014) Bcl2L13 is a ceramide synthase inhibitor in glioblastoma. Proc Natl Acad Sci U S A 111:5682–5687. doi:10.1073/pnas.1316700111
92. Jin J et al (2008) Ceramide generated by sphingomyelin hydrolysis and the salvage pathway is involved in hypoxia/reoxygenation-induced Bax redistribution to mitochondria in NT-2 cells. J Biol Chem 283:26509–26517. doi:10.1074/jbc.M801597200
93. Karasavvas N, Erukulla RK, Bittman R, Lockshin R, Hockenbery D, Zakeri Z (1996) BCL-2 suppresses ceramide-induced cell killing. Cell Death Differ 3:149–151
94. Kawano M, Kumagai K, Nishijima M, Hanada K (2006) Efficient trafficking of ceramide from the endoplasmic reticulum to the Golgi apparatus requires a VAMP-associated protein-interacting FFAT motif of CERT. J Biol Chem 281:30279–30288. doi:10.1074/jbc.M605032200
95. Kim HJ, Mun JY, Chun YJ, Choi KH, Kim MY (2001) Bax-dependent apoptosis induced by ceramide in HL-60 cells. FEBS Lett 505:264–268
96. Kim HJ, Oh JE, Kim SW, Chun YJ, Kim MY (2008) Ceramide induces p38 MAPK-dependent apoptosis and Bax translocation via inhibition of Akt in HL-60 cells. Cancer Lett 260:88–95. doi:10.1016/j.canlet.2007.10.030
97. Kogot-Levin A, Saada A (2014) Ceramide and the mitochondrial respiratory chain. Biochimie 100:88–94. doi:10.1016/j.biochi.2013.07.027
98. Kolter T (2011) A view on sphingolipids and disease. Chem Phys Lipids 164:590–606. doi:10.1016/j.chemphyslip.2011.04.013
99. Kroesen BJ, Pettus B, Luberto C, Busman M, Sietsma H, de Leij L, Hannun YA (2001) Induction of apoptosis through B-cell receptor cross-linking occurs via de novo generated C16-ceramide and involves mitochondria. J Biol Chem 276:13606–13614
100. Kucuksayan E, Konuk EK, Demir N, Mutus B, Aslan M (2014) Neutral sphingomyelinase inhibition decreases ER stress-mediated apoptosis and inducible nitric oxide synthase in retinal pigment epithelial cells. Free Radic Biol Med 72:113–123. doi:10.1016/j.freeradbiomed.2014.04.013
101. Kujjo LL et al (2013) Ceramide and its transport protein (CERT) contribute to deterioration of mitochondrial structure and function in aging oocytes. Mech Ageing Dev 134:43–52. doi:10.1016/j.mad.2012.12.001
102. Laviad EL, Kelly S, Merrill AH Jr, Futerman AH (2012) Modulation of ceramide synthase activity via dimerization. J Biol Chem 287:21025–21033. doi:10.1074/jbc.M112.363580
103. Lee H et al (2011) Mitochondrial ceramide-rich macrodomains functionalize Bax upon irradiation. PLoS ONE 6:e19783. doi:10.1371/journal.pone.0019783
104. Li R, Liu Y, Ladisch S (2001) Enhancement of epidermal growth factor signaling and activation of SRC kinase by gangliosides. J Biol Chem 276:42782–42792. doi:10.1074/jbc.M101481200
105. Lima S, Spiegel S (2013) Sphingosine kinase: a closer look at last. Structure 21:690–692. doi:10.1016/j.str.2013.04.006
106. Lin CF et al (2004) Sequential caspase-2 and caspase-8 activation upstream of mitochondria during ceramideand etoposide-induced apoptosis. J Biol Chem 279:40755–40761
107. Lin CF et al (2005) Bcl-2 rescues ceramide- and etoposide-induced mitochondrial apoptosis through blockage of caspase-2 activation. J Biol Chem 280:23758–23765. doi:10.1074/jbc.M412292200
108. Lindsten T et al (2000) The combined functions of proapoptotic Bcl-2 family members bak and bax are essential for normal development of multiple tissues. Mol Cell 6:1389–1399
109. Liu H et al (2000) Molecular cloning and functional characterization of a novel mammalian sphingosine kinase type 2 isoform. J Biol Chem 275:19513–19520. doi:10.1074/jbc.M002759200
110. Liu H et al (2003) Sphingosine kinase type 2 is a putative BH3-only protein that induces apoptosis. J Biol Chem 278:40330–40336. doi:10.1074/jbc.M304455200
111. Liu Y, Li R, Ladisch S (2004) Exogenous ganglioside GD1a enhances epidermal growth factor receptor binding and dimerization. J Biol Chem 279:36481–36489. doi:10.1074/jbc.M402880200
112. Liu YY et al (2008) A role for ceramide in driving cancer cell resistance to doxorubicin. FASEB J: Off Publ Fed Am Soc Exp Biol 22:2541–2551. doi:10.1096/fj.07-092981
113. Liu X et al (2010) Targeting of survivin by nanoliposomal ceramide induces complete remission in a rat model of NK-LGL leukemia. Blood 116:4192–4201. doi:10.1182/blood-2010-02-271080
114. Lu FG, Wong CS (2004) Radiation-induced apoptosis of oligodendrocytes and its association with increased ceramide and down-regulated protein kinase B/Akt activity. Int J Radiat Biol 80:39–51. doi:10.1080/09553000310001642876
115. Lucke T, Hoppner W, Schmidt E, Illsinger S, Das AM (2004) Fabry disease: reduced activities of respiratory chain enzymes with decreased levels of energy-rich phosphates in fibroblasts. Mol Genet Metab 82:93–97. doi:10.1016/j.ymgme.2004.01.011
116. Malina HZ, Hess OM (2004) Xanthurenic acid translocates proapoptotic Bcl-2 family proteins into mitochondria and impairs mitochondrial function. BMC Cell Biol 5:14
117. Mansat V, Bettaieb A, Levade T, Laurent G, Jaffrezou JP (1997) Serine protease inhibitors block neutral sphingomyelinase activation, ceramide generation, and apoptosis triggered by daunorubicin. FASEB J: Off Publ Fed Am Soc Exp Biol 11:695–702
118. Mao C, Xu R, Szulc ZM, Bielawska A, Galadari SH, Obeid LM (2001) Cloning and characterization of a novel human alkaline ceramidase. A mammalian enzyme that hydrolyzes phytoceramide. J Biol Chem 276:26577–26588. doi:10.1074/jbc.M102818200
119. Mao C et al (2003) Cloning and characterization of a mouse endoplasmic reticulum alkaline ceramidase: an enzyme that preferentially regulates metabolism of very long chain ceramides. J Biol Chem 278:31184–31191. doi:10.1074/jbc.M303875200
120. Martinez-Abundis E, Correa F, Pavon N, Zazueta C (2009) Bax distribution into mitochondrial detergent-resistant microdomains is related to ceramide and cholesterol content in postischemic hearts. FEBS J 276:5579–5588. doi:10.1111/j.1742-4658.2009.07239.x
121. Matarrese P et al (2005) Galectin-1 sensitizes resting human T lymphocytes to Fas (CD95)-mediated cell death via mitochondrial hyperpolarization, budding, and fission. J Biol Chem 280:6969–6985. doi:10.1074/jbc.M409752200
122. McIlwain H (1975) The second Thudichum lecture. Cerebral isolates and neurochemical discovery. Biochem Soc Trans 3:579–590
123. Mesicek J et al (2010) Ceramide synthases 2, 5, and 6 confer distinct roles in radiation-induced apoptosis in HeLa cells. Cell Signal 22:1300–1307. doi:10.1016/j.cellsig.2010.04.006
124. Min J, Mesika A, Sivaguru M, Van Veldhoven PP, Alexander H, Futerman AH, Alexander S (2007) (Dihydro)ceramide synthase 1 regulated sensitivity to cisplatin is associated with the activation of p38 mitogen-activated protein kinase and is abrogated by sphingosine kinase 1. Mol Cancer Res: MCR 5:801–812. doi:10.1158/1541-7786.MCR-07-0100
125. Moeller BJ, Pasqualini R, Arap W (2009) Ceramide-mediated apoptosis following ionizing radiation in human prostate cancer cells: PKCalpha joins the fray. Cancer Biol Ther 8:64–65
126. Mullen TD, Spassieva S, Jenkins RW, Kitatani K, Bielawski J, Hannun YA, Obeid LM (2011) Selective knockdown of ceramide synthases reveals complex interregulation of sphingolipid metabolism. J Lipid Res 52:68–77. doi:10.1194/jlr.M009142
127. Mullen TD, Hannun YA, Obeid LM (2012) Ceramide synthases at the centre of sphingolipid metabolism and biology. Biochem J 441:789–802. doi:10.1042/BJ20111626
128. Noda S, Yoshimura S, Sawada M, Naganawa T, Iwama T, Nakashima S, Sakai N (2001) Role of ceramide during cisplatin-induced apoptosis in C6 glioma cells. J Neuro-Oncol 52:11–21
129. Nomura M, Shimizu S, Ito T, Narita M, Matsuda H, Tsujimoto Y (1999) Apoptotic cytosol facilitates Bax translocation to mitochondria that involves cytosolic factor regulated by Bcl-2. Cancer Res 59:5542–5548
130. Novgorodov SA, Gudz TI (2009) Ceramide and mitochondria in ischemia/reperfusion. J Cardiovasc Pharmacol 53:198–208. doi:10.1097/FJC.0b013e31819b52d5
131. Novgorodov SA, Gudz TI (2011) Ceramide and mitochondria in ischemic brain injury. Int J Biochem Mol Biol 2:347–361
132. Novgorodov SA, Wu BX, Gudz TI, Bielawski J, Ovchinnikova TV, Hannun YA, Obeid LM (2011) Novel pathway of ceramide production in mitochondria: thioesterase and neutral ceramidase produce ceramide from sphingosine and acyl-CoA. J Biol Chem 286:25352–25362. doi:10.1074/jbc.M110.214866
133. Novgorodov SA et al (2014) Essential roles of neutral ceramidase and sphingosine in mitochondrial dysfunction due to traumatic brain injury. J Biol Chem 289:13142–13154. doi:10.1074/jbc.M113.530311
134. Obeid LM, Linardic CM, Karolak LA, Hannun YA (1993) Programmed cell death induced by ceramide. Science 259:1769–1771
135. Pacher P, Hajnoczky G (2001) Propagation of the apoptotic signal by mitochondrial waves. EMBO J 20:4107–4121
136. Park JH, Schuchman EH (2006) Acid ceramidase and human disease. Biochim Biophys Acta 1758:2133–2138. doi:10.1016/j.bbamem.2006.08.019
137. Park JY, Kim MJ, Kim YK, Woo JS (2011) Ceramide induces apoptosis via caspase-dependent and caspase-independent pathways in mesenchymal stem cells derived from human adipose tissue. Arch Toxicol 85:1057–1065. doi:10.1007/s00204-011-0645-x
138. Park JW, Park WJ, Kuperman Y, Boura-Halfon S, Pewzner-Jung Y, Futerman AH (2013a) Ablation of very long acyl chain sphingolipids causes hepatic insulin resistance in mice due to altered detergent-resistant membranes. Hepatology 57:525–532. doi:10.1002/hep.26015
139. Park WJ et al (2013b) Protection of a ceramide synthase 2 null mouse from drug-induced liver injury: role of gap junction dysfunction and connexin 32 mislocalization. J Biol Chem 288:30904–30916. doi:10.1074/jbc.M112.448852
140. Park JW, Park WJ, Futerman AH (2014) Ceramide synthases as potential targets for therapeutic intervention in human diseases. Biochim Biophys Acta 1841:671–681. doi:10.1016/j.bbalip.2013.08.019
141. Parra V et al (2008) Changes in mitochondrial dynamics during ceramide-induced cardiomyocyte early apoptosis. Cardiovasc Res 77:387–397
142. Patwardhan GA, Liu YY (2011) Sphingolipids and expression regulation of genes in cancer. Prog Lipid Res 50:104–114. doi:10.1016/j.plipres.2010.10.003
143. Perera MN, Lin SH, Peterson YK, Bielawska A, Szulc ZM, Bittman R, Colombini M (2012) Bax and Bcl-xL exert their regulation on different sites of the ceramide channel. Biochem J 445:81–91. doi:10.1042/BJ20112103
144. Perfettini JL, Kroemer RT, Kroemer G (2004) Fatal liaisons of p53 with Bax and Bak. Nat Cell Biol 6:386–388
145. Perry DK, Carton J, Shah AK, Meredith F, Uhlinger DJ, Hannun YA (2000) Serine palmitoyltransferase regulates de novo ceramide generation during etoposide-induced apoptosis. J Biol Chem 275:9078–9084
146. Petrache I et al (2013) Ceramide synthases expression and role of ceramide synthase-2 in the lung: insight from human lung cells and mouse models. PLoS ONE 8:e62968. doi:10.1371/journal.pone.0062968
147. Pewzner-Jung Y et al. A critical role for ceramide synthase 2 in liver homeostasis: I. alterations in lipid metabolic pathways. J Biol Chem 285:10902–10910 doi: 10.1074/jbc.M109.077594.
148. Pewzner-Jung Y et al. A critical role for ceramide synthase 2 in liver homeostasis: II. Insights into molecular changes leading to hepatopathy. J Biol Chem 285:10911–10923 doi: 10.1074/jbc.M109.077610.
149. Pewzner-Jung Y et al (2010a) A critical role for ceramide synthase 2 in liver homeostasis: II. insights into molecular changes leading to hepatopathy. J Biol Chem 285:10911–10923. doi:10.1074/jbc.M109.077610
150. Pewzner-Jung Y et al (2010b) A critical role for ceramide synthase 2 in liver homeostasis: I. alterations in lipid metabolic pathways. J Biol Chem 285:10902–10910. doi:10.1074/jbc.M109.077594
151. Phillips DC, Martin S, Doyle BT, Houghton JA (2007) Sphingosine-induced apoptosis in rhabdomyosarcoma cell lines is dependent on pre-mitochondrial Bax activation and post-mitochondrial caspases. Cancer Res 67:756–764. doi:10.1158/0008-5472.CAN-06-2374
152. Pinton P, Giorgi C, Pandolfi PP (2011) The role of PML in the control of apoptotic cell fate: a new key player at ER-mitochondria sites. Cell Death Differ 18:1450–1456. doi:10.1038/cdd.2011.31
153. Pitson SM (2011) Regulation of sphingosine kinase and sphingolipid signaling. Trends Biochem Sci 36:97–107. doi:10.1016/j.tibs.2010.08.001
154. Pitson SM et al (2005) Phosphorylation-dependent translocation of sphingosine kinase to the plasma membrane drives its oncogenic signalling. J Exp Med 201:49–54. doi:10.1084/jem.20040559
155. Pyne NJ, Tonelli F, Lim KG, Long J, Edwards J, Pyne S (2012) Targeting sphingosine kinase 1 in cancer. Adv Biol Regul 52:31–38. doi:10.1016/j.advenzreg.2011.07.001
156. Quillet-Mary A, Jaffrezou JP, Mansat V, Bordier C, Naval J, Laurent G (1997) Implication of mitochondrial hydrogen peroxide generation in ceramide-induced apoptosis. J Biol Chem 272:21388–21395
157. Rao RP et al (2014) Ceramide transfer protein deficiency compromises organelle function and leads to senescence in primary cells. PLoS ONE 9:e92142. doi:10.1371/journal.pone.0092142
158. Rathmell JC, Lindsten T, Zong WX, Cinalli RM, Thompson CB (2002) Deficiency in Bak and Bax perturbs thymic selection and lymphoid homeostasis. Nat Immunol 3:932–939. doi:10.1038/ni834
159. Rego A et al (2012) Modulation of mitochondrial outer membrane permeabilization and apoptosis by ceramide metabolism. PLoS ONE 7:e48571. doi:10.1371/journal.pone.0048571
160. Rizzuto R et al (1998) Close contacts with the endoplasmic reticulum as determinants of mitochondrial Ca2+ responses. Science 280:1763–1766
161. Rodriguez-Lafrasse C, Alphonse G, Broquet P, Aloy MT, Louisot P, Rousson R (2001) Temporal relationships between ceramide production, caspase activation and mitochondrial dysfunction in cell lines with varying sensitivity to anti-Fas-induced apoptosis. Biochem J 357:407–416
162. Rogasevskaia T, Coorssen JR (2006) Sphingomyelin-enriched microdomains define the efficiency of native Ca(2+)-triggered membrane fusion. J Cell Sci 119:2688–2694. doi:10.1242/jcs.03007
163. Rojas-Charry L, Cookson MR, Nino A, Arboleda H, Arboleda G (2014) Downregulation of Pink1 influences mitochondrial fusion-fission machinery and sensitizes to neurotoxins in dopaminergic cells. Neurotoxicology 44C:140–148. doi:10.1016/j.neuro.2014.04.007
164. Russo SB, Ross JS, Cowart LA (2013) Sphingolipids in obesity, type 2 diabetes, and metabolic disease. Handb Exp Pharmacol:373–401 doi:10.1007/978-3-7091-1511-4_19.
165. Samanta S, Stiban J, Maugel TK, Colombini M (2011) Visualization of ceramide channels by transmission electron microscopy. Biochim Biophys Acta 1808:1196–1201. doi:10.1016/j.bbamem.2011.01.007
166. Sawada M et al (2000) Ordering of ceramide formation, caspase activation, and Bax/Bcl-2 expression during etoposide-induced apoptosis in C6 glioma cells. Cell Death Differ 7:761–772. doi:10.1038/sj.cdd.4400711
167. Schneider-Brachert W et al (2004) Compartmentalization of TNF receptor 1 signaling: internalized TNF receptosomes as death signaling vesicles. Immunity 21:415–428. doi:10.1016/j.immuni.2004.08.017 S1074761304002341
168. Scorrano L, Oakes SA, Opferman JT, Cheng EH, Sorcinelli MD, Pozzan T, Korsmeyer SJ (2003) BAX and BAK regulation of endoplasmic reticulum Ca2+: a control point for apoptosis. Science 300:135–139
169. Senkal CE, Ponnusamy S, Bielawski J, Hannun YA, Ogretmen B (2010) Antiapoptotic roles of ceramide-synthase-6-generated C16-ceramide via selective regulation of the ATF6/CHOP arm of ER-stress-response pathways. FASEB J: Off Publ Fed Am Soc Exp Biol 24:296–308. doi:10.1096/fj.09-135087
170. Senkal CE et al (2011) Alteration of ceramide synthase 6/C16-ceramide induces activating transcription factor 6-mediated endoplasmic reticulum (ER) stress and apoptosis via perturbation of cellular Ca2+ and ER/Golgi membrane network. J Biol Chem 286:42446–42458. doi:10.1074/jbc.M111.287383
171. Shida D, Takabe K, Kapitonov D, Milstien S, Spiegel S (2008) Targeting SphK1 as a new strategy against cancer. Curr Drug Targets 9:662–673
172. Silva LC et al (2012) Ablation of ceramide synthase 2 strongly affects biophysical properties of membranes. J Lipid Res 53:430–436. doi:10.1194/jlr.M022715
173. Siow DL, Anderson CD, Berdyshev EV, Skobeleva A, Natarajan V, Pitson SM, Wattenberg BW (2011) Sphingosine kinase localization in the control of sphingolipid metabolism. Adv Enzym Regul 51:229–244. doi:10.1016/j.advenzreg.2010.09.004
174. Siskind LJ (2005) Mitochondrial ceramide and the induction of apoptosis. J Bioenerg Biomembr 37:143–153. doi:10.1007/s10863-005-6567-7
175. Siskind LJ, Colombini M (2000) The lipids C2- and C16-ceramide form large stable channels. Implications for apoptosis. J Biol Chem 275:38640–38644. doi:10.1074/jbc.C000587200
176. Siskind LJ, Kolesnick RN, Colombini M (2002) Ceramide channels increase the permeability of the mitochondrial outer membrane to small proteins. J Biol Chem 277:26796–26803. doi:10.1074/jbc.M200754200
177. Siskind LJ, Davoody A, Lewin N, Marshall S, Colombini M (2003) Enlargement and contracture of C2-ceramide channels. Biophys J 85:1560–1575. doi:10.1016/S0006-3495(03)74588-3
178. Siskind LJ, Kolesnick RN, Colombini M (2006) Ceramide forms channels in mitochondrial outer membranes at physiologically relevant concentrations. Mitochondrion 6:118–125. doi:10.1016/j.mito.2006.03.002
179. Siskind LJ et al (2008) Anti-apoptotic Bcl-2 family proteins disassemble ceramide channels. J Biol Chem 283:6622–6630. doi:10.1074/jbc.M706115200
180. Siskind LJ, Mullen TD, Romero Rosales K, Clarke CJ, Hernandez-Corbacho MJ, Edinger AL, Obeid LM (2010) The BCL-2 protein BAK is required for long-chain ceramide generation during apoptosis. J Biol Chem 285:11818–11826. doi:10.1074/jbc.M109.078121
181. Smith ME et al (2013) Mitochondrial fission mediates ceramide-induced metabolic disruption in skeletal muscle. Biochem J 456:427–439. doi:10.1042/BJ20130807
182. Snider AJ (2013) Sphingosine kinase and sphingosine-1-phosphate: regulators in autoimmune and inflammatory disease. Int J Clin Rheumatol 8 doi:10.2217/ijr.13.40.
183. Sonnino S, Mauri L, Chigorno V, Prinetti A (2007) Gangliosides as components of lipid membrane domains. Glycobiology 17:1R–13R. doi:10.1093/glycob/cwl052
184. Sot J, Aranda FJ, Collado MI, Goni FM, Alonso A (2005) Different effects of long- and short-chain ceramides on the gel-fluid and lamellar-hexagonal transitions of phospholipids: a calorimetric, NMR, and x-ray diffraction study. Biophys J 88:3368–3380. doi:10.1529/biophysj.104.057851
185. Sridevi P, Alexander H, Laviad EL, Pewzner-Jung Y, Hannink M, Futerman AH, Alexander S (2009) Ceramide synthase 1 is regulated by proteasomal mediated turnover. Biochim Biophys Acta 1793:1218–1227. doi:10.1016/j.bbamcr.2009.04.006
186. Sridevi P et al (2010) Stress-induced ER to Golgi translocation of ceramide synthase 1 is dependent on proteasomal processing. Exp Cell Res 316:78–91. doi:10.1016/j.yexcr.2009.09.027
187. Stevenson CE, Takabe K, Nagahashi M, Milstien S, Spiegel S (2011) Targeting sphingosine-1-phosphate in hematologic malignancies. Anti Cancer Agents Med Chem 11:794–798
188. Stiban J, Caputo L, Colombini M (2008) Ceramide synthesis in the endoplasmic reticulum can permeabilize mitochondria to proapoptotic proteins. J Lipid Res 49:625–634. doi:10.1194/jlr. M700480-JLR200
189. Stoica BA, Movsesyan VA, Lea PM 4th, Faden AI (2003) Ceramide-induced neuronal apoptosis is associated with dephosphorylation of Akt, BAD, FKHR, GSK-3beta, and induction of the mitochondrial-dependent intrinsic caspase pathway. Mol Cell Neurosci 22:365–382
190. Strub GM et al (2011) Sphingosine-1-phosphate produced by sphingosine kinase 2 in mitochondria interacts with prohibitin 2 to regulate complex IV assembly and respiration. FASEB J: Off Publ Fed Am Soc Exp Biol 25:600–612. doi:10.1096/fj.10-167502
191. Sun W et al (2010) Substrate specificity, membrane topology, and activity regulation of human alkaline ceramidase 2 (ACER2). J Biol Chem 285:8995–9007. doi:10.1074/jbc.M109.069203
192. Tafesse FG et al (2014) Sphingomyelin synthase-related protein SMSr is a suppressor of ceramide-induced mitochondrial apoptosis. J Cell Sci 127:445–454. doi:10.1242/jcs.138933
193. Takabe K, Spiegel S (2014) Export of sphingosine-1-phosphate and cancer progression. J Lipid Res 55:1839–1846. doi:10.1194/jlr.R046656
194. Tani M, Okino N, Mitsutake S, Tanigawa T, Izu H, Ito M (2000) Purification and characterization of a neutral ceramidase from mouse liver. A single protein catalyzes the reversible reaction in which ceramide is both hydrolyzed and synthesized. J Biol Chem 275:3462–3468
195. Tani M, Igarashi Y, Ito M (2005) Involvement of neutral ceramidase in ceramide metabolism at the plasma membrane and in extracellular milieu. J Biol Chem 280:36592–36600. doi:10.1074/jbc.M506827200
196. Thomas RL Jr, Matsko CM, Lotze MT, Amoscato AA (1999) Mass spectrometric identification of increased C16 ceramide levels during apoptosis. J Biol Chem 274:30580–30588
197. Uchida Y et al (2010) Hydrolytic pathway protects against ceramide-induced apoptosis in keratinocytes exposed to UVB. J Investig Dermatol 130:2472–2480. doi:10.1038/jid.2010.153
198. van Echten-Deckert G, Walter J (2012) Sphingolipids: critical players in Alzheimer’s disease. Prog Lipid Res 51:378–393. doi:10.1016/j.plipres.2012.07.001
199. Vit JP, Rosselli F (2003) Role of the ceramide-signaling pathways in ionizing radiation-induced apoptosis. Oncogene 22:8645–8652. doi:10.1038/sj.onc.1207087
200. von Haefen C, Wieder T, Gillissen B, Starck L, Graupner V, Dorken B, Daniel PT (2002) Ceramide induces mitochondrial activation and apoptosis via a Bax-dependent pathway in human carcinoma cells. Oncogene 21:4009–4019. doi:10.1038/sj.onc.1205497
201. Wang X et al (2009) Mitochondrial degeneration and not apoptosis is the primary cause of embryonic lethality in ceramide transfer protein mutant mice. J Cell Biol 184:143–158. doi:10.1083/jcb.200807176
202. Wattenberg BW (2010) Role of sphingosine kinase localization in sphingolipid signaling. World J Biol Chem 1:362–368. doi:10.4331/wjbc.v1.i12.362
203. Wei MC et al (2001) Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science 292:727–730
204. Weigert A, Cremer S, Schmidt MV, von Knethen A, Angioni C, Geisslinger G, Brune B (2010) Cleavage of sphingosine kinase 2 by caspase-1 provokes its release from apoptotic cells. Blood 115:3531–3540. doi:10.1182/blood-2009-10-243444
205. Wiesner DA, Dawson G (1996) Staurosporine induces programmed cell death in embryonic neurons and activation of the ceramide pathway. J Neurochem 66:1418–1425
206. Wiesner DA, Kilkus JP, Gottschalk AR, Quintans J, Dawson G (1997) Anti-immunoglobulin-induced apoptosis in WEHI 231 cells involves the slow formation of ceramide from sphingomyelin and is blocked by bcl-XL. J Biol Chem 272:9868–9876
207. Wolter KG, Hsu YT, Smith CL, Nechushtan A, Xi XG, Youle RJ (1997) Movement of Bax from the cytosol to mitochondria during apoptosis. J Cell Biol 139:1281–1292
208. Wu BX, Rajagopalan V, Roddy PL, Clarke CJ, Hannun YA (2010) Identification and characterization of murine mitochondria-associated neutral sphingomyelinase (MA-nSMase), the mammalian sphingomyelin phosphodiesterase 5. J Biol Chem 285:17993–18002. doi:10.1074/jbc.M110.102988
209. Yamaguchi K et al (2005) Evidence for mitochondrial localization of a novel human sialidase (NEU4). Biochem J 390:85–93. doi:10.1042/BJ20050017
210. Yang Y, Uhlig S (2011) The role of sphingolipids in respiratory disease. Ther Adv Respir Dis 5:325–344. doi:10.1177/1753465811406772
211. Yao J et al (2013) Ultraviolet (UV) and hydrogen peroxide activate ceramide-ER stress-AMPK signaling axis to promote retinal pigment epithelium (RPE) cell apoptosis. Int J Mol Sci 14:10355–10368. doi:10.3390/ijms140510355
212. Zhang J, Alter N, Reed JC, Borner C, Obeid LM, Hannun YA (1996) Bcl-2 interrupts the ceramide-mediated pathway of cell death. Proc Natl Acad Sci U S A 93:5325–5328
213. Zhang Y, Wang Y, Wan Z, Liu S, Cao Y, Zeng Z (2014) Sphingosine kinase 1 and cancer: a systematic review and meta-analysis. PLoS ONE 9:e90362. doi:10.1371/journal.pone.0090362
214. Zigdon H et al (2013) Ablation of ceramide synthase 2 causes chronic oxidative stress due to disruption of the mitochondrial respiratory chain. J Biol Chem 288:4947–4956. doi:10.1074/jbc.M112.402719
215. Zong WX, Li C, Hatzivassiliou G, Lindsten T, Yu QC, Yuan J, Thompson CB (2003) Bax and Bak can localize to the endoplasmic reticulum to initiate apoptosis. J Cell Biol 162:59–69