Role of Mitochondria in Apoptosis Induced by Tumor Necrosis Factor-α

  • Cynthia A. Bradham
  • Ting Qian
  • John J. Lemasters
  • Konrad Streetz
  • Christian Trautwein
  • David A. Brenner


Mitochondrial Permeability Transition Death Domain Primary Hepatocyte Mitochondrial Depolarization Primary Hepatocyte Culture 
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  1. Alnemri, E. S., 1997. Mammalian cell death proteases: A family of highly conserved aspartate specific cysteine proteases, J. Cell. Biochem. 64:33–42.CrossRefPubMedGoogle Scholar
  2. Banner, D., D’Arcy, A., Janes, W., Gentz, R., Schoenfeld, H. J., Broger, C., Loetscher, H., and Lesslauer, W., 1993, Crystal structure of the soluble human 55 kd TNF receptor-human TNF beta complex: Implications for TNF receptor activation, Cell 73:431–145.CrossRefPubMedGoogle Scholar
  3. Bossy-Wetzel, E., Newmeyer, D. D., and Green, D. R., 1998, Mitochondrial cytochrome c release in apoptosis occurs upstream of DEVD-specific caspase activation and independently of mitochondrial transmembrane depolarization, EMBO J. 17:37–49.CrossRefPubMedGoogle Scholar
  4. Bradham, C. A., Plumpe, J., Manns, M. P., Brenner, D. A., and Trautwein, C., 1998a, Mechanisms of hepatic toxicity: I TNF-mduced liver injury, Am. J. Physiol. 275:G387–G392.PubMedGoogle Scholar
  5. Bradham, C. A., Qian, T, Streetz, K., Brenner, D. A., and Lemasters, J. J., 1998b, The mitochondrial permeability transition is required for TNFα-mediated apoptosis and cytochrome c release, Mol. Cell. Biol. 18:6353–6364.PubMedGoogle Scholar
  6. Cheng, E. H.-Y., Kirsh, D. G., Clem, R. J., Ravi, R., Kastan, M. B., Bedi, A., Ueno, K., and Hardwick, J. M., 1997, Conversion of bcl-2 to a bax-like death effector by caspases, Science 278:1966–1968.CrossRefPubMedGoogle Scholar
  7. Chinnaiyan, A. M., O’Rourke, K., Tewari, M., and Dixit, V. M., 1995, FADD, a novel death domain-containing protein, interacts with the death domain of Fas and initiates apoptosis. Cell 81:505–512.CrossRefPubMedGoogle Scholar
  8. Chinnaiyan, A. M., Tepper, C. G., Seldin, M. F, O’Rourke, K., Kischkel, F. C., Hellbardt, S., Krammer, P. H., Peter, M. E., and Dixit, V M., 1996, FADD/MORT1 is a common mediator of CD95 (Fas/APO-1) and tumor necrosis factor receptor-induced apoptosis, J. Biol. Chem. 271:4961–4965.PubMedGoogle Scholar
  9. Chu, Z. L., McKinsey, T. A., Liu, L., Gentry, J. J., Malim, M. H., and Ballard, D. W., 1997, Suppression of tumor necrosis factor-induced cell death by inhibitor of apoptosis c-IAP2 is under NFB control, Proc. Natl. Acad. Sci. USA 94:10057–10062.PubMedGoogle Scholar
  10. de Jong, D., Prins, F. A., Mason, D. Y., Reed, J. C., van Ommen, G. B., and Kluin, P. M., 1994, Subcellular localization of the bcl-2 protein in malignant and normal lymphoid cells, Cancer Res. 54:256–260.PubMedGoogle Scholar
  11. Deveraux, Q. L., Roy, N., Stennicke, H. R., Van Arsdale, T., Zhou, Q., Srinivasula, S. M., Alnemri, E. S., Salveson, G. S., and Reed, J. C., 1998, IAPs block apoptotic events induced by caspase 8 and cytochrome c by direct inhibition of distinct caspases, EMBO J. 17:2215–2223.CrossRefPubMedGoogle Scholar
  12. DiDonato, J. A., Hayakawa, M., Rothwarf, D. M., Zandi, E., and Karin, M., 1997, A cytokine-responsive IκB kinase that activates the transcription factor NFB, Nature 388:548–554.PubMedGoogle Scholar
  13. Enari, M., Talanian, R. V, Wong, W. W., and Nagata, S., 1996, Sequential activation of ICE-like and CPP32-like proteases during Fas-mediated apoptosis, Nature 380:723–726.CrossRefPubMedGoogle Scholar
  14. Enari, M., Shakahira, H., Yokoyama, H., Okawa, K., Iwamatsu, A., and Nagata, S., 1998, A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD, Nature 391:43–50.PubMedGoogle Scholar
  15. Halestrap, A. P., Connern, C. P., Griffiths, E. J., and Kerr, P. M., 1997, Cyclosporin A binding to mitochondrial cyclophilin inhibits the permeability transition pore and protects hearts from ischemia/reperfusion injury, Mol. Cell. Biochem. 174:167–172.CrossRefPubMedGoogle Scholar
  16. Henke, W., and Jung, K., 1993, Comparison of the effects of the immunosuppressive agents FK 506 and cyclosporin A on rat kidney mitochondria, Biochem. Pharm. 45:829–832.Google Scholar
  17. Hsu, H., Huang, J., Shu, H. B., Baichwal, V, and Goeddel, D. V, 1996a, TNF-dependent recruitment of the protein kinase RIP to the TNF receptor-1 signaling complex, Immunity 4:387–396.CrossRefPubMedGoogle Scholar
  18. Hsu, H., Shu, H.-B., Pan, M.-G., and Goeddel, D. V, 1996b, TRADD-TRAF2 and TRADD-FADD interactions define two distinct TNF receptor 1 signal transduction pathways, Cell 84:299–308.CrossRefPubMedGoogle Scholar
  19. Hsu, H., Xiong, J., and Goeddel, D. V, 1995, The TNF receptor 1-associated protein TRADD signals cell death and NFB activation, Cell 81:495–504.CrossRefPubMedGoogle Scholar
  20. Hu, Y., Benedict, M. A., Wu, D., Inohara, N., and Nunez, G., 1998, Bcl-xL interacts with Apaf-1 and inhibits Apaf-1-dependent caspase 9 activation, Proc. Natl. Acad. Sci. USA 95:4386–4391.PubMedGoogle Scholar
  21. Limura, Y., Nishiura, T, Hellerbrand, C., Behrns, K. E., Schoonhoven, R., Grisham, J. W., and Brenner, D. A., 1998, NFB prevents apoptosis and liver dysfunction during liver regeneration, J. Clin. Invest. 101:802–811.Google Scholar
  22. Itoh, N., and Nagata, S., 1993, A novel protein domain required for apoptosis, J. Biol. Chem. 268:10932–10937.PubMedGoogle Scholar
  23. Jones, E. Y., Stuart, D. I., and Walker, N. P., 1989, Structure of tumour necrosis factor, Nature 338: 225–228.PubMedGoogle Scholar
  24. Juo, P., Kuo, C. J., Yuan, J., and Blenis, J., 1998, Essential requirement for caspase 8/FLICE in the initiation of the Fas-induced apoptotic cascade, Curr. Biol. 8:1001–1008.CrossRefPubMedGoogle Scholar
  25. Kettelhut, I. C., Fiers, W., and Goldberg, A. L., 1987, The toxic effects of tumor necrosis factor in vivo and their prevention by cyclooxygenase inhibitors, Proc. Natl. Acad. Sci. USA 84:4273–4277.PubMedGoogle Scholar
  26. Kluck, R. M., Bossy-Wetzel, E., Green, D. R., and Newmeyer, D. D., 1997, The release of cytochrome c from mitochondria: A primary site for Bcl-2 regulation of apoptosis, Science 275:1132–1136.CrossRefPubMedGoogle Scholar
  27. Kuida, K., Zheng, T. S., Na, S., Kuan, C., Yang, D., Karasuyama, H., Rakic, P., and Flavell, R., 1996, Decreased apoptosis in the brain and premature lethality in CPP32-deficient mice, Nature 384:368–372.CrossRefPubMedGoogle Scholar
  28. Kuida, K., Haydar, T. F., Kuan, C. Y., Gu, Y, Taya, C., Karasuyama, H., Su, M. S., Rakic, P., and Flavell, R. A., 1998, Reduced apoptosis and cytochrome c-mediated caspase activation in mice lacking caspase 9, Cell 94:325–337.CrossRefPubMedGoogle Scholar
  29. Leist, M., Gantner, F., Bohlinger, I., Germann, P. G., Tiegs, G., and Wendel, A., 1994, Murine hepatocyte apoptosis induced in vitro and in vivo by TNF-alpha requires transcriptional arrest, J. Immunol. 153:1778–1787.PubMedGoogle Scholar
  30. Li, F., Srinivasan, A., Wang, Y, Armstrong, R. C., Tomaselli, K. J., and Fritz, L. C., 1997a, Cell-specific induction of apoptosis by microinjection of cytochrome c: Bcl-x1 has activity independent of cytochrome c release, J. Biol. Chem. 272:30299–30305.PubMedGoogle Scholar
  31. Li, P. D. N., Budihardjo, I., Srinivasula, S. M., Ahmed, M., Alnemri, E. S., and Wang, X., 1997b, Cytochrome c and dATP-dependent formation of Apaf-1/caspase 9 complex initiates an apoptotic protease cascade, Cell 91:479–489.CrossRefPubMedGoogle Scholar
  32. Li, H., Zhu, H., Xu, C.-J., and Yuan, J., 1998, Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis, Cell 94:491–501.CrossRefPubMedGoogle Scholar
  33. Liu, X., Kim, C. N., Yang, J., Jemmerson, R., and Wang, X., 1996, Induction of apoptosis in cell-free extracts: Requirement for dATP and cytochrome c, Cell 86:147–157.PubMedGoogle Scholar
  34. Liu, X., Zou, H., Slaughter, C., and Wang, X., 1997, DFF, a heteromeric protein that functions down stream of caspase 3 to trigger DNA fragmentation during apoptosis, Cell 89:175–184.PubMedGoogle Scholar
  35. Luo, X., Budihardjo, I., Zou, H., Slaughter, C., and Wang, X., 1998, Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors, Cell 94:481–490.CrossRefPubMedGoogle Scholar
  36. Malinin, N. L., Boldin, M. P., Kovalenko, A. V., and Wallach, D., 1997, MAP3K-related kinase involved in NFB induction by TNF, CD-95, and IL-1, Nature 385:540–544.CrossRefPubMedGoogle Scholar
  37. Marchetti, P., Castedo, M., Susin, S. A., Zamzami, N., Hirsch, T., Macho, A., Haeffner, A., Hirsch, F., Geuskens, M., and Kroemer, G., 1996, Mitochondrial permeability transition is a central coordinating event of apoptosis, J. Exp. Med. 184:1155–1160.CrossRefPubMedGoogle Scholar
  38. Martin, D. A., Siegel, R. M., Zheng, L., and Lenardo, M. J., 1998, Membrane oligomerization and cleavage activates the caspase 8 (FLICE/MACHα1) death signal, J. Biol. Chem. 273:4345–4349.PubMedGoogle Scholar
  39. Muzio, M., Chinnaiyan, A. M., Kischkel, F. C., O’Rourke, K., Shevchenko, A., Ni, J., Scaffidi, C., Bretz, J. D., Zhang, M., Gentz, R., Mann, M., Krammer, P. H., Peter, M. E., and Dixit, V. M., 1996, FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (FAS/APO-1) death-inducing signaling complex, Cell 85:817–827.CrossRefPubMedGoogle Scholar
  40. Natoli, G., Costanzo, A., Ianni, A., Templeton, D. J., Woodjet, J. R., Balsano, C., and Levrero, M., 1997, Activation of SAPK/JNK by TNF receptor 1 through a nontoxic TRAF2-dependent pathway, Science 275:200–203.CrossRefPubMedGoogle Scholar
  41. Nicholson, D. W., Ali, A., Thornberry, N. A., Vaillancourt, J. P., Ding, C. K., Gallant, M., Gareau, Y., Griffen, P. R., Labelle, M., Lazebnik, Y. A., Munday, N. A., Raju, S. M., Smulson, M. E., Yamin, T.-T, Yu, V. L., and Miller, D. K., 1995, Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis, Nature 376:37–43.CrossRefPubMedGoogle Scholar
  42. Orth, K., and Dixit, V. M., 1997, Bik and Bak induce apoptosis downstream of crmA but upstream of inhibitor of apoptosis, J. Biol. Chem. 272:8841–8844.PubMedGoogle Scholar
  43. Pastorino, J. G., Chen, S. T., Tafani, M., and Farber, J. L., 1998, The overexpression of Bax produces cell death upon induction of the mitochondrial permeability transition, J. Biol. Chem. 273:7770–7775.CrossRefPubMedGoogle Scholar
  44. Ray, C. A., Black, R. A., Kronheim, S. R., Greenstreet, T. A., Sleath, P. R., Galvesen, G. S., and Pickup, D. J., 1992, Viral inhibition of inflammation: Cowpox virus encodes an inhibitor of the interleukin-1β converting enzyme, Cell 69:597–604.CrossRefPubMedGoogle Scholar
  45. Rosen, A., and Casciola-Rosen, L., 1997, Macromolecular substrates for the ICE-like proteases during apoptosis, J.Cell.Biochem. 64:50–54.CrossRefPubMedGoogle Scholar
  46. Rosse, T, Olivier, R., Monney, L., Rager, M., Conus, S., Fellay, I., Jansen, B., and Borner, C., 1998, Bcl-2 prolongs cell survival after bax-induced release of cytochrome c, Nature 391:496–499.PubMedGoogle Scholar
  47. Roy, N., Deveraux, Q. L., Takahashi, R., Salveson, G. S., and Reed, J. C., 1997, The c-IAP-1 and c-IAP-2 proteins are direct inhibitors of specific caspases, EMBO J. 16:6914–6925.PubMedGoogle Scholar
  48. Salveson, G. S., and Dixit, V M., 1997, Caspases: Intracellular signaling by proteolysis, Cell 91:443–446.Google Scholar
  49. Scaffidi, C., Fulda, S., Srinivasan, A., Fiesen, C., Li, F, Tomaselli, K. J., and Peter, M. E., 1998, Two CD95 (APO-1/Fas) signaling pathways, EMBO J. 17:1675–1687.CrossRefPubMedGoogle Scholar
  50. Schlesinger, P. H., Gross, A., Yin, X.-M., Yamamoto, K., Saito, M., Waksman, G., and Korsmeyer, S. J., 1997, Comparison of the ion channel characteristics of proapoptotic BAX and antiapoptotic BCL-2, Proc. Natl. Acad. Sci. USA 94:11357–11362.CrossRefPubMedGoogle Scholar
  51. Schweizer, M., Schengel, J., Baumgartner, D., and Richer, C., 1993, Sensitivity of mitochondrial peptidyl-prolyl cis-trans isomerase, pyridine nucleotide hydrolysis, and Ca2+ release to cyclosporin A and related compounds, Biochem. Pharm. 45:641–646.CrossRefPubMedGoogle Scholar
  52. Shimizi, S., Eguchi, Y., Kamiike, W., Funahashi, Y., Mignon, A., Lacronique, V, Matsuda, H., and Tsujimoto, Y, 1998, Bcl-2 prevents apoptotic mitochondrial dysfunction by regulating proton flux, Proc. Natl. Acad. Sci. USA 95:1455–1459.Google Scholar
  53. Susin, S. A., Zamzami, N., Castedo, M., Hirsch, T, Marchetti, P., Macho, A., Daugas, E., Geuskens, M., and Kroemer, G., 1996, Bcl-2 inhibits the mitochondrial release of an apoptogenic protease, J. Exp. Med. 184:1331–1341.CrossRefPubMedGoogle Scholar
  54. Susin, S. A., Zamzami, N., Castedo, M., Daugas, E., Wang, H.-G., Geley, S., Fassy, R, Reed, J. C., and Kroemer, G., 1997, The central executioner of apoptosis: Multiple connections between proteaseactivation and mitochondria in Fas/APO-l/CD95-and ceramide-induced apoptosis, J. Exp. Med. 186:25–37.CrossRefPubMedGoogle Scholar
  55. Tartaglia, L. A., Ayres, T. M., Wong, G. H. W., and Goeddel, D. V, 1993, A novel domain within the 55 kd TNF receptor signals cell death, Cell 74:845–853.CrossRefPubMedGoogle Scholar
  56. Ting, A. T., Pimentel-Muinos, F. X., and Seed, B., 1996, RIP mediates tumor necrosis factor receptor 1 activation of NF-kappaB but not Fas/APO-1-initiated apoptosis, EMBO J. 15:6189–6196.PubMedGoogle Scholar
  57. Vander Heiden, M. G., Chandel, N. S., Williamson, E. K., Schumacker, P. T, and Thompson, C. B., 1997, Bcl-x1 regulates the membrane potential and volume homeostasis of mitochondria, Cell 91:627–637.Google Scholar
  58. Varfolomeèv, E. E., Schuchmann, M., Luria, V, Chiannilkulchai, N., Beckmann, J. S., Mett, I. L., Rebrikov, D., Brodianski, V M., Kemper, O. C., Kollet, O., Lapidot, T., Sorter, D., Sobe, T., Avraham, K. B., Goncharov, T., Holtmann, H., Lonai, P., and Wallach, D., 1998, Targeted disruption of the mouse caspase 8 gene ablates cell death induction by TNF receptors, Fas/Apo 1, and DR3 and is lethal prenatally, Immunity 9:267–276.PubMedGoogle Scholar
  59. Wallach, D., Boldin, M., Varfolomeev, E., Beyaert, R., Vandenabeele, P., and Fiers, W., 1997, Cell death induction by receptors of the TNF family: Toward a molecular understanding, FEBS Lett. 410:96–106.CrossRefPubMedGoogle Scholar
  60. Wang, C.-Y., Mayo, M. W., and Baldwin, A. S. J., 1996, TNF-and cancer therapy-induced apoptosis: Potentiation by inhibiting NFB, Science 274:784–787.CrossRefPubMedGoogle Scholar
  61. Yang, J., Liu, X., Bhalla, K., Kim, C. N., Ibrado, A. M., Cai, J., Peng, T.-I., Jones, D. P., and Wang, X., 1997, Prevention of apoptosis by bcl-2: Release of cytochrome c from mitochondria blocked, Science 275:1129–1132.CrossRefPubMedGoogle Scholar
  62. Yeh, W. C., Shaninian, A., Speiser, D., Kraunus, J., Billia, F, Wakeham, A., de la Pompa, J. L., Ferrick, D., Hum, B., Iscove, N., Ohashi, P., Rothe, M., Goeddel, D. V, and Mak, T. M., 1997, Early lethality, functional NFB activation, and increased sensitivity to TNF-induced cell death in TRAF2-deficient mice, Immunity 7:715–725.CrossRefPubMedGoogle Scholar
  63. You, M., Ku, P. T, Hrdlickova, R., and Bose, H. R. J., 1997, ch-IAP, a member of the inhibitor of apoptosis protein family, is a mediator of the antiapoptotic activities of the v-Rel oncoprotein, Mol. Cell. Biol. 17:7328–7341.PubMedGoogle Scholar
  64. Zamzami, N., Susin, S. A., Marchetti, P., Hirsch, T., Gomez-Monterrey, I., Castedo, M., and Kroemer, G., 1996, Mitochondrial control of nuclear apoptosis, J. Exp. Med. 183:1533–1544.CrossRefPubMedGoogle Scholar
  65. Zhou, Q., Snipas, S., Orth, K., Muzio, M., Dixit, V. M., and Salveson, G. S., 1997, Target protease specificity of the viral serpin crmA: Analysis of five caspases, J. Biol. Chem. 272:7797–7800.PubMedGoogle Scholar
  66. Zou, H., Henzel, W. J., Liu, X., Lutschg, A., and Wang, X., 1997, Apaf-1, a human protein homologous to C. elegans CED-4, participates in cytochrome c-dependent activation of caspase 3, Cell 90:405–413.PubMedGoogle Scholar

Copyright information

© Kluwer Academic Publishers 2002

Authors and Affiliations

  • Cynthia A. Bradham
    • 1
  • Ting Qian
    • 2
  • John J. Lemasters
    • 2
  • Konrad Streetz
    • 3
  • Christian Trautwein
    • 3
  • David A. Brenner
    • 4
    • 5
  1. 1.Department of MedicineUniversity of North Carolina at Chapel HillChapel Hill
  2. 2.Department of Cell Biology and AnatomyUniversity of North Carolina at Chapel HillChapel Hill
  3. 3.Department of Gastroenterology and HepatologyMediziniche Hochschule HannoverHannoverGermany
  4. 4.Department of MedicineUniversity of North Carolina at Chapel HillChapel Hill
  5. 5.Department of Biochemistry and BiophysicsUniversity of North Carolina at Chapel HillChapel Hill

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