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Apoptosis and Mitochondria

  • Jose C. Fernández-ChecaEmail author
  • Carmen Garcia-Ruiz
Chapter

Abstract

Among the various recognized forms of cell death that include necrosis and autophagy, apoptosis or programmed cell death is evolutionarily conserved, highly organized, and characterized by unique nuclear changes, chromatin shrinkage, DNA fragmentation, membrane blebbing, and formation of apoptotic bodies that contain components of the dying cell. Apoptosis is a crucial component of life that eliminates unwanted cells and is vital for embryonic development, homeostasis, and immune defense. Dysregulation of apoptosis underlies many pathophysiological states and diseases. The key mediators of apoptotic cell death are cysteine proteases, called caspases, that work in a coordinated cascade to cleave key substrates and dismantle the cell [1]. The caspase cascade involves “initiator” caspases and “executioner” caspases that can be activated in different ways by different apoptotic stimuli. While changes in nuclei are characteristic in apoptotic cell death, other subcellular organelles are also involved such as endoplasmic reticulum, lysosomes, and, particularly, mitochondria. Moreover, although caspases are crucial in apoptosis, similar morphologic changes can be produced in a caspase-independent fashion. In vertebrates, caspase-dependent apoptosis occurs through two main pathways, the extrinsic pathway and the intrinsic pathway (Fig. 29.1). The extrinsic pathway is initiated upon the binding of an extracellular ligand to transmembrane death receptors of the TNF superfamily (see below), which leads to the assembly of the death-inducing signaling complex (DISC). The DISC then activates an initiator caspase, which triggers the enzymatic cascade that leads to apoptotic death. The intrinsic pathway, also known as the mitochondrial pathway, is activated by stimuli that lead to the permeabilization of the outer mitochondrial membrane (OMM) and the subsequent release of proteins from the mitochondrial intermembrane space (IMS), which initiate or regulate caspase activation, such as cytochrome c. Cytochrome c normally resides within the cristae of the inner mitochondrial membrane (IMM) and is effectively sequestered by narrow cristae junctions. Within the IMM, cytochrome c participates in the mitochondrial electron-transport chain, using its heme group as a redox intermediate to shuttle electrons between complex III and complex IV. However, when the cell detects an apoptotic stimulus, such as DNA damage, or metabolic stress, the intrinsic apoptotic pathway is triggered and mitochondrial cytochrome c is released into the cytosol. This process is thought to occur in two phases, first the mobilization of cytochrome c and then its translocation through permeabilized OMM. In addition to cytochrome c, other IMS proteins are mobilized and released into the cytosol where they are engaged in a strategic battle to promote or counteract caspase activation and hence cell death.

Keywords

Outer Mitochondrial Membrane Mitochondrial Permeability Transition Outer Mitochondrial Membrane Permeabilization Hepatocyte Apoptosis Adenine Nucleotide Translocator 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

This work was supported in part by the Research Center for Liver and Pancreatic Diseases Grant P50 AA 11999 funded by the US National Institute on Alcohol Abuse and Alcoholism, Plan Nacional de I + D Grants: SAF2005-03923, SAF2005-03943, SAF2006-06780, and FIS06/0395 and by the Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas (CIBEREHD) supported by the Instituto de Salud Carlos III.

References

  1. 1.
    Taylor RC, Cullen SP, Martin SJ (2008) Apoptosis: controlled demolition at the cellular level. Nat Rev Mol Cell Biol 9:231–241CrossRefPubMedGoogle Scholar
  2. 2.
    Schneider-Brachert W et al (2004) Compartmentalization of TNF receptor 1 signaling: internalized TNF receptosomes as death signaling vesicles. Immunity 21:415–428CrossRefPubMedGoogle Scholar
  3. 3.
    Galle PR, Krammer PH (1998) CD95-induced apoptosis in human liver disease. Sem Liver Dis 18:141–151CrossRefGoogle Scholar
  4. 4.
    Rudiger HA, Clavien PA (2002) Tumor necrosis factor alpha, but not Fas, mediates hepatocellular apoptosis in the murine ischemic liver. Gastroenterology 122:202–210CrossRefPubMedGoogle Scholar
  5. 5.
    Hsu H, Shu HB, Pan MG et al (1996) TRADD–TRAF2 and TRADD–FADD interactions define two distinct TNF receptor 1 signal transduction pathways. Cell 84:299–308CrossRefPubMedGoogle Scholar
  6. 6.
    Kischkel FC, Hellbardt S, Behmann I et al (1995) Cytotoxicity-dependent APO-1 (Fas/CD95)-associated proteins form a death-inducing signaling complex (DISC) with the receptor. EMBO J 14:5579–5588PubMedGoogle Scholar
  7. 7.
    Scaffidi C, Medema JP, Krammer PH, Peter ME (1997) FLICE is predominantly expressed as two functionally active isoforms, caspase-8/a and caspase-8/b. J Biol Chem 272:26953–26958CrossRefPubMedGoogle Scholar
  8. 8.
    Grech AP, Amesbury M, Chan T et al (2004) TRAF2 differentially regulates the canonical and noncanonical pathways of NF-B activation in mature B cells. Immunity 21:629–642CrossRefPubMedGoogle Scholar
  9. 9.
    Lee SY, Reichlin A, Santana A et al (1997) TRAF2 is essential for JNK but not NF-B activation and regulates lymphocyte proliferation and survival. Immunity 7:703–713CrossRefPubMedGoogle Scholar
  10. 10.
    Harper N, Hughes M, MacFarlane M et al (2003) Fas-associated death domain protein and caspase-8 are not recruited to the tumor necrosis factor receptor 1 signaling complex during tumor necrosis factor-induced apoptosis. J Biol Chem 278:25534–25541CrossRefPubMedGoogle Scholar
  11. 11.
    Micheau O, Tschopp J (2003) Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. Cell 114:181–190CrossRefPubMedGoogle Scholar
  12. 12.
    Scaffidi C, Fulda S, Srinivasan A et al (1998) Two CD95 siganaling pathways. EMBO J 16:1675–1687CrossRefGoogle Scholar
  13. 13.
    Schütze S, Machleidt T, Adam D et al (1999) Inhibition of receptor internalization by monodansylcadaverine selectively blocks p55 tumor necrosis factor receptor death domain signaling. J Biol Chem 274:10203–10212CrossRefPubMedGoogle Scholar
  14. 14.
    Morales A, Lee H, Goñi F et al (2007) Sphingolipids and cell death. Apoptosis 12:923–939CrossRefPubMedGoogle Scholar
  15. 15.
    Lin T et al (2000) Role of acidic sphingomyelinase in Fas CD95-mediated cell death. J Biol Chem 275: 8657–8663CrossRefPubMedGoogle Scholar
  16. 16.
    Manthey CL, Schuchman EH (1998) Acid sphingomyelinase-derived ceramide is not required for inflammatory cytokine signalling in murine macrophages. Cytokine 10:654–661CrossRefPubMedGoogle Scholar
  17. 17.
    Nix M, Stoffel W (2000) Perturbation of membrane microdomains reduces mitogenic signaling and increases susceptibility to apoptosis after T cell receptor stimulation. Cell Death Differ 7:413–424CrossRefPubMedGoogle Scholar
  18. 18.
    Boone E, Vandevoorde V, De Wilde G et al (1998) Activation of p42/p44 mitogen-activated protein kinases (MAPK) and p38 MAPK by tumor necrosis factor (TNF) is mediated through the death domain of the 55-kDa TNF receptor. FEBS Lett 441:275–280CrossRefPubMedGoogle Scholar
  19. 19.
    Garcia-Ruiz C, Colell A, Mari M et al (2003) Defective TNF–mediated hepatocellular apoptosis and liver damage in acidic sphingomyelinase knockout mice. J Clin Invest 111: 197–208PubMedGoogle Scholar
  20. 20.
    Heinrich M, Neumeyer J, Jakob M et al (2004) Cathepsin D links TNF-induced acid sphingomyelinase to Bid-mediated caspase-9 and -3 activation. Cell Death Differ 11:550–563CrossRefPubMedGoogle Scholar
  21. 21.
    Brenner B, Ferlinz K, Grassmé H et al (1998) Fas/CD95/Apo-I activates the acidic sphingomyelinase via caspases. Cell Death Differ 5:29–37CrossRefPubMedGoogle Scholar
  22. 22.
    Cifone MG, De Maria R, Ronciaioli P et al (1994) Apoptotic signaling through CD95 (Fas/Apo-1) activates an acidic sphingomyelinase. J Exp Med 180:1547–1552CrossRefPubMedGoogle Scholar
  23. 23.
    Dumitru CA, Gulbins E (2006) TRAIL activates acid sphingomyelinase via a redox mechanism and releases ceramide to trigger apoptosis. Oncogene 25:5612–5625CrossRefPubMedGoogle Scholar
  24. 24.
    Heinrich M, Wickel M, Schneider-Brachert W et al (1999) Cathepsin D targeted by acid sphingomyelinase-derived ceramide. EMBO J 18:5252–5263CrossRefPubMedGoogle Scholar
  25. 25.
    Canbay A, Guicciardi ME, Miyoshi H et al (2003) Cathepsin B inactivation attenuates hepatic injury and fibrosis during cholestasis. J Clin Invest 112:152–159PubMedGoogle Scholar
  26. 26.
    Guicciardi ME, Deussing J, Miyoshi H et al (2000) Cathepsin B contributes to TNF-a-mediated hepatocyte apoptosis by promoting mitochondrial release of cytochrome c. J Clin Invest 106:1127–1137CrossRefPubMedGoogle Scholar
  27. 27.
    Moles A, Tarrats N, Fernandez-Checa JC et al (2006) Cathepsins B and D drive hepatic stellate cell proliferation and promote their fibrogenic potential. Hepatology 49: 1297–1307Google Scholar
  28. 28.
    Du C, Fang M, Li Y et al (2000) Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. Cell 102:33–42CrossRefPubMedGoogle Scholar
  29. 29.
    Verhagen AM, Ekert PG, Pakusch M et al (2000) Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins. Cell 102: 43–53CrossRefPubMedGoogle Scholar
  30. 30.
    Hedge R, Srinivasula SM, Zhang Z et al (2002) Identification of Omi/HtrA2 as a mitochondrial apoptotic serine protease that disrupts IAP-caspase interaction. J Biol Chem 277: 432–438Google Scholar
  31. 31.
    Van Loo G, van Gurp M, Depuydt B et al (2002) The serine protease Omi/HtrA2 is released from mitochondria during apoptosis. Omi interacts with caspase-inhibitor XIAP and induces enhanced caspase activity. Cell Death Differ 9: 20–26CrossRefPubMedGoogle Scholar
  32. 32.
    Susin SA, Lorenzo HK, Zamzami N et al (1999) Molecular characterization of mitochondrial apoptosis-inducing factor. Nature 397:441–446CrossRefPubMedGoogle Scholar
  33. 33.
    Li LY, Luo X, Wang X et al (2001) Endonuclease G is an apoptotic Dnase when released from mitochondria. Nature 412:95–99CrossRefPubMedGoogle Scholar
  34. 34.
    Kroemer G, Galluzi L, Brenner C (2007) Mitochondrial membrane permeabilization in cell death. Physiol Rev 87: 99–163CrossRefPubMedGoogle Scholar
  35. 35.
    Martinou JC, Green DR (2001) Breaking the mitochondrial barrier. Nat Rev Mol Cell Biol 2:63–67CrossRefPubMedGoogle Scholar
  36. 36.
    Gonzalvez F, Gottlieb E (2007) Cardiolipin: setting the beat of apoptosis. Apoptosis 12:877–885CrossRefPubMedGoogle Scholar
  37. 37.
    Kalanxhi E, Wallace C (2007) Cytochrome c impaled: investigation of the extended lipid anchorage of a soluble protein to mitochondrial membrane models. Biochem J 407: 179–187CrossRefPubMedGoogle Scholar
  38. 38.
    Kriska T, Korytowski W, Girotti AW (2005) Role of mitochondrial cardiolipin peroxidation in apoptotic photokilling of 5-aminolevulinate-treated tumor cells. Arch Biochem Biophys 433:435–446CrossRefPubMedGoogle Scholar
  39. 39.
    Mari M, Colell A, Morales A et al (2008) Mechanisms of mitochondrial glutathione-dependent hepatocellular susceptibility to TNF despite NF-kB activation. Gastroenterology 134:1507–1520CrossRefPubMedGoogle Scholar
  40. 40.
    Kagan VE, Tyurin VA, Jiang J et al (2005) Cytochrome c acts as a cardiolipin oxygenase required for release of 42 proapoptotic factors. Nat Chem Biol 1:223–232CrossRefPubMedGoogle Scholar
  41. 41.
    Uren RT, Dewson G, Bonson C et al (2005) Mitochondrial release of pro-apoptotic proteins: electrostatic interactions can hold cytochrome c but not Smac/DIABLO to mitochondrial membranes. J Biol Chem 280:2266–2274CrossRefPubMedGoogle Scholar
  42. 42.
    Muñoz-Pinedo C, Guio-Carrion A, Goldstein JC et al (2006) Different mitochondrial intermembrane space proteins are released during apoptosis in a manner that is coordinately initiated but can vary in duration. Proc Natl Acad Sci USA 103:11573–11578CrossRefPubMedGoogle Scholar
  43. 43.
    Scorrano L, Ashiya M, Buttle K et al (2002) A distinct pathway remodels mitochondrial cristae and mobilizes cytochrome c during apoptosis. Dev Cell 2:55–67CrossRefPubMedGoogle Scholar
  44. 44.
    Frezza C, Cipolat S, Martins deBrito O et al (2006) OPA1 controls apoptotic cristae remodeling independently from mitochondrial fusion. Cell 126:177–189CrossRefPubMedGoogle Scholar
  45. 45.
    Sun MG, Williams J, Muñoz-Pinedo C et al (2007) Correlated three-dimensional light and electron microscopy reveals transformation of mitochondria during apoptosis. Nat Cell Biol 9:1057–1072CrossRefPubMedGoogle Scholar
  46. 46.
    Yamaguchi R, Lartigue L, Perkins G et al (2008) OPA1-mediated cristae opening is Bax/Bak and BH3 dependent, required for apoptosis, and independent of Bak oligomerization. Mol Cell 31:557–569CrossRefPubMedGoogle Scholar
  47. 47.
    Sheridan C, Delivani P, Cullen SP et al (2008) Bax- or Bak-Induced Mitochondrial Fission Can Be Uncoupled from Cytochrome c Release. Mol Cell 31:570–585CrossRefPubMedGoogle Scholar
  48. 48.
    He L, Lemasters JJ (2002) Regulated and unregulated mitochondrial permeability transition pores: a new paradigm of pore structure and function? FEBS Lett 512:1–7CrossRefPubMedGoogle Scholar
  49. 49.
    Alcala S, Klee M, Fernandez J et al (2008) A high-throughput screening for mammalian cell death effectors identifies the mitochondrial phosphate carrier as a regulator of cytochrome c release. Oncogene 27:44–54CrossRefPubMedGoogle Scholar
  50. 50.
    Nakagawa T, Shimizu S, Watanabe T et al (2005) Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death. Nature. 434: 652–658CrossRefPubMedGoogle Scholar
  51. 51.
    Baines CP, Kaiser RA, Sheiko T et al (2007) Voltage-dependent anion channels are dispensable for mitochondrial-dependent cell death. Nat Cell Biol 9:550–555CrossRefPubMedGoogle Scholar
  52. 52.
    Cheng EH, Sheiko TV, Fisher JK et al (2003) VDAC2 inhibits BAK activation and mitochondrial apoptosis. Science 301:513–517CrossRefPubMedGoogle Scholar
  53. 53.
    Kokoska R, Waymire KG, Levy SE et al (2004) The ADP/ANT translocator is not essential for the mitochondrial permeability transition pore. Nature 427:461–465CrossRefGoogle Scholar
  54. 54.
    Dolce V, Scarcia P, Iacopetta D et al (2005) A fourth ADP/ATP carrier isoform in man: identification, bacterial expression, functional characterization and tissue distribution. FEBS Lett 579:633–637CrossRefPubMedGoogle Scholar
  55. 55.
    Youle RJ, Strasser A (2008) The BCL-2 protein family: opposing activities that mediate cell death. Nature Rev Mol Cell Biol 9:47–59CrossRefGoogle Scholar
  56. 56.
    Basañez G, Sharpe JC, Gallanis J et al (2002) Bax-type apoptotic proteins porate pure lipid bilayers through a mechanism sensitive to intrinsic monolayer curvature. J Biol Chem 277: 49360–49365CrossRefPubMedGoogle Scholar
  57. 57.
    Kuwana T, Mackey MR, Perkins G et al (2002) Bid, Bax and lipids cooperate to form supramolecular openings in the outer mitochondrial membrane. Cell 111:331–342CrossRefPubMedGoogle Scholar
  58. 58.
    Orrenius S, Gogvadze V, Zhivotovsky B (2007) Mitochondrial oxidative stress: implications for cell death. Annu Rev Pharmacol Toxicol 47:143–183CrossRefPubMedGoogle Scholar
  59. 59.
    Wang W, Fang H, Groom L et al (2008) Superoxide flushes in single mitochondria. Cell 134:279–290CrossRefPubMedGoogle Scholar
  60. 60.
    Chang TS, Cho CS, Park S et al (2004) Peroxiredoxin III, a mitochondrion-specific peroxidase, regulates apoptotic signaling by mitochondria. J Biol Chem 279:41975–41984CrossRefPubMedGoogle Scholar
  61. 61.
    Hansen JM, Zhang H, Jones DP (2006) Mitochondrial thioredoxin-2 has a key role in determining tumor necrosis factor-a induced reactive oxygen species generation, NF-kB activation and apoptosis. Toxicol Sci 91:643–650CrossRefPubMedGoogle Scholar
  62. 62.
    Garcia-Ruiz C, Mari M, Colell A et al (2009) Mitochondrial cholesterol in health and disease. Histol Histopathol 24(1): 117–132PubMedGoogle Scholar
  63. 63.
    Ikonen E (2008) Cellular cholesterol trafficking and compartmentalization. Nat Rev Mol Cell Biol 9:125–138CrossRefPubMedGoogle Scholar
  64. 64.
    Van Meer G, Voelker DR, Feigenson GW (2008) Membrane lipids: where they are and how they behave. Nat Rev Mol Cell Biol 9:112–124CrossRefPubMedGoogle Scholar
  65. 65.
    Maxfield FR, Tabas I (2005) Role of cholesterol and lipid organization in disease. Nature 438:612–621CrossRefPubMedGoogle Scholar
  66. 66.
    Beltroy EP, Richardson JA, Horton JD et al (2005) Choles­terol accumulation and liver cell death in mice with Niemann Pick type C disease. Hepatology 42:886–893CrossRefPubMedGoogle Scholar
  67. 67.
    Rimkunas VM, Graham MJ, Crooke RM et al (2009) TNF plays a role in hepatocyte apoptosis in Niemann Pick type C liver disease. J Lip Res 50: 327–333Google Scholar
  68. 68.
    Mari M, Caballero F, Colell A et al (2006) Mitochondrial free cholesterol loading sensitizes to TNF- and Fas-mediated steatohepatitis. Cell Metab 4:185–198CrossRefPubMedGoogle Scholar
  69. 69.
    Fernández-Checa JC, Kaplowitz N (2005) Hepatic mitochondrial glutathione: transport and role in disease and toxicity. Toxicol Appl Pharmacol 204:263–273CrossRefPubMedGoogle Scholar
  70. 70.
    Colell A, Garcia-Ruiz C, Lluis JM et al (2003) Cholesterol impairs the adenine nucleotide translocator-mediated mitochondrial permeability transition through altered membrane fluidity. J Biol Chem 278:33928–33935CrossRefPubMedGoogle Scholar
  71. 71.
    Montero J, Morales A, Llacuna L et al (2008) Mitochondrial cholesterol contributes to chemotherapy resistance in hepatocellular carcinoma. Cancer Res 68:5246–5256CrossRefPubMedGoogle Scholar
  72. 72.
    Garcia-Ruiz C, Colell A, Morales A et al (2002) Trafficking of ganglioside GD3 to mitochondria by tumor necrosis factor-alpha. J Biol Chem 277:36443–36448CrossRefPubMedGoogle Scholar
  73. 73.
    Mari M, Colell A, Morales A et al (2004) Acidic sphingomyelinase downregulates the liver-specific methionine adenosyltransferase 1A, contributing to tumor necrosis factor-induced lethal hepatitis. J Clin Invest 113:895–904PubMedGoogle Scholar
  74. 74.
    Garcia-Ruiz C, Colell A, Paris R et al (2000) Direct interaction of GD3 ganglioside with mitochondria generates reactive oxygen species followed by mitochondrial permeability transition, cytochrome c release, and caspase activation. FASEB J 14:847–58PubMedGoogle Scholar
  75. 75.
    Colell A, Garcia-Ruiz C, Roman J et al (2001) Ganglioside GD3 enhances apoptosis by suppressing the nuclear ­factor-kappa B-dependent survival pathway. FASEB J 15: 1068–1070PubMedGoogle Scholar
  76. 76.
    Angulo P (2002) Nonalcoholic fatty liver disease. N Engl J Med 346:1221–1231CrossRefPubMedGoogle Scholar
  77. 77.
    Tomita K, Tamiya G, Ando S et al (2006) Tumour necrosis factor a signaling through activation of Kupffer cells plays an essential role in liver fibrosis of non-alcoholic steatohepatitis in mice. Gut 55:415–424CrossRefPubMedGoogle Scholar
  78. 78.
    Colell A, Garcia-Ruiz C, Miranda M et al (1998) Selective glutathione depletion of mitochondria by ethanol sensitizes hepatocytes to tumor necrosis factor. Gastroenterology 115: 1541–1551CrossRefPubMedGoogle Scholar
  79. 79.
    Minagawa M, Deng Q, Liu ZX et al (2004) Activated natural killer T cells induce liver injury by Fas and tumor necrosis factor-alpha during alcohol consumption. Gastroenterology 126:1327–1399CrossRefGoogle Scholar
  80. 80.
    Pastorino JG, Hoek JW (2000) Ethanol potentiates tumor necrosis factor cytotoxicity in hepatoma cells and primary rat hepatocytes by promoting induction of the mitochondrial permeability transition. Hepatology 31:1141–1152CrossRefPubMedGoogle Scholar
  81. 81.
    Shulga N, Hoek JB, Pastorino JG (2005) Elevated PTEN levels account for the increased sensitivity of ethanol-exposed cells to tumor necrosis factor-induced cytotoxicity. J Biol Chem 280:9416–9424CrossRefPubMedGoogle Scholar
  82. 82.
    Lluis JM, Colell A, García-Ruiz C et al (2003) Acetaldehyde impairs the mitochondrial glutathione transport in HepG2 cells through endoplasmic reticulum stress. Gastroenter­ology 124:708–724CrossRefPubMedGoogle Scholar
  83. 83.
    Colell A, Garcia-Ruiz C, Morales A et al (1997) Transport of reduced glutathione in hepatic mitochondria and mitoplasts from ethanol-treated rats: effect of membrane physical properties and S-adenosyl-L-methionine. Hepatology 26:699–708PubMedGoogle Scholar
  84. 84.
    Zhao P, Kahorn TF, Slattery JT (2002) Selective mitochondrial glutathione depletion by ethanol enhances acetaminophen toxicity in rat liver. Hepatology 36:326–335CrossRefPubMedGoogle Scholar
  85. 85.
    Nakagami M, Wheeler MD, Bradford BU et al (2001) Overexpression of manganese superoxide dismutase prevents alcohol-induced liver injury in the rat. J Biol Chem 276:36664–36672CrossRefPubMedGoogle Scholar
  86. 86.
    Velasquez A, Bechara RI, Lewis JF et al (2002) Glutathione replacement preserves the functional surfactant phospholipid pool size and decreases sepsis-mediated lung dysfunction in ethanol-fed rats. Alcohol Clin Exp Res 26:1245–1251PubMedGoogle Scholar
  87. 87.
    Lamlé J, Marhenke S, Borlak J et al (2008) Nuclear factor-eythroid 2-related factor 2 prevents alcohol-induced fulminant liver injury. Gastroenterology 134:1159–1168CrossRefPubMedGoogle Scholar
  88. 88.
    Matsuzawa N, Takamura T, Kurita S et al (2007) Lipid-induced oxidative stress causes steatohepatitis in mice fed an atherogenic diet. Hepatology 46:1392–1403CrossRefPubMedGoogle Scholar
  89. 89.
    Zheng S, Hoos L, Cook J et al (2008) Ezetimibe improves high fat and cholesterol diet-induced non-alcoholic fatty liver disease in mice. Eur J Pharmacol 584:118–124CrossRefPubMedGoogle Scholar
  90. 90.
    Selzner N, Rudiger H, Ralf R et al (2003) Protective strategies against ischemic injury of the liver. Gastroenterology 125:917–936CrossRefPubMedGoogle Scholar
  91. 91.
    Jang JH, Moritz W, Graf R et al (2008) Preconditioning with death ligands FasL and TNF-a protecs the cirrhotic mouse liver against ischaemic injury. Gut 57:492–499CrossRefPubMedGoogle Scholar
  92. 92.
    Iñiguez M, Berasain C, Martinez-Anso E et al (2006) Cardiotrophin-1 defends the liver against ischemia-reperfusion injury and mediates the protective effect of ischemic preconditioning. J Exp Med 203:2809–2815CrossRefPubMedGoogle Scholar
  93. 93.
    Llacuna L, Mari M, Garcia-Ruiz C et al (2006) Criticial role of acidic sphingomyelinase in murine hepatic ischemia-reperfusion injury. Hepatology 44:561–572CrossRefPubMedGoogle Scholar
  94. 94.
    Siperstein MD (1995) Cholesterol, cholesterogenesis and cancer. Adv Exp Med Biol 369:155–166PubMedGoogle Scholar
  95. 95.
    Nguyen AD, McDonald JG, Bruick RK et al (2007) Hypoxia stimulates degradation of 3-hydroxy-3-methylglutaryl Coenzyme A reductase through accumulation of lanosterol and hypoxia-inducible factor (HIF)-mediated induction of Insigs. J Biol Chem 282:27436–27446CrossRefPubMedGoogle Scholar
  96. 96.
    Lluis JM, Burichi F, Chiarugi P et al (2007) Dual role of mitochondrial reactive oxygen species in hypoxia signaling: activation of nuclear factor-kB via c-Src and oxidant-dependent cell death. Cancer Res 67:7368–7377CrossRefPubMedGoogle Scholar
  97. 97.
    Pennachietti S, Michielli P, Gallazo M et al (2003) Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene. Cancer Cell 3:347–361CrossRefGoogle Scholar
  98. 98.
    Crain RC, Clark RW, Harvey BE (1983) Role of lipid transfer proteins in the abnormal lipid content of Morris hepatoma mitochondria and microsomes. Cancer Res 43:3197–3202PubMedGoogle Scholar
  99. 99.
    Giaccia A, Siim BG, Jonson RS (2003) HIF-1 as a target for drug development. Nat Rev Drug Discov 2:803–811CrossRefPubMedGoogle Scholar
  100. 100.
    Lucken-Ardjomande S, Montessuit S, Martinou JC (2008) Bax activation and stress-induced apoptosis delayed by the accumulation of cholesterol in mitochondrial membranes. Cell Death Differ 15:484–493CrossRefPubMedGoogle Scholar
  101. 101.
    Schutze S, Tchikov V, Schneider-Brachert W (2008) Regu­lation of TNFR1 and CD95 signaling by receptor compartmentalization. Nat Rev Mol Cell Biol 9: 655–662CrossRefPubMedGoogle Scholar

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© Springer-Verlag Berlin Heidelberg 2010

Authors and Affiliations

  1. 1.Liver Unit and Centro de Investigaciones Biomédicas Esther Koplowitz, IMDiMHospital Clínic i Provincial and CIBEREHD, IDIBAPSBarcelonaSpain

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