Loss of Neutral Ceramidase Protects Cells from Nutrient- and Energy -deprivation-induced Cell Death

Overview

Journal Biochem J

Specialty Biochemistry

Date 2016 Jan 10

PMID 26747710

Citations 23

Authors

Kumaran Sundaram

Andrew R Mather

Subathra Marimuthu

Parag P Shah

Ashley J Snider

Lina M Obeid

Yusuf A Hannun

Levi J Beverly

Leah J Siskind

Affiliations

Soon will be listed here.

Abstract

Sphingolipids are a family of lipids that regulate the cell cycle, differentiation and cell death. Sphingolipids are known to play a role in the induction of apoptosis, but a role for these lipids in necroptosis is largely unknown. Necroptosis is a programmed form of cell death that, unlike apoptosis, does not require ATP. Necroptosis can be induced under a variety of conditions, including nutrient deprivation and plays a major role in ischaemia/reperfusion injury to organs. Sphingolipids play a role in ischaemia/reperfusion injury in several organs. Thus, we hypothesized that sphingolipids mediate nutrient-deprivation-induced necroptosis. To address this, we utilized mouse embryonic fibroblast (MEFs) treated with 2-deoxyglucose (2DG) and antimycin A (AA) to inhibit glycolysis and mitochondrial electron transport. 2DG/AA treatment of MEFs induced necroptosis as it was receptor- interacting protein (RIP)-1/3 kinase-dependent and caspase-independent. Ceramides, sphingosine (Sph) and sphingosine 1-phosphate (S1P) were increased following 2DG/AA treatment. Cells lacking neutral ceramidase (nCDase(-/-)) were protected from 2DG/AA. Although nCDase(-/-) cells generated ceramides following 2DG/AA treatment, they did not generate Sph or S1P. This protection was stimulus-independent as nCDase(-/-) cells were also protected from endoplasmic reticulum (ER) stressors [tunicamycin (TN) or thapsigargin (TG)]. nCDase(-/-) MEFs had higher autophagic flux and mitophagy than wild-type (WT) MEFs and inhibition of autophagy sensitized them to necroptosis. These data indicate that loss of nCDase protects cells from nutrient- deprivation-induced necroptosis via autophagy, and clearance of damaged mitochondria. Results suggest that nCDase is a mediator of necroptosis and might be a novel therapeutic target for protection from ischaemic injury.

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References

Toops K, Tan L, Jiang Z, Radu R, Lakkaraju A . Cholesterol-mediated activation of acid sphingomyelinase disrupts autophagy in the retinal pigment epithelium. Mol Biol Cell. 2014; 26(1):1-14. PMC: 4279221. DOI: 10.1091/mbc.E14-05-1028. View

Toman R, Movsesyan V, Murthy S, Milstien S, Spiegel S, Faden A . Ceramide-induced cell death in primary neuronal cultures: upregulation of ceramide levels during neuronal apoptosis. J Neurosci Res. 2002; 68(3):323-30. DOI: 10.1002/jnr.10190. View

Castillo K, Valenzuela V, Matus S, Nassif M, Onate M, Fuentealba Y . Measurement of autophagy flux in the nervous system in vivo. Cell Death Dis. 2013; 4:e917. PMC: 3847309. DOI: 10.1038/cddis.2013.421. View

Guenther G, Liu G, Ramirez M, McMonigle R, Kim S, McCracken A . Loss of TSC2 confers resistance to ceramide and nutrient deprivation. Oncogene. 2013; 33(14):1776-87. PMC: 3858574. DOI: 10.1038/onc.2013.139. View

LINDSTEN T, Ross A, King A, Zong W, Rathmell J, Shiels H . The combined functions of proapoptotic Bcl-2 family members bak and bax are essential for normal development of multiple tissues. Mol Cell. 2001; 6(6):1389-99. PMC: 3057227. DOI: 10.1016/s1097-2765(00)00136-2. View

Taniguchi M, Kitatani K, Kondo T, Hashimoto-Nishimura M, Asano S, Hayashi A . Regulation of autophagy and its associated cell death by "sphingolipid rheostat": reciprocal role of ceramide and sphingosine 1-phosphate in the mammalian target of rapamycin pathway. J Biol Chem. 2012; 287(47):39898-910. PMC: 3501064. DOI: 10.1074/jbc.M112.416552. View

Bray K, Mathew R, Lau A, Kamphorst J, Fan J, Chen J . Autophagy suppresses RIP kinase-dependent necrosis enabling survival to mTOR inhibition. PLoS One. 2012; 7(7):e41831. PMC: 3406086. DOI: 10.1371/journal.pone.0041831. View

Yadav R, Chae S, Kim H, Chae H . Endoplasmic reticulum stress and cancer. J Cancer Prev. 2014; 19(2):75-88. PMC: 4204165. DOI: 10.15430/JCP.2014.19.2.75. View

Zhou W, Yuan J . SnapShot: Necroptosis. Cell. 2014; 158(2):464-464.e1. DOI: 10.1016/j.cell.2014.06.041. View

10.

Liang X, Chen Y, Zhang L, Jiang F, Wang W, Ye Z . Necroptosis, a novel form of caspase-independent cell death, contributes to renal epithelial cell damage in an ATP-depleted renal ischemia model. Mol Med Rep. 2014; 10(2):719-24. DOI: 10.3892/mmr.2014.2234. View

11.

Bajwa A, Rosin D, Chroscicki P, Lee S, Dondeti K, Ye H . Sphingosine 1-phosphate receptor-1 enhances mitochondrial function and reduces cisplatin-induced tubule injury. J Am Soc Nephrol. 2014; 26(4):908-25. PMC: 4378101. DOI: 10.1681/ASN.2013121351. View

12.

Shen W, Henry A, Paumier K, Li L, Mou K, Dunlop J . Inhibition of glucosylceramide synthase stimulates autophagy flux in neurons. J Neurochem. 2014; 129(5):884-94. DOI: 10.1111/jnc.12672. View

13.

King M, Whitaker-Lea W, Campbell J, Alleyne Jr C, Dhandapani K . Necrostatin-1 reduces neurovascular injury after intracerebral hemorrhage. Int J Cell Biol. 2014; 2014:495817. PMC: 3963111. DOI: 10.1155/2014/495817. View

14.

Zager R, Conrad D, Burkhart K . Ceramide accumulation during oxidant renal tubular injury: mechanisms and potential consequences. J Am Soc Nephrol. 1998; 9(9):1670-80. DOI: 10.1681/ASN.V991670. View

15.

Bajwa A, Jo S, Ye H, Huang L, Dondeti K, Rosin D . Activation of sphingosine-1-phosphate 1 receptor in the proximal tubule protects against ischemia-reperfusion injury. J Am Soc Nephrol. 2010; 21(6):955-65. PMC: 2900956. DOI: 10.1681/ASN.2009060662. View

16.

Cruickshanks N, Roberts J, Bareford M, Tavallai M, Poklepovic A, Booth L . Differential regulation of autophagy and cell viability by ceramide species. Cancer Biol Ther. 2015; 16(5):733-42. PMC: 4623104. DOI: 10.1080/15384047.2015.1026509. View

17.

Russo S, Baicu C, Van Laer A, Geng T, Kasiganesan H, Zile M . Ceramide synthase 5 mediates lipid-induced autophagy and hypertrophy in cardiomyocytes. J Clin Invest. 2012; 122(11):3919-30. PMC: 3484448. DOI: 10.1172/JCI63888. View

18.

Signorelli P, Munoz-Olaya J, Gagliostro V, Casas J, Ghidoni R, Fabrias G . Dihydroceramide intracellular increase in response to resveratrol treatment mediates autophagy in gastric cancer cells. Cancer Lett. 2009; 282(2):238-43. DOI: 10.1016/j.canlet.2009.03.020. View

19.

Lavieu G, Scarlatti F, Sala G, Carpentier S, Levade T, Ghidoni R . Regulation of autophagy by sphingosine kinase 1 and its role in cell survival during nutrient starvation. J Biol Chem. 2006; 281(13):8518-27. DOI: 10.1074/jbc.M506182200. View

20.

Hla T . Signaling and biological actions of sphingosine 1-phosphate. Pharmacol Res. 2003; 47(5):401-7. DOI: 10.1016/s1043-6618(03)00046-x. View