Skip to main content
SpringerLink
Log in
Book cover

Cell Death pp 15–40Cite as

The Intrinsic Apoptotic Pathway

  • Chapter
  • First Online:

Abstract

The intrinsic apoptotic pathway, also known as the mitochondria-mediated apoptotic pathway, plays important roles in a variety of biological processes and is involved in the pathogenesis of human diseases ranging from immune disorders and neurodegeneration to cancer. Over the last two decades, much has been learned about the molecular basis of this pathway as well as its delicate regulatory mechanisms. The central role of the cellular organelle, the mitochondrion, in this pathway is well appreciated. Importantly, several potential therapeutic agents have been developed to target specific components of this pathway. Further, growing evidence indicates that cytochrome c release from mitochondria, a hallmark of the pathway, does not always lead to irreversible cell death; and the downstream caspase activation can also perform certain non-death biological functions. This chapter reviews our understanding of the intrinsic apoptotic pathway with a focus on the mechanisms and regulation downstream of cytochrome c release. We also discuss unsolved questions and new challenges in this exciting research area. Other important topics, such as the role of the Bcl-2 family in this pathway and the relationship of this pathway with cancer, will be discussed in other chapters of this book and thus will not be elaborated in detail in this chapter.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  1. Horvitz HR. Genetic control of programmed cell death in the nematode Caenorhabditis elegans. Cancer Res. 1999;59(7 Suppl):1701s–6.

    PubMed  CAS  Google Scholar 

  2. Horvitz HR, Shaham S, Hengartner MO. The genetics of programmed cell death in the nematode Caenorhabditis elegans. Cold Spring Harb Symp Quant Biol. 1994;59:377–85.

    Article  PubMed  CAS  Google Scholar 

  3. Ellis HM, Horvitz HR. Genetic control of programmed cell death in the nematode C. elegans. Cell. 1986;44(6):817–29.

    Article  PubMed  CAS  Google Scholar 

  4. Bakhshi A, Jensen JP, Goldman P, Wright JJ, McBride OW, Epstein AL, Korsmeyer SJ. Cloning the chromosomal breakpoint of t(14;18) human lymphomas: clustering around JH on chromosome 14 and near a transcriptional unit on 18. Cell. 1985;41(3):899–906.

    Article  PubMed  CAS  Google Scholar 

  5. Hockenbery D, Nunez G, Milliman C, Schreiber RD, Korsmeyer SJ. Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature. 1990;348(6299):334–6.

    Article  PubMed  CAS  Google Scholar 

  6. Vaux DL, Cory S, Adams JM. Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. Nature. 1988;335(6189):440–2.

    Article  PubMed  CAS  Google Scholar 

  7. Hengartner MO, Horvitz HR. C. elegans cell survival gene ced-9 encodes a functional homolog of the mammalian proto-oncogene bcl-2. Cell. 1994;76(4):665–76.

    Article  PubMed  CAS  Google Scholar 

  8. Liu X, Kim CN, Yang J, Jemmerson R, Wang X. Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c. Cell. 1996;86(1):147–57.

    Article  PubMed  CAS  Google Scholar 

  9. Zou H, Henzel WJ, Liu X, Lutschg A, Wang X. Apaf-1, a human protein homologous to C. elegans CED-4, participates in cytochrome c-dependent activation of caspase-3. Cell. 1997;90(3):405–13.

    Article  PubMed  CAS  Google Scholar 

  10. Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES, Wang X. Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell. 1997;91(4):479–89.

    Article  PubMed  CAS  Google Scholar 

  11. Yang J, Liu X, Bhalla K, Kim CN, Ibrado AM, Cai J, Peng TI, Jones DP, Wang X. Prevention of apoptosis by Bcl-2: release of cytochrome c from mitochondria blocked. Science. 1997;275(5303):1129–32.

    Article  PubMed  CAS  Google Scholar 

  12. Kluck RM, Bossy-Wetzel E, Green DR, Newmeyer DD. The release of cytochrome c from mitochondria: a primary site for Bcl-2 regulation of apoptosis. Science. 1997;275(5303):1132–6.

    Article  PubMed  CAS  Google Scholar 

  13. Yan N, Chai J, Lee ES, Gu L, Liu Q, He J, Wu JW, Kokel D, Li H, Hao Q, Xue D, Shi Y. Structure of the CED-4-CED-9 complex provides insights into programmed cell death in Caenorhabditis elegans. Nature. 2005;437(7060):831–7.

    Article  PubMed  CAS  Google Scholar 

  14. Yoshida H, Kong YY, Yoshida R, Elia AJ, Hakem A, Hakem R, Penninger JM, Mak TW. Apaf1 is required for mitochondrial pathways of apoptosis and brain development. Cell. 1998;94(6):739–50.

    Article  PubMed  CAS  Google Scholar 

  15. Cecconi F, Alvarez-Bolado G, Meyer BI, Roth KA, Gruss P. Apaf1 (CED-4 homolog) regulates programmed cell death in mammalian development. Cell. 1998;94(6):727–37.

    Article  PubMed  CAS  Google Scholar 

  16. Hakem R, Hakem A, Duncan GS, Henderson JT, Woo M, Soengas MS, Elia A, de la Pompa JL, Kagi D, Khoo W, Potter J, Yoshida R, Kaufman SA, Lowe SW, Penninger JM, Mak TW. Differential requirement for caspase 9 in apoptotic pathways in vivo. Cell. 1998;94(3):339–52.

    Article  PubMed  CAS  Google Scholar 

  17. Kuida K, Haydar TF, Kuan CY, Gu Y, Taya C, Karasuyama H, Su MS, Rakic P, Flavell RA. Reduced apoptosis and cytochrome c-mediated caspase activation in mice lacking caspase 9. Cell. 1998;94(3):325–37.

    Article  PubMed  CAS  Google Scholar 

  18. Kuida K, Zheng TS, Na S, Kuan C, Yang D, Karasuyama H, Rakic P, Flavell RA. Decreased apoptosis in the brain and premature lethality in CPP32-deficient mice. Nature. 1996;384(6607):368–72.

    Article  PubMed  CAS  Google Scholar 

  19. Woo M, Hakem R, Soengas MS, Duncan GS, Shahinian A, Kagi D, Hakem A, McCurrach M, Khoo W, Kaufman SA, Senaldi G, Howard T, Lowe SW, Mak TW. Essential contribution of caspase 3/CPP32 to apoptosis and its associated nuclear changes. Genes Dev. 1998;12(6):806–19.

    Article  PubMed  CAS  Google Scholar 

  20. Yu T, Wang X, Purring-Koch C, Wei Y, McLendon GL. A mutational epitope for cytochrome C binding to the apoptosis protease activation factor-1. J Biol Chem. 2001;276(16):13034–8.

    Article  PubMed  CAS  Google Scholar 

  21. Hao Z, Duncan GS, Chang CC, Elia A, Fang M, Wakeham A, Okada H, Calzascia T, Jang Y, You-Ten A, Yeh WC, Ohashi P, Wang X, Mak TW. Specific ablation of the apoptotic functions of cytochrome C reveals a differential requirement for cytochrome C and Apaf-1 in apoptosis. Cell. 2005;121(4):579–91.

    Article  PubMed  CAS  Google Scholar 

  22. Newmeyer DD, Farschon DM, Reed JC. Cell-free apoptosis in Xenopus egg extracts: inhibition by Bcl-2 and requirement for an organelle fraction enriched in mitochondria. Cell. 1994;79(2):353–64.

    Article  PubMed  CAS  Google Scholar 

  23. Zou H, Li Y, Liu X, Wang X. An APAF-1.cytochrome c multimeric complex is a functional apoptosome that activates procaspase-9. J Biol Chem. 1999;274(17):11549–56.

    Article  PubMed  CAS  Google Scholar 

  24. Jiang X, Wang X. Cytochrome c promotes caspase-9 activation by inducing nucleotide binding to Apaf-1. J Biol Chem. 2000;275(40):31199–203.

    Article  PubMed  CAS  Google Scholar 

  25. Kim HE, Du F, Fang M, Wang X. Formation of apoptosome is initiated by cytochrome c-induced dATP hydrolysis and subsequent nucleotide exchange on Apaf-1. Proc Natl Acad Sci U S A. 2005;102(49):17545–50.

    Article  PubMed  CAS  Google Scholar 

  26. Hu Y, Ding L, Spencer DM, Nunez G. WD-40 repeat region regulates Apaf-1 self-association and procaspase-9 activation. J Biol Chem. 1998;273(50):33489–94.

    Article  PubMed  CAS  Google Scholar 

  27. Riedl SJ, Li W, Chao Y, Schwarzenbacher R, Shi Y. Structure of the apoptotic protease-activating factor 1 bound to ADP. Nature. 2005;434(7035):926–33.

    Article  PubMed  CAS  Google Scholar 

  28. Yu X, Wang L, Acehan D, Wang X, Akey CW. Three-dimensional structure of a double apoptosome formed by the Drosophila Apaf-1 related killer. J Mol Biol. 2006;355(3):577–89.

    Article  PubMed  CAS  Google Scholar 

  29. Arama E, Agapite J, Steller H. Caspase activity and a specific cytochrome C are required for sperm differentiation in Drosophila. Dev Cell. 2003;4(5):687–97.

    Article  PubMed  CAS  Google Scholar 

  30. Arama E, Bader M, Srivastava M, Bergmann A, Steller H. The two Drosophila cytochrome C proteins can function in both respiration and caspase activation. EMBO J. 2006;25(1):232–43.

    Article  PubMed  CAS  Google Scholar 

  31. Evans EK, Kuwana T, Strum SL, Smith JJ, Newmeyer DD, Kornbluth S. Reaper-induced apoptosis in a vertebrate system. EMBO J. 1997;16(24):7372–81.

    Article  PubMed  CAS  Google Scholar 

  32. Kluck RM, Martin SJ, Hoffman BM, Zhou JS, Green DR, Newmeyer DD. Cytochrome c activation of CPP32-like proteolysis plays a critical role in a Xenopus cell-free apoptosis system. EMBO J. 1997;16(15):4639–49.

    Article  PubMed  CAS  Google Scholar 

  33. Inohara N, Nunez G. Genes with homology to mammalian apoptosis regulators identified in zebrafish. Cell Death Differ. 2000;7(5):509–10.

    Article  PubMed  CAS  Google Scholar 

  34. Bender CE, Fitzgerald P, Tait SW, Llambi F, McStay GP, Tupper DO, Pellettieri J, Sanchez Alvarado A, Salvesen GS, Green DR. Mitochondrial pathway of apoptosis is ancestral in metazoans. Proc Natl Acad Sci U S A. 2012;109(13):4904–9.

    Article  PubMed  CAS  Google Scholar 

  35. Chen F, Hersh BM, Conradt B, Zhou Z, Riemer D, Gruenbaum Y, Horvitz HR. Translocation of C. elegans CED-4 to nuclear membranes during programmed cell death. Science. 2000;287(5457):1485–9.

    Article  PubMed  CAS  Google Scholar 

  36. Acehan D, Jiang X, Morgan DG, Heuser JE, Wang X, Akey CW. Three-dimensional structure of the apoptosome: implications for assembly, procaspase-9 binding, and activation. Mol Cell. 2002;9(2):423–32.

    Article  PubMed  CAS  Google Scholar 

  37. Yu X, Acehan D, Menetret JF, Booth CR, Ludtke SJ, Riedl SJ, Shi Y, Wang X, Akey CW. A structure of the human apoptosome at 12.8 A resolution provides insights into this cell death platform. Structure. 2005;13(11):1725–35.

    Article  PubMed  CAS  Google Scholar 

  38. Yuan S, Yu X, Topf M, Dorstyn L, Kumar S, Ludtke SJ, Akey CW. Structure of the Drosophila apoptosome at 6.9 a resolution. Structure. 2011;19(1):128–40.

    Article  PubMed  CAS  Google Scholar 

  39. Yan N, Gu L, Kokel D, Chai J, Li W, Han A, Chen L, Xue D, Shi Y. Structural, biochemical, and functional analyses of CED-9 recognition by the proapoptotic proteins EGL-1 and CED-4. Mol Cell. 2004;15(6):999–1006.

    Article  PubMed  CAS  Google Scholar 

  40. Thornberry NA, Lazebnik Y. Caspases: enemies within. Science. 1998;281(5381):1312–6.

    Article  PubMed  CAS  Google Scholar 

  41. Rodriguez J, Lazebnik Y. Caspase-9 and APAF-1 form an active holoenzyme. Genes Dev. 1999;13(24):3179–84.

    Article  PubMed  CAS  Google Scholar 

  42. Zou H, Yang R, Hao J, Wang J, Sun C, Fesik SW, Wu JC, Tomaselli KJ, Armstrong RC. Regulation of the Apaf-1/caspase-9 apoptosome by caspase-3 and XIAP. J Biol Chem. 2003;278(10):8091–8.

    Article  PubMed  CAS  Google Scholar 

  43. Crook NE, Clem RJ, Miller LK. An apoptosis-inhibiting baculovirus gene with a zinc finger-like motif. J Virol. 1993;67(4):2168–74.

    PubMed  CAS  Google Scholar 

  44. Deveraux QL, Takahashi R, Salvesen GS, Reed JC. X-linked IAP is a direct inhibitor of cell-death proteases. Nature. 1997;388(6639):300–4.

    Article  PubMed  CAS  Google Scholar 

  45. Roy N, Deveraux QL, Takahashi R, Salvesen GS, Reed JC. The c-IAP-1 and c-IAP-2 proteins are direct inhibitors of specific caspases. EMBO J. 1997;16(23):6914–25.

    Article  PubMed  CAS  Google Scholar 

  46. White K, Tahaoglu E, Steller H. Cell killing by the Drosophila gene reaper. Science. 1996;271(5250):805–7.

    Article  PubMed  CAS  Google Scholar 

  47. Grether ME, Abrams JM, Agapite J, White K, Steller H. The head involution defective gene of Drosophila melanogaster functions in programmed cell death. Genes Dev. 1995;9(14):1694–708.

    Article  PubMed  CAS  Google Scholar 

  48. Chen P, Nordstrom W, Gish B, Abrams JM. grim, a novel cell death gene in Drosophila. Genes Dev. 1996;10(14):1773–82.

    Article  PubMed  CAS  Google Scholar 

  49. Vucic D, Kaiser WJ, Harvey AJ, Miller LK. Inhibition of reaper-induced apoptosis by interaction with inhibitor of apoptosis proteins (IAPs). Proc Natl Acad Sci U S A. 1997;94(19):10183–8.

    Article  PubMed  CAS  Google Scholar 

  50. Vucic D, Kaiser WJ, Miller LK. Inhibitor of apoptosis proteins physically interact with and block apoptosis induced by Drosophila proteins HID and GRIM. Mol Cell Biol. 1998;18(6):3300–9.

    PubMed  CAS  Google Scholar 

  51. Goyal L, McCall K, Agapite J, Hartwieg E, Steller H. Induction of apoptosis by Drosophila reaper, hid and grim through inhibition of IAP function. EMBO J. 2000;19(4):589–97.

    Article  PubMed  CAS  Google Scholar 

  52. Wang SL, Hawkins CJ, Yoo SJ, Muller HA, Hay BA. The Drosophila caspase inhibitor DIAP1 is essential for cell survival and is negatively regulated by HID. Cell. 1999;98(4):453–63.

    Article  PubMed  CAS  Google Scholar 

  53. Du C, Fang M, Li Y, Li L, Wang X. Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. Cell. 2000;102(1):33–42.

    Article  PubMed  CAS  Google Scholar 

  54. Verhagen AM, Ekert PG, Pakusch M, Silke J, Connolly LM, Reid GE, Moritz RL, Simpson RJ, Vaux DL. Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins. Cell. 2000;102(1):43–53.

    Article  PubMed  CAS  Google Scholar 

  55. Chai J, Du C, Wu JW, Kyin S, Wang X, Shi Y. Structural and biochemical basis of apoptotic activation by Smac/DIABLO. Nature. 2000;406(6798):855–62.

    Article  PubMed  CAS  Google Scholar 

  56. Wu G, Chai J, Suber TL, Wu JW, Du C, Wang X, Shi Y. Structural basis of IAP recognition by Smac/DIABLO. Nature. 2000;408(6815):1008–12.

    Article  PubMed  CAS  Google Scholar 

  57. Liu Z, Sun C, Olejniczak ET, Meadows RP, Betz SF, Oost T, Herrmann J, Wu JC, Fesik SW. Structural basis for binding of Smac/DIABLO to the XIAP BIR3 domain. Nature. 2000;408(6815):1004–8.

    Article  PubMed  CAS  Google Scholar 

  58. Srinivasula SM, Hegde R, Saleh A, Datta P, Shiozaki E, Chai J, Lee RA, Robbins PD, Fernandes-Alnemri T, Shi Y, Alnemri ES. A conserved XIAP-interaction motif in caspase-9 and Smac/DIABLO regulates caspase activity and apoptosis. Nature. 2001;410(6824):112–6.

    Article  PubMed  CAS  Google Scholar 

  59. Chai J, Shiozaki E, Srinivasula SM, Wu Q, Datta P, Alnemri ES, Shi Y, Dataa P. Structural basis of caspase-7 inhibition by XIAP. Cell. 2001;104(5):769–80.

    Article  PubMed  CAS  Google Scholar 

  60. Huang Y, Park YC, Rich RL, Segal D, Myszka DG, Wu H. Structural basis of caspase inhibition by XIAP: differential roles of the linker versus the BIR domain. Cell. 2001;104(5):781–90.

    PubMed  CAS  Google Scholar 

  61. Gao Z, Tian Y, Wang J, Yin Q, Wu H, Li YM, Jiang X. A dimeric Smac/diablo peptide directly relieves caspase-3 inhibition by XIAP. Dynamic and cooperative regulation of XIAP by Smac/Diablo. J Biol Chem. 2007;282(42):30718–27.

    Article  PubMed  CAS  Google Scholar 

  62. Ryoo HD, Bergmann A, Gonen H, Ciechanover A, Steller H. Regulation of Drosophila IAP1 degradation and apoptosis by reaper and ubcD1. Nat Cell Biol. 2002;4(6):432–8.

    Article  PubMed  CAS  Google Scholar 

  63. Schile AJ, Garcia-Fernandez M, Steller H. Regulation of apoptosis by XIAP ubiquitin-ligase activity. Genes Dev. 2008;22(16):2256–66.

    Article  PubMed  CAS  Google Scholar 

  64. Verhagen AM, Silke J, Ekert PG, Pakusch M, Kaufmann H, Connolly LM, Day CL, Tikoo A, Burke R, Wrobel C, Moritz RL, Simpson RJ, Vaux DL. HtrA2 promotes cell death through its serine protease activity and its ability to antagonize inhibitor of apoptosis proteins. J Biol Chem. 2002;277(1):445–54.

    Article  PubMed  CAS  Google Scholar 

  65. Yang QH, Church-Hajduk R, Ren J, Newton ML, Du C. Omi/HtrA2 catalytic cleavage of inhibitor of apoptosis (IAP) irreversibly inactivates IAPs and facilitates caspase activity in apoptosis. Genes Dev. 2003;17(12):1487–96.

    Article  PubMed  CAS  Google Scholar 

  66. Martins LM, Iaccarino I, Tenev T, Gschmeissner S, Totty NF, Lemoine NR, Savopoulos J, Gray CW, Creasy CL, Dingwall C, Downward J. The serine protease Omi/HtrA2 regulates apoptosis by binding XIAP through a reaper-like motif. J Biol Chem. 2002;277(1):439–44.

    Article  PubMed  CAS  Google Scholar 

  67. van Loo G, van Gurp M, Depuydt B, Srinivasula SM, Rodriguez I, Alnemri ES, Gevaert K, Vandekerckhove J, Declercq W, Vandenabeele P. 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. 2002;9(1):20–6.

    Article  PubMed  Google Scholar 

  68. Hegde R, Srinivasula SM, Zhang Z, Wassell R, Mukattash R, Cilenti L, DuBois G, Lazebnik Y, Zervos AS, Fernandes-Alnemri T, Alnemri ES. Identification of Omi/HtrA2 as a mitochondrial apoptotic serine protease that disrupts inhibitor of apoptosis protein-caspase interaction. J Biol Chem. 2002;277(1):432–8.

    Article  PubMed  CAS  Google Scholar 

  69. Suzuki Y, Imai Y, Nakayama H, Takahashi K, Takio K, Takahashi R. A serine protease, HtrA2, is released from the mitochondria and interacts with XIAP, inducing cell death. Mol Cell. 2001;8(3):613–21.

    Article  PubMed  CAS  Google Scholar 

  70. Larisch S, Yi Y, Lotan R, Kerner H, Eimerl S, Tony Parks W, Gottfried Y, Birkey Reffey S, de Caestecker MP, Danielpour D, Book-Melamed N, Timberg R, Duckett CS, Lechleider RJ, Steller H, Orly J, Kim SJ, Roberts AB. A novel mitochondrial septin-like protein, ARTS, mediates apoptosis dependent on its P-loop motif. Nat Cell Biol. 2000;2(12):915–21.

    Article  PubMed  CAS  Google Scholar 

  71. Gottfried Y, Rotem A, Lotan R, Steller H, Larisch S. The mitochondrial ARTS protein promotes apoptosis through targeting XIAP. EMBO J. 2004;23(7):1627–35.

    Article  PubMed  CAS  Google Scholar 

  72. Edison N, Zuri D, Maniv I, Bornstein B, Lev T, Gottfried Y, Kemeny S, Garcia-Fernandez M, Kagan J, Larisch S. The IAP-antagonist ARTS initiates caspase activation upstream of cytochrome C and SMAC/Diablo. Cell Death Differ. 2012;19(2):356–68.

    Article  PubMed  CAS  Google Scholar 

  73. Garcia-Fernandez M, Kissel H, Brown S, Gorenc T, Schile AJ, Rafii S, Larisch S, Steller H. Sept4/ARTS is required for stem cell apoptosis and tumor suppression. Genes Dev. 2010;24(20):2282–93.

    Article  PubMed  CAS  Google Scholar 

  74. Li LY, Luo X, Wang X. Endonuclease G is an apoptotic DNase when released from mitochondria. Nature. 2001;412(6842):95–9.

    Article  PubMed  CAS  Google Scholar 

  75. Wang X, Yang C, Chai J, Shi Y, Xue D. Mechanisms of AIF-mediated apoptotic DNA degradation in Caenorhabditis elegans. Science. 2002;298(5598):1587–92.

    Article  PubMed  CAS  Google Scholar 

  76. Parrish J, Li L, Klotz K, Ledwich D, Wang X, Xue D. Mitochondrial endonuclease G is important for apoptosis in C. elegans. Nature. 2001;412(6842):90–4.

    Article  PubMed  CAS  Google Scholar 

  77. Blackstone NW, Green DR. The evolution of a mechanism of cell suicide. Bioessays. 1999;21(1):84–8.

    Article  PubMed  CAS  Google Scholar 

  78. Luo X, Budihardjo I, Zou H, Slaughter C, Wang X. Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors. Cell. 1998;94(4):481–90.

    Article  PubMed  CAS  Google Scholar 

  79. Li H, Zhu H, Xu CJ, Yuan J. Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell. 1998;94(4):491–501.

    Article  PubMed  CAS  Google Scholar 

  80. Jiang X, Wang X. Cytochrome C-mediated apoptosis. Annu Rev Biochem. 2004;73:87–106.

    Article  PubMed  CAS  Google Scholar 

  81. Scaffidi C, Fulda S, Srinivasan A, Friesen C, Li F, Tomaselli KJ, Debatin KM, Krammer PH, Peter ME. Two CD95 (APO-1/Fas) signaling pathways. EMBO J. 1998;17(6):1675–87.

    Article  PubMed  CAS  Google Scholar 

  82. Sun XM, Bratton SB, Butterworth M, MacFarlane M, Cohen GM. Bcl-2 and Bcl-xL inhibit CD95-mediated apoptosis by preventing mitochondrial release of Smac/DIABLO and subsequent inactivation of X-linked inhibitor-of-apoptosis protein. J Biol Chem. 2002;277(13):11345–51.

    Article  PubMed  CAS  Google Scholar 

  83. Jost PJ, Grabow S, Gray D, McKenzie MD, Nachbur U, Huang DC, Bouillet P, Thomas HE, Borner C, Silke J, Strasser A, Kaufmann T. XIAP discriminates between type I and type II FAS-induced apoptosis. Nature. 2009;460(7258):1035–9.

    Article  PubMed  CAS  Google Scholar 

  84. Kim HE, Jiang X, Du F, Wang X. PHAPI, CAS, and Hsp70 promote apoptosome formation by preventing Apaf-1 aggregation and enhancing nucleotide exchange on Apaf-1. Mol Cell. 2008;30(2):239–47.

    Article  PubMed  CAS  Google Scholar 

  85. Gao Z, Shao Y, Jiang X. Essential roles of the Bcl-2 family of proteins in caspase-2-induced apoptosis. J Biol Chem. 2005;280(46):38271–5.

    Article  PubMed  CAS  Google Scholar 

  86. Bonzon C, Bouchier-Hayes L, Pagliari LJ, Green DR, Newmeyer DD. Caspase-2-induced apoptosis requires bid cleavage: a physiological role for bid in heat shock-induced death. Mol Biol Cell. 2006;17(5):2150–7.

    Article  PubMed  CAS  Google Scholar 

  87. Upton JP, Austgen K, Nishino M, Coakley KM, Hagen A, Han D, Papa FR, Oakes SA. Caspase-2 cleavage of BID is a critical apoptotic signal downstream of endoplasmic reticulum stress. Mol Cell Biol. 2008;28(12):3943–51.

    Article  PubMed  CAS  Google Scholar 

  88. Jiang X, Kim HE, Shu H, Zhao Y, Zhang H, Kofron J, Donnelly J, Burns D, Ng SC, Rosenberg S, Wang X. Distinctive roles of PHAP proteins and prothymosin-alpha in a death regulatory pathway. Science. 2003;299(5604):223–6.

    Article  PubMed  CAS  Google Scholar 

  89. Cardone MH, Roy N, Stennicke HR, Salvesen GS, Franke TF, Stanbridge E, Frisch S, Reed JC. Regulation of cell death protease caspase-9 by phosphorylation. Science. 1998;282(5392):1318–21.

    Article  PubMed  CAS  Google Scholar 

  90. Kim J, Parrish AB, Kurokawa M, Matsuura K, Freel CD, Andersen JL, Johnson CE, Kornbluth S. Rsk-mediated phosphorylation and 14-3-3varepsilon binding of Apaf-1 suppresses cytochrome c-induced apoptosis. EMBO J. 2012;31(5):1279–92.

    Article  PubMed  CAS  Google Scholar 

  91. Kurokawa M, Zhao C, Reya T, Kornbluth S. Inhibition of apoptosome formation by suppression of Hsp90beta phosphorylation in tyrosine kinase-induced leukemias. Mol Cell Biol. 2008;28(17):5494–506.

    Article  PubMed  CAS  Google Scholar 

  92. Chau BN, Cheng EH, Kerr DA, Hardwick JM. Aven, a novel inhibitor of caspase activation, binds Bcl-xL and Apaf-1. Mol Cell. 2000;6(1):31–40.

    PubMed  CAS  Google Scholar 

  93. Mei Y, Yong J, Liu H, Shi Y, Meinkoth J, Dreyfuss G, Yang X. tRNA binds to cytochrome c and inhibits caspase activation. Mol Cell. 2010;37(5):668–78.

    Article  PubMed  CAS  Google Scholar 

  94. Purring-Koch C, McLendon G. Cytochrome c binding to Apaf-1: the effects of dATP and ionic strength. Proc Natl Acad Sci U S A. 2000;97(22):11928–31.

    Article  PubMed  CAS  Google Scholar 

  95. Cain K, Langlais C, Sun XM, Brown DG, Cohen GM. Physiological concentrations of K + inhibit cytochrome c-dependent formation of the apoptosome. J Biol Chem. 2001;276(45):41985–90.

    Article  PubMed  CAS  Google Scholar 

  96. Goldstein JC, Waterhouse NJ, Juin P, Evan GI, Green DR. The coordinate release of cytochrome c during apoptosis is rapid, complete and kinetically invariant. Nat Cell Biol. 2000;2(3):156–62.

    Article  PubMed  CAS  Google Scholar 

  97. Goldstein JC, Munoz-Pinedo C, Ricci JE, Adams SR, Kelekar A, Schuler M, Tsien RY, Green DR. Cytochrome c is released in a single step during apoptosis. Cell Death Differ. 2005;12(5):453–62.

    Article  PubMed  CAS  Google Scholar 

  98. Cheng EH, Wei MC, Weiler S, Flavell RA, Mak TW, Lindsten T, Korsmeyer SJ. BCL-2, BCL-X(L) sequester BH3 domain-only molecules preventing BAX- and BAK-mediated mitochondrial apoptosis. Mol Cell. 2001;8(3):705–11.

    Article  PubMed  CAS  Google Scholar 

  99. Ricci JE, Munoz-Pinedo C, Fitzgerald P, Bailly-Maitre B, Perkins GA, Yadava N, Scheffler IE, Ellisman MH, Green DR. Disruption of mitochondrial function during apoptosis is mediated by caspase cleavage of the p75 subunit of complex I of the electron transport chain. Cell. 2004;117(6):773–86.

    Article  PubMed  CAS  Google Scholar 

  100. Yu J, Wang P, Ming L, Wood MA, Zhang L. SMAC/Diablo mediates the proapoptotic function of PUMA by regulating PUMA-induced mitochondrial events. Oncogene. 2007;26(29):4189–98.

    Article  PubMed  CAS  Google Scholar 

  101. Slee EA, Keogh SA, Martin SJ. Cleavage of BID during cytotoxic drug and UV radiation-induced apoptosis occurs downstream of the point of Bcl-2 action and is catalysed by caspase-3: a potential feedback loop for amplification of apoptosis-associated mitochondrial cytochrome c release. Cell Death Differ. 2000;7(6):556–65.

    Article  PubMed  CAS  Google Scholar 

  102. Chen Q, Gong B, Almasan A. Distinct stages of cytochrome c release from mitochondria: evidence for a feedback amplification loop linking caspase activation to mitochondrial dysfunction in genotoxic stress induced apoptosis. Cell Death Differ. 2000;7(2):227–33.

    Article  PubMed  CAS  Google Scholar 

  103. Von Ahsen O, Waterhouse NJ, Kuwana T, Newmeyer DD, Green DR. The ‘harmless’ release of cytochrome c. Cell Death Differ. 2000;7(12):1192–9.

    Article  CAS  Google Scholar 

  104. Kirsch DG, Doseff A, Chau BN, Lim DS, de Souza-Pinto NC, Hansford R, Kastan MB, Lazebnik YA, Hardwick JM. Caspase-3-dependent cleavage of Bcl-2 promotes release of cytochrome c. J Biol Chem. 1999;274(30):21155–61.

    Article  PubMed  CAS  Google Scholar 

  105. Tait SW, Parsons MJ, Llambi F, Bouchier-Hayes L, Connell S, Munoz-Pinedo C, Green DR. Resistance to caspase-independent cell death requires persistence of intact mitochondria. Dev Cell. 2010;18(5):802–13.

    Article  PubMed  CAS  Google Scholar 

  106. Li Z, Jo J, Jia JM, Lo SC, Whitcomb DJ, Jiao S, Cho K, Sheng M. Caspase-3 activation via mitochondria is required for long-term depression and AMPA receptor internalization. Cell. 2010;141(5):859–71.

    Article  PubMed  CAS  Google Scholar 

  107. Kuranaga E, Miura M. Nonapoptotic functions of caspases: caspases as regulatory molecules for immunity and cell-fate determination. Trends Cell Biol. 2007;17(3):135–44.

    Article  PubMed  CAS  Google Scholar 

  108. Lamkanfi M, Festjens N, Declercq W, Vanden Berghe T, Vandenabeele P. Caspases in cell survival, proliferation and differentiation. Cell Death Differ. 2007;14(1):44–55.

    Article  PubMed  CAS  Google Scholar 

  109. Zermati Y, Garrido C, Amsellem S, Fishelson S, Bouscary D, Valensi F, Varet B, Solary E, Hermine O. Caspase activation is required for terminal erythroid differentiation. J Exp Med. 2001;193(2):247–54.

    Article  PubMed  CAS  Google Scholar 

  110. Nikolaev A, McLaughlin T, O’Leary DD, Tessier-Lavigne M. APP binds DR6 to trigger axon pruning and neuron death via distinct caspases. Nature. 2009;457(7232):981–9.

    Article  PubMed  CAS  Google Scholar 

  111. Crawford ED, Wells JA. Caspase substrates and cellular remodeling. Annu Rev Biochem. 2011;80:1055–87.

    Article  PubMed  CAS  Google Scholar 

  112. Gray DC, Mahrus S, Wells JA. Activation of specific apoptotic caspases with an engineered small-molecule-activated protease. Cell. 2010;142(4):637–46.

    Article  PubMed  CAS  Google Scholar 

  113. Shimbo K, Hsu GW, Nguyen H, Mahrus S, Trinidad JC, Burlingame AL, Wells JA. Quantitative profiling of caspase-cleaved substrates reveals different drug-induced and cell-type patterns in apoptosis. Proc Natl Acad Sci U S A. 2012;109(31):12432–7.

    Article  PubMed  CAS  Google Scholar 

  114. Rolland SG, Conradt B. New role of the BCL2 family of proteins in the regulation of mitochondrial dynamics. Curr Opin Cell Biol. 2010;22(6):852–8.

    Article  PubMed  CAS  Google Scholar 

  115. Danial NN, Gimenez-Cassina A, Tondera D. Homeostatic functions of BCL-2 proteins beyond apoptosis. Adv Exp Med Biol. 2010;687:1–32.

    Article  PubMed  CAS  Google Scholar 

  116. Popgeorgiev N, Bonneau B, Ferri KF, Prudent J, Thibaut J, Gillet G. The apoptotic regulator Nrz controls cytoskeletal dynamics via the regulation of Ca2+ trafficking in the zebrafish blastula. Dev Cell. 2011;20(5):663–76.

    Article  PubMed  CAS  Google Scholar 

  117. Chen R, Valencia I, Zhong F, McColl KS, Roderick HL, Bootman MD, Berridge MJ, Conway SJ, Holmes AB, Mignery GA, Velez P, Distelhorst CW. Bcl-2 functionally interacts with inositol 1,4,5-trisphosphate receptors to regulate calcium release from the ER in response to inositol 1,4,5-trisphosphate. J Cell Biol. 2004;166(2):193–203.

    Article  PubMed  CAS  Google Scholar 

  118. Danial NN, Gramm CF, Scorrano L, Zhang CY, Krauss S, Ranger AM, Datta SR, Greenberg ME, Licklider LJ, Lowell BB, Gygi SP, Korsmeyer SJ. BAD and glucokinase reside in a mitochondrial complex that integrates glycolysis and apoptosis. Nature. 2003;424(6951):952–6.

    Article  PubMed  CAS  Google Scholar 

  119. Zermati Y, Mouhamad S, Stergiou L, Besse B, Galluzzi L, Boehrer S, Pauleau AL, Rosselli F, D’Amelio M, Amendola R, Castedo M, Hengartner M, Soria JC, Cecconi F, Kroemer G. Nonapoptotic role for Apaf-1 in the DNA damage checkpoint. Mol Cell. 2007;28(4):624–37.

    Article  PubMed  CAS  Google Scholar 

  120. Speliotes EK, Uren A, Vaux D, Horvitz HR. The survivin-like C. elegans BIR-1 protein acts with the Aurora-like kinase AIR-2 to affect chromosomes and the spindle midzone. Mol Cell. 2000;6(2):211–23.

    Article  PubMed  CAS  Google Scholar 

  121. Skoufias DA, Mollinari C, Lacroix FB, Margolis RL. Human survivin is a kinetochore-associated passenger protein. J Cell Biol. 2000;151(7):1575–82.

    Article  PubMed  CAS  Google Scholar 

  122. Beug ST, Cheung HH, Lacasse EC, Korneluk RG. Modulation of immune signalling by inhibitors of apoptosis. Trends Immunol. 2012;33(11):535–45.

    Article  PubMed  CAS  Google Scholar 

  123. Li L, Thomas RM, Suzuki H, De Brabander JK, Wang X, Harran PG. A small molecule Smac mimic potentiates TRAIL- and TNFalpha-mediated cell death. Science. 2004;305(5689):1471–4.

    Article  PubMed  CAS  Google Scholar 

  124. Vince JE, Wong WW, Khan N, Feltham R, Chau D, Ahmed AU, Benetatos CA, Chunduru SK, Condon SM, McKinlay M, Brink R, Leverkus M, Tergaonkar V, Schneider P, Callus BA, Koentgen F, Vaux DL, Silke J. IAP antagonists target cIAP1 to induce TNFalpha-dependent apoptosis. Cell. 2007;131(4):682–93.

    Article  PubMed  CAS  Google Scholar 

  125. Varfolomeev E, Blankenship JW, Wayson SM, Fedorova AV, Kayagaki N, Garg P, Zobel K, Dynek JN, Elliott LO, Wallweber HJ, Flygare JA, Fairbrother WJ, Deshayes K, Dixit VM, Vucic D. IAP antagonists induce autoubiquitination of c-IAPs, NF-kappaB activation, and TNFalpha-dependent apoptosis. Cell. 2007;131(4):669–81.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Cell Biology, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY, 10065, USA

    Xuejun Jiang

Authors
  1. Xuejun Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Xuejun Jiang .

Editor information

Editors and Affiliations

  1. Dept. of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA

    Hao Wu

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer Science+Business Media New York

About this chapter

Cite this chapter

Jiang, X. (2014). The Intrinsic Apoptotic Pathway. In: Wu, H. (eds) Cell Death. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-9302-0_2

Download citation

Publish with us

Policies and ethics

Search

Navigation