Regulation of Mitochondrial Function by Bioactive Sphingolipids
Cell Biology
Volume 3, Issue 2-1, April 2015, Pages: 1-7
Received: Nov. 24, 2014; Accepted: Dec. 18, 2014; Published: Feb. 10, 2015
Views 4087      Downloads 261
Rajeev Nema, Department of Biochemistry, All India Institute of Medical Sciences (AIIMS) Bhopal, Saket Nagar, Bhopal 462020, India
Ashok Kumar, Department of Biochemistry, All India Institute of Medical Sciences (AIIMS) Bhopal, Saket Nagar, Bhopal 462020, India
Article Tools
Follow on us
Sphingolipids such as ceramide, sphingosine and sphingosine 1-phosphate [S1P] are key regulators of various cellular functions. Sphingolipids mediates of cell-stress responses and regulate mitochondrial function. Ceramide and its metabolites play an important role in the development and progression of mitochondria related disorders. Ceramide functions as an important second messenger in apoptosis signaling and is generated by de novo synthesis, sphingomyelin hydrolysis, or recycling of sphingolipids. S1P, a potent signaling sphingolipid exerts myriads of pathophysiological function, including lymphocyte trafficking, angiogenesis, vascular development and inflammation. This review is focused on the role of signaling sphingolipids, such as S1P, sphingosine, and ceramide-1 phosphate on mitochondrial function, particularly mitochondrial respiratory function, apoptosis and calcium homeostasis. Further, we discuss the role of sphingolipids in mitochondrial diseases and targeting them for drug development. This review article is a part of special issue on Mitochondria: Implications in human health and disease.
Sphingolipid, Ceramide, Sphingosine-1-Phosphate [S1P], Mitochondria, Apoptosis
To cite this article
Rajeev Nema, Ashok Kumar, Regulation of Mitochondrial Function by Bioactive Sphingolipids, Cell Biology. Special Issue: Mitochondria: Implications in Human Health and Diseases. Vol. 3, No. 2-1, 2015, pp. 1-7. doi: 10.11648/j.cb.s.2015030201.11
Hannun YA, Obeid LM. Principles of bioactive lipid signalling: lessons from sphingolipids. Nat Rev Mol Cell Biol. 2008; 9(2):139-50.
Ogretmen, B., Hannun, Y. A. Biologically active sphingolipids in cancer pathogenesis and treatment. Nat Rev Cancer. 2004; 4(8):604-16.
Spiegel S, Milstien S. Sphingosine-1-phosphate: an enigmatic signalling lipid. Nat Rev Mol Cell Biol. 2003;4:397–407
Kumar, A., Saba, JD. Sphingosine-1-Phosphate. In: Encyclopedia of Signaling Molecules. Sangdun Choi (Ed). Springer Publication. 2012, p1771.
Pyne NJ, Pyne S. Sphingosine 1-phosphate and cancer. Nat Rev Cancer. 2010; 10:489–503
Fyrst H, Saba JD. An update on sphingosine-1-phosphate and other sphingolipid mediators. Nat Chem Biol. 2010 Jul;6(7):489-97.
Maceyka M, Spiegel S. Sphingolipid metabolites in inflammatory disease. Nature. 2014 Jun 5;510(7503):58-67.
Kunkel GT, Maceyka M, Milstien S, Spiegel S. Targeting the sphingosine-1-phosphate axis in cancer, inflammation and beyond. Nat Rev Drug Discov. 2013 Sep;12(9):688-702.
Westermann B. Mitochondrial fusion and fission in cell life and death. Nat Rev Mol Cell Biol. 2010; 11(12):872-84.
Cheng Z, Ristow M. Mitochondria and metabolic homeostasis. Antioxid Redox Signal. 2013; 20; 19(3):240-2.
Brenner C, Kroemer G. Apoptosis. Mitochondria--the death signal integrators. Science. 2000; 18; 289(5482):1150-1.
Rustin P, Kroemer G. Mitochondria and cancer. Ernst Schering Found Symp Proc. 2007; (4):1-21.
Hsu CC, Lee HC, Wei YH. Mitochondrial DNA alterations and mitochondrial dysfunction in the progression of hepatocellular carcinoma. World J Gastroenterol. 2013; 21; 19(47):8880-6.
Boland ML, Chourasia AH, Macleod KF. Mitochondrial dysfunction in cancer. Front Oncol. 2013; 2; 3:292.
Dai DF, Chiao YA, Marcinek DJ, Szeto HH, Rabinovitch PS. Mitochondrial oxidative stress in aging and healthspan. Longev Health span. 2014; 1; 3:6.
Zuo L, Motherwell MS. The impact of reactive oxygen species and genetic mitochondrial mutations in Parkinson's disease. Gene. 2013; 10; 532(1):18-23.
Serý O, Povová J, Míšek I, Pešák L, Janout V. Molecular mechanisms of neuropathological changes in Alzheimer's disease: a review. Folia Neuropathol. 2013; 51(1):1-9.
Shi Y, Rehman H, Ramshesh VK, Schwartz J, Liu Q, Krishnasamy Y, Zhang X, Lemasters JJ, Smith CD, Zhong Z. Sphingosine kinase-2 inhibition improves mitochondrial function and survival after hepatic ischemia-reperfusion. J Hepatol. 2012; 56(1):137-45.
Stiles L, Shirihai OS. Mitochondrial dynamics and morphology in beta-cells. Best Pract Res Clin Endocrinol Metab. 2012; 26(6):725-38.
Gomez L, Paillard M, Price M, Chen Q, Teixeira G, Spiegel S, Lesnefsky EJ. A novel role for mitochondrial sphingosine-1-phosphate produced by sphingosine kinase-2 in PTP-mediated cell survival during cardioprotection. Basic Res Cardiol. 2011; 106(6):1341-53.
Yu T, Wang L, Lee H, O'Brien DK, Bronk SF, Gores GJ, Yoon Y. Decreasing Mitochondrial Fission Prevents Cholestatic Liver Injury. J Biol Chem. 2014; 23. pii: jbc.M114.588616.
Obeid LM, Linardic CM, Karolak LA, Hannun YA. Programmed cell death induced by ceramide. Science. 1993; 19; 259(5102):1769-71.
Chipuk, J.E.; McStay, G.P.; Bharti, A.; Kuwana, T.; Clarke, C.J.; Siskind, L.J.; Obeid, L.M.; Green, D.R. Sphingolipid metabolism cooperates with BAK and BAX to promote the mitochondrial pathway of apoptosis. Cell 2012, 148, 988–1000.
Novgorodov SA, Gudz TI. Ceramide and mitochondria in ischemic brain injury. Int J Biochem Mol Biol. 2011; 2(4):347-61.
Kogot-Levin A, Saada A. Ceramide and the mitochondrial respiratory chain. Biochimie. 2014; 100:88-94.
Ardail D, Popa I, Alcantara K, Pons A, Zanetta JP, Louisot P, Thomas L, Portoukalian J. Occurrence of ceramides and neutral glycolipids with unusual long-chain base composition in purified rat liver mitochondria. FEBS Lett 2001; 488: 160-4.
Tidhar R, Futerman AH. The complexity of sphingolipid biosynthesis in the endoplasmic reticulum. Biochim Biophys Acta. 2013; 1833(11):2511-8.
Ribas V, García-Ruiz C, Fernández-Checa JC. Glutathione and mitochondria. Front Pharmacol. 2014; 1; 5:151.
García-Ruiz C, Colell A, París R, Fernández-Checa JC. Direct interaction of GD3 ganglioside with mitochondria generates reactive oxygen species followed by mitochondrial permeability transition, cytochrome c release, and caspase activation. FASEB J. 2000; 14(7):847-58.
Zigdon H, Kogot-Levin A, Park JW, Goldschmidt R, Kelly S, Merrill AH Jr, Scherz A, Pewzner-Jung Y, Saada A, Futerman AH. Ablation of ceramide synthase 2 causes chronic oxidative stress due to disruption of the mitochondrial respiratory chain. J Biol Chem. 2013; 15; 288(7):4947-56.
Yu J, Novgorodov SA, Chudakova D, Zhu H, Bielawska A, Bielawski J, Obeid LM, Kindy MS, Gudz TI. JNK3 signaling pathway activates ceramide synthase leading to mitochondrial dysfunction. J Biol Chem. 2007; 31; 282(35):25940-9.
Otera H, Mihara K. Mitochondrial dynamics: functional link with apoptosis. Int J Cell Biol. 2012; 2012:821676.
Harris MH, Thompson CB. The role of the Bcl-2 family in the regulation of outer mitochondrial membrane permeability. Cell Death Differ. 2000; 7(12):1182-91.
Wang C, Youle RJ. The role of mitochondria in apoptosis. Annu Rev Genet. 2009; 43:95-118.
Siskind LJ, Mullen TD, Romero Rosales K, Clarke CJ, Hernandez-Corbacho MJ, Edinger AL, Obeid LM. The BCL-2 protein BAK is required for long-chain ceramide generation during apoptosis. J Biol Chem. 2010; 16; 285(16):11818-26.
Pettus BJ, Chalfant CE, Hannun YA. Ceramide in apoptosis: an overview and current perspectives. Biochim Biophys Acta. 2002; 30; 1585(2-3):114-25.
Birbes H, El Bawab S, Hannun YA, Obeid LM. Selective hydrolysis of a mitochondrial pool of sphingomyelin induces apoptosis. FASEB J. 2001; 15(14):2669-79.
Hearps AC, Burrows J, Connor CE, Woods GM, Lowenthal RM, Ragg SJ. Mitochondrial cytochrome c release precedes transmembrane depolarisation and caspase-3 activation during ceramide-induced apoptosis of Jurkat T cells. Apoptosis. 2002; 7(5):387-94.
Won JS, Singh I. Sphingolipid signaling and redox regulation. Free Radic Biol Med. 2006; 1;40(11):1875-88.
Lin CF, Chen CL, Chang WT, Jan MS, Hsu LJ, Wu RH, Tang MJ, Chang WC, Lin YS. Sequential caspase-2 and caspase-8 activation upstream of mitochondria during ceramide and etoposide-induced apoptosis. J Biol Chem. 2004; 24; 279(39):40755-61.
Birbes H, Luberto C, Hsu YT, El Bawab S, Hannun YA, Obeid LM. A mitochondrial pool of sphingomyelin is involved in TNF alpha-induced Bax translocation to mitochondria. Biochem J. 2005; 15; 386(Pt 3):445-51.
Dai Q, Liu J, Chen J, Durrant D, McIntyre TM, Lee RM. Mitochondrial ceramide increases in UV-irradiated HeLa cells and is mainly derived from hydrolysis of sphingomyelin. Oncogene. 2004.
Kumar A, Byun HS, Bittman R, Saba JD. The sphingolipid degradation product trans-2-hexadecenal induces cytoskeletal reorganization and apoptosis in a JNK-dependent manner. Cell Signal. 2011; 23(7):1144-52.
Kumar A, Oskouian B, Fyrst H, Zhang M, Paris F, Saba JD. S1P lyase regulates DNA damage responses through a novel sphingolipid feedback mechanism. Cell Death Dis. 2011; 10; 2:e119.
Fyrst H, Saba JD. Sphingosine-1-phosphate lyase in development and disease: sphingolipid metabolism takes flight. Biochim Biophys Acta. 2008; 1781(9):448-58.
Eskes R, Antonsson B, Osen-Sand A, Montessuit S, Richter C, Sadoul R, Mazzei G, Nichols A, Martinou JC. Bax-induced cytochrome C release from mitochondria is independent of the permeability transition pore but highly dependent on Mg2+ ions. J Cell Biol. 1998; 5; 143(1):217-24.
Wei MC, Zong WX, Cheng EH, Lindsten T, Panoutsakopoulou V, Ross AJ, Roth KA, MacGregor GR, Thompson CB, Korsmeyer SJ. Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science. 2001; 27; 292(5517):727-30.
Jiang X, Jiang H, Shen Z, Wang X. Activation of mitochondrial protease OMA1 by Bax and Bak promotes cytochrome c release during apoptosis. Proc Natl Acad Sci U S A. 2014; 14; 111(41):14782-7.
Colombini M. Ceramide channels and their role in mitochondria-mediated apoptosis. Biochim Biophys Acta. 2010; 1797(6-7):1239-44.
Perera MN, Lin SH, Peterson YK, Bielawska A, Szulc ZM, Bittman R, Colombini M. Bax and Bcl-xL exert their regulation on different sites of the ceramide channel. Biochem J. 2012; 1; 445(1):81-91.
Siskind LJ, Fluss S, Bui M, Colombini M. Sphingosine forms channels in membranes that differ greatly from those formed by ceramide. J Bioenerg Biomembr. 2005; 37 (4):227-36.
Gómez-Muñoz A, Gangoiti P, Granado MH, Arana L, Ouro A. Ceramide-1-phosphate in cell survival and inflammatory signaling. Adv Exp Med Biol. 2010; 688:118-30.
Gómez-Muñoz A. Ceramide 1-phosphate/ceramide, a switch between life and death. Biochim Biophys Acta. 2006; 1758(12):2049-56.
Arana L, Gangoiti P, Ouro A, Trueba M, Gómez-Muñoz A. Ceramide and ceramide 1-phosphate in health and disease. Lipids Health Dis. 2010; 5; 9:15.
Hoeferlin LA, Wijesinghe DS, Chalfant CE. The role of ceramide-1-phosphate in biological functions. Handb Exp Pharmacol. 2013; (215):153-66.
Gangoiti P, Granado MH, Alonso A, Goñi FM, Gómez-Muñoz A. Implication of ceramide, ceramide 1-phosphate and sphingosine 1-phosphate in tumorigenesis. Transl Oncogenomics. 2008; 10; 3:81-98.
Cuvillier O, Pirianov G, Kleuser B, Vanek PG, Coso OA, Gutkind S, Spiegel S. Suppression of ceramide-mediated programmed cell death by sphingosine-1-phosphate. Nature. 1996 Jun 27;381(6585):800-3.
Cuvillier O, Levade T. Sphingosine 1-phosphate antagonizes apoptosis of human leukemia cells by inhibiting release of cytochrome c and Smac/DIABLO from mitochondria. Blood. 2001; 1; 98(9):2828-36.
Jin ZQ, Goetzl EJ, Karliner JS. Sphingosine kinase activation mediates ischemic preconditioning in murine heart. Circulation. 2004; 5; 110(14):1980-9.
Karliner JS. Sphingosine kinase and sphingosine 1-phosphate in cardioprotection. J Cardiovasc Pharmacol. 2009; 53(3):189-97.
Zhang J, Honbo N, Goetzl EJ, Chatterjee K, Karliner JS, Gray MO. Signals from type 1 sphingosine 1-phosphate receptors enhance adult mouse cardiac myocyte survival during hypoxia. Am J Physiol Heart Circ Physiol. 2007; 293(5):H3150-8.
Strub GM, Paillard M, Liang J, Gomez L, Allegood JC, Hait NC, Maceyka M, Price MM, Chen Q, Simpson DC, Kordula T, Milstien S, Lesnefsky EJ, Spiegel S. Sphingosine-1-phosphate produced by sphingosine kinase 2 in mitochondria interacts with prohibitin 2 to regulate complex IV assembly and respiration. FASEB J. 2011; 25(2):600-12.
Gomez L, Paillard M, Price M, Chen Q, Teixeira G, Spiegel S, Lesnefsky EJ. A novel role for mitochondrial sphingosine-1-phosphate produced by sphingosine kinase-2 in PTP-mediated cell survival during cardioprotection. Basic Res Cardiol. 2011; 106(6):1341-53.
Shi Y, Rehman H, Ramshesh VK, Schwartz J, Liu Q, Krishnasamy Y, Zhang X, Lemasters JJ, Smith CD, Zhong Z. Sphingosine kinase-2 inhibition improves mitochondrial function and survival after hepatic ischemia-reperfusion. Hepatol. 2012; 56(1):137-45.
Calì T, Ottolini D, Brini M. Mitochondrial Ca(2+) and neurodegeneration. Cell Calcium. 2012; 52(1):73-85.
Pimentel AA, Benaim G. Ca2+ and sphingolipids as modulators for apoptosis and cancer. Invest Clin. 2012; 53(1):84-110.
Parra V, Moraga F, Kuzmicic J, López-Crisosto C, Troncoso R, Torrealba N, Criollo A, Díaz-Elizondo J, Rothermel BA, Quest AF, Lavandero S. Calcium and mitochondrial metabolism in ceramide-induced cardiomyocyte death. Biochim Biophys Acta. 2013; 1832(8):1334-44.
Smaili SS, Hsu YT, Carvalho AC, Rosenstock TR, Sharpe JC, Youle RJ. Mitochondria, calcium and pro-apoptotic proteins as mediators in cell death signaling. Braz J Med Biol Res. 2003; 36(2):183-90.
Distelhorst CW, Bootman MD. Bcl-2 interaction with the inositol 1,4,5-trisphosphate receptor: role in Ca(2+) signaling and disease. Cell Calcium. 2011; 50(3):234-41.
Smyth JT, Hwang SY, Tomita T, DeHaven WI, Mercer JC, Putney JW. Activation and regulation of store-operated calcium entry. J Cell Mol Med. 2010; 14(10):2337-49.
Pinton P, Giorgi C, Siviero R, Zecchini E, Rizzuto R. Calcium and apoptosis: ER-mitochondria Ca2+ transfer in the control of apoptosis. Oncogene. 2008; 27; 27(50):6407-18.
Ajith TA, Jayakumar TG. Mitochondria-targeted agents: Future perspectives of mitochondrial pharmaceutics in cardiovascular diseases. World J Cardiol. 2014; 26; 6(10):1091-9.
Bereiter-Hahn J. Mitochondrial dynamics in aging and disease. Prog Mol Biol Transl Sci. 2014; 127:93-131.
Brandon M, Baldi P, Wallace DC. Mitochondrial mutations in cancer. Oncogene. 2006; 7; 25(34):4647-62.
Chatterjee A, Mambo E, Sidransky D. Mitochondrial DNA mutations in human cancer. Oncogene. 2006; 7; 25(34):4663-74.
King A, Selak MA, Gottlieb E. Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer. Oncogene. 2006; 7; 25(34):4675-82.
Robey RB, Hay N. Mitochondrial hexokinases, novel mediators of the antiapoptotic effects of growth factors and Akt. Oncogene. 2006; 7; 25(34):4683-96.
Vázquez MC, Balboa E, Alvarez AR, Zanlungo S. Oxidative stress: a pathogenic mechanism for Niemann-Pick type C disease. Oxid Med Cell Longev. 2012; 2012:205713.
Yu W, Gong JS, Ko M, Garver WS, Yanagisawa K, Michikawa M. Altered cholesterol metabolism in Niemann-Pick type C1 mouse brains affects mitochondrial function. J Biol Chem. 2005 Mar 25; 280(12):11731-9.
Sharma S, Mathur AG, Pradhan S, Singh DB, Gupta S. Fingolimod (FTY720): First approved oral therapy for multiple sclerosis. J Pharmacol Pharmacother. 201; 2(1):49-51.
Kunkel GT, Maceyka M, Milstien S, Spiegel S. Targeting the sphingosine-1-phosphate axis in cancer, inflammation and beyond. Nat Rev Drug Discov. 2013; 12(9):688-702.
Science Publishing Group
1 Rockefeller Plaza,
10th and 11th Floors,
New York, NY 10020
Tel: (001)347-983-5186