Skip to main content
SpringerLink
Log in

Insights into the Mitochondrial Signaling Pathway: What Lessons for Chemotherapy?

  • Published:
Journal of Clinical Immunology Aims and scope Submit manuscript

Abstract

Mitochondria are potent integrators/coordinators of apoptosis signaling pathways. Indeed, under physiological conditions, the initiation of apoptosis leads to the accumulation of second messengers that converge on mitochondria. In response, these organelles undergo a membrane permeabilization, presumably due to the opening of protein channels, culminating in the release of proapoptotic proteins into the cytosol. Under pathological conditions, a failure of mitochondrial membrane permeabilization (MMP) can result in an inhibition of apoptosis and enhanced resistance to chemotherapy. Several non-mutually exclusive mechanisms may account for a defect in the execution or regulation of MMP. These include (i) alterations in gene transcription, (ii) gene mutations resulting in protein inactivation, and (iii) defects of intracellular localization. This may concern structural proteins of the permeability transition pore complex, as well as MMP regulatory proteins, such as Bax/Bcl-2 family members, p53, and cyclophilin D. Analysis of these mechanisms should improve our understanding of the basic function of mitochondria in apoptosis and help elaborate new strategies to correct MMP failure from a therapeutic perspective.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  1. Kerr JF, Wyllie AH, Currie AR: Apoptosis: A basic biological phe-nomenon with wide-ranging implications in tissue kinetics. Br J Cancer 26:239–257, 1972

    Google Scholar 

  2. Green DR, Reed JC: Mitochondria and apoptosis. Science 281:1309–1312, 1998

    Google Scholar 

  3. Kroemer G, Reed J: Mitochondrial control of cell death. Nat Med 6:513–519, 2000

    Google Scholar 

  4. Desagher S, Martinou JC: Mitochondria as the central control point of apoptosis. Trends Cell Biol 10:369–377, 2000

    Google Scholar 

  5. Zamzami N, Marchetti P, Castedo M, Zanin C, Vayssiére J-L, Petit PX, Kroemer G: Reduction in mitochondrial potential constitutes an early irreversible step of programmed lymphocyte death in vivo. J Exp Med 181:1661–1672, 1995

    Google Scholar 

  6. Marchetti P, Decaudin D, Macho A, Zamzami N, Hirsch T, Susin SA, Kroemer G: Redox regulation of apoptosis: Impact of thiol oxi-dation status on mitochondrial function. Eur J Immunol 27:289–296, 1997

    Google Scholar 

  7. Liu X, Kim CN, Yang J, Jemmerson R, Wang X: Induction of apoptic program in cell-free extracts: Requirement for dATP and cytochrome C. Cell 86:147–157, 1996

    Google Scholar 

  8. 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 90:405–413, 1997

    Google Scholar 

  9. Susin SA, Lorenzo HK, Zamzami N, Marzo I, Brenner C, Larochette N, Prevost MC, Alzari PM, Kroemer G: Mitochondrial release of caspase-2 and-9 during the apoptotic process. J Exp Med 189:381–393, 1999

    Google Scholar 

  10. Adrain C, Creagh EM, Martin SJ: Apoptosis-associated release of Smac/DIABLO from mitochondria requires active caspases and is blocked by Bcl-2. EMBO J 20:6627–6636, 2001

    Google Scholar 

  11. Li LY, Luo X, Wang X: Endonuclease G is an apoptotic DNase when released from mitochondria. Nature 412:95–99, 2001

    Google Scholar 

  12. Brenner C, Kroemer G: Apoptosis. Mitochondria-The death signal integrators. Science 289:1150–1151, 2000

    Google Scholar 

  13. Scaffidi C, Fulda S, Srinivasan A, Friesen C, Li F, Tomaselli K, Debatin K, Krammer P, Peter P: Two CD95 (APO-1/Fas) signaling pathways. EMBO J 17:1675–1687, 1998

    Google Scholar 

  14. Bernardi P, Colonna R, Costantini P, Eriksson O, Fontaine E, Ichas F, Massari S, Nicolli A, Petronilli V, Scorrano L: The mitochondrial permeability transition. Biofactors 8:273–281, 1998.

    Google Scholar 

  15. Crompton M: The mitochondrial permeability transition pore and its role in cell death. Biochem J 341:233–249, 1999

    Google Scholar 

  16. Zamzami N, Marchetti P, Castedo M, Decaudin D, Macho A, Hirsch T, Susin SA, Petit PX, Mignotte B, Kroemer G: Sequential reduction of mitochondrial transmembrane potential and generation of reactive oxygen species in early programmed cell death. J Exp Med 182:367–377, 1995

    Google Scholar 

  17. Zamzami N, Marchetti P, Castedo M, Hirsch T, Susin SA, Masse B, Kroemer G: Inhibitors of permeability transition interfere with the disruption of the mitochondrial transmembrane potential during apoptosis. FEBS Lett. 384:53–57, 1996

    Google Scholar 

  18. Susin SA, Zamzami N, Castedo M, Hirsch T, Marchetti P, Macho A, Daugas E, Geuskens M, Kroemer G: Bcl-2 inhibits the mitochon-drial release of an apoptogenic protease. J Exp Med 184:1331–1342, 1996

    Google Scholar 

  19. Marzo I, Brenner C, Zamzami N, Jurgensmeier JM, Susin SA, Vieira HL, Prevost MC, Xie Z, Matsuyama S, Reed JC, Kroemer G: Bax and adenine nucleotide translocator cooperate in the mitochondrial control of apoptosis. Science 281:2027–2031, 1998

    Google Scholar 

  20. Marzo I, Brenner C, Zamzami N, Susin SA, Beutner G, Brdiczka D, Remy R, Xie ZH, Reed JC, Kroemer G: The permeabil-ity transition pore complex: A target for apoptosis regulation by caspases and Bcl-2-related proteins. J Exp Med 187:1261–1271, 1998

    Google Scholar 

  21. Zamzami N, Hamel CE, Maisse C, Brenner C, Munoz-Pinedo C, Belzacq AS, Costantini P, Vieira H, Loeffler M, Molle G, Kroemer G: Bid acts on the permeability transition pore complex to induce apoptosis. Oncogene 19:6342–6350, 2000

    Google Scholar 

  22. Vieira HL, Haouzi D, Hamel CE, Jacotot E, Belzacq AS, Brenner C, Kroemer G: Permeabilization of the mitochondrial inner membrane during apoptosis: Impact of the adenine nucleotide translocator. Cell Death Different 7:1146–1154, 2000

    Google Scholar 

  23. Belzacq AS, Vieira HL, Kroemer G, Brenner C: The adenine nu-cleotide translocator in apoptosis. Biochimie 84:167–176, 2002

    Google Scholar 

  24. De Giorgi F, Lartigue L, Bauer MK, Schubert A, Grimm S, Hanson GT, Remington SJ, Youle RJ, Ichas F: The permeability transition pore signals apoptosis by directing Bax translocation and multimer-ization. FASEB J 16:607–609, 2002

    Google Scholar 

  25. Panaretakis T, Pokrovskaja K, Shoshan MC, Grander D: Activation of Bak, Bax, and BH3-only proteins in the apoptotic response to doxorubicin. J Biol Chem 277:44317–44326, 2002

    Google Scholar 

  26. Ott M, Robertson JD, Gogvadze V, Zhivotovsky B, Orrenius S: Cy-tochrome c release from mitochondria proceeds by a two-step pro-cess. Proc Natl Acad Sci USA 99:1259–1263, 2002

    Google Scholar 

  27. FaureVigny H, Heddi A, Giraud S, Chautard D, Stepien G: Expres-sion of oxidative phosphorylation genes in renal tumors and tumoral cell lines. Mol Carcinogen 16:165–172, 1996

    Google Scholar 

  28. Sebastian S, Kenkare UW: Expression of two type II-like tumor hexokinase RNAtranscripts in cancer cell lines. Tumor Biol 19:253–260, 1998

    Google Scholar 

  29. Maaser K, Grabowski P, Sutter AP, Hopfner M, Foss HD, Stein H, Berger G, Gavish M, Zeitz M, Scherubl H: Overexpression of the peripheral benzodiazepine receptor is a relevant prognostic fac-tor in stage III colorectal cancer. Clin Cancer Res 8:3205–3209, 2002

    Google Scholar 

  30. Shinohara Y, Ishida T, Hino M, Yamazaki N, Baba Y, Terada H: Characterization of porin isoforms expressed in tumor cells. Eur J Biochem 267:6067–6073, 2000

    Google Scholar 

  31. Shiio Y, Donohoe S, Yi EC, Goodlett D, Aebersold R, Eisenman RN: Quantitative proteomic analysis of Myc oncoproteins function. EMBO J 21:5088–5096, 2002

    Google Scholar 

  32. Giraud S, Bonod-Bidaud C, Wesolowski-Louvel M, Stepien G: Ex-pression of human ANT2gene in highly proliferative cells: GRBOX, a new transcriptional element, is involved in the regulation of gly-colytic ATP import into mitochondria. J Mol Biol 281:409–418, 1998

    Google Scholar 

  33. Barath P, Luciakova K, Hodny Z, Li R, Nelson BD: The growth-dependent expression of the adenine nucleotide translocase-2 (ANT2) gene is regulated at the level of transcription and is a marker of cell proliferation. Exp Cell Res 248:583–588, 1999

    Google Scholar 

  34. Bauer MK, Schubert A, Rocks O, Grimm S: Adenine nucleotide translocase-1, a component of the permeability transition pore, can dominantly induce apoptosis. J Cell Biol 147:1493–1502, 1999

    Google Scholar 

  35. Fagiolari G, Sciacco M, Chiveri L, Lamperti C, Comi GP, Scarlato G, Moggio M, Prelle A: Lack of apoptosis in patients with pro-gressive external ophthalmoplegia and mutated adenine nucleotide translocator-1 gene. Muscle Nerve 26:265–269, 2002

    Google Scholar 

  36. Komaki H, Fukazawa T, Houzen H, Yoshida K, Nonaka I, Goto Y: A novel D104G mutation in the adenine nucleotide translocator 1 gene in autosomal dominant progressive external ophthalmople-gia patients with mitochondrial DNA with multiple deletions. Ann Neurol 51:645–648, 2002

    Google Scholar 

  37. Elpeleg O, Mandel H, Saada A: Depletion of the other genome-mitochondrial DNA depletion syndromes in humans. J Mol Med 80:389–396, 2002

    Google Scholar 

  38. Van Goethem G, Martin JJ, Van Broeckhoven C: Progressive ex-ternal ophthalmoplegia and multiple mitochondrial DNA deletions. Acta Neurol Belg 102:39–42, 2002

    Google Scholar 

  39. Reed JC, Jurgensmeier JM, Matsuyama S: Bcl-2 family proteins and mitochondria. Biochim Biophys Acta 1366:127–137, 1998

    Google Scholar 

  40. Konopleva M, Zhao S, Hu W, Jiang S, Snell V, Weidner D, Jackson CE, Zhang X, Champlin R, Estey E, Reed JC, Andreeff M: The anti-apoptotic genes Bcl-X(L) and Bcl-2 are over-expressed and contribute to chemoresistance of non-proliferating leukaemic CD34+ cells. Br J Haematol 118:521–534, 2002

    Google Scholar 

  41. Kitada S, Pedersen IM, Schimmer AD, Reed JC: Dysregulation of apoptosis genes in hematopoietic malignancies. Oncogene 21:3459–3474, 2002

    Google Scholar 

  42. Gascoyne RD, Krajewska M, Krajewski S, Connors JM, Reed JC: Prognostic significance of Bax protein expression in dif-fuse aggressive non-Hodgkin's lymphoma. Blood 90:3173–3178, 1997

    Google Scholar 

  43. Del Poeta G, Venditti A, Del Principe MI, Maurillo L, Buccisano F, Tamburini A, Cox MC, Franchi A, Bruno A, Mazzone C, Panetta P, Suppo G, Masi M, Amadori S: The amount of spontaneous apop-tosis detected by bax/bcl-2 ratio predicts outcome in acute myeloid leukemia (AML). Blood 7:7, 2002

    Google Scholar 

  44. Brenner C, Cadiou H, Vieira HL, Zamzami N, Marzo I, Xie Z, Leber B, Andrews D, Duclohier H, Reed JC, Kroemer G: Bcl-2 and Bax regulate the channel activity of the mitochondrial adenine nucleotide translocator. Oncogene 19:329–336, 2000

    Google Scholar 

  45. Soussi T, Beroud C: Assessing TP53 status in human tumours to evaluate clinical outcome. Natl Rev Cancer 1:233–240, 2001

    Google Scholar 

  46. Guimaraes DP, Hainaut P: TP53: A key gene in human cancer. Biochimie 84:83–93, 2002

    Google Scholar 

  47. Marchenko ND, Zaika A, Moll UM: Death signal-induced localiza-tion of p53 protein to mitochondria. A potential role in apoptotic signaling. J Biol Chem 275:16202–16212, 2000

    Google Scholar 

  48. Flores ER, Tsai KY, Crowley D, Sengupta S, Yang A, McKeon F, Jacks T: p63 and p73 are required for p53-dependent apoptosis in response to DNA damage. Nature 416:560–564, 2002

    Google Scholar 

  49. Halestrap AP, McStay GP, Clarke SJ: The permeability transition pore complex: Another view. Biochimie 84:153–166, 2002

    Google Scholar 

  50. Lin DT, Lechleiter JD: Mitochondrial targeted cyclophilin Dprotects cells from cell death by peptidyl prolyl isomerization. J Biol Chem 277:31134–31141, 2002

    Google Scholar 

  51. Costantini P, Jacotot E, Decaudin D, Kroemer G: Mitochondrion as a novel target of anticancer chemotherapy. J Natl Cancer Inst 92:1042–1053, 2000

    Google Scholar 

  52. Debatin K-M, Poncet D, Kroemer G: Chemotherapy: Targeting the mitochondrial cell death pathway. Oncogene (in press)

  53. Belzacq AS, El Hamel C, Vieira HL, Cohen I, Haouzi D, Metivier D, Marchetti P, Brenner C, Kroemer G: Adenine nucleotide transloca-tor mediates the mitochondrial membrane permeabilization induced by lonidamine, arsenite and CD437. Oncogene 20:7579–7587, 2001

    Google Scholar 

  54. Terminella C, Tollefson K, Kroczynski J, Pelli J, and Cutaia M: Inhibition of apoptosis in pulmonary endothelial cells by altered pH, mitochondrial function, and ATP supply. Am J Physiol Lung Cell Mol Physiol 283:L1291–L1302, 2002

    Google Scholar 

  55. Rempel A, Mathupala SP, Griffin CA, Hawkins AL, Pedersen PL: Glucose catabolism in cancer cells: Amplification of the gene en-coding type II hexokinase. Cancer Res 56:2468–2471, 1996

    Google Scholar 

  56. Owen-Schaub LB, Zhang W, Cusack JC, et al.: Wild-type human p53 and a temperature-sensitive mutant induce Fas/APO-1 expression. Mol Cell Biol 15:3032–3040, 1995

    Google Scholar 

  57. Attardi LD, Reczek EE, Cosmas C, Demicco EG, McCurrach ME, Lowe SW, Jacks T: PERP, an apoptosis-associated target of p53, is a novel member of the PMP-22/gas3 family. Genes Dev 14:704–718, 2000

    Google Scholar 

  58. Wu GS, Burns TF, McDonald ER, 3rd, Jiang W, Meng R, Krantz ID, Kao G, Gan DD, Zhou JY, Muschel R, Hamilton SR, Spinner NB, Markowitz S, Wu G, El-Deiry WS: KILLER/DR5 is a DNAdamage-inducible p53-regulated death receptor gene. Nat Genet 17:141–143, 1997

    Google Scholar 

  59. Takimoto R, El-Deiry WS: Wild-type p53 transactivates the KILLER/DR5 gene through an intronic sequence-specific DNA-binding site. Oncogene 19:1735–1743, 2000

    Google Scholar 

  60. Contente A, Dittmer A, Koch MC, Roth J, Dobbelstein M: A poly-morphic microsatellite that mediates induction of PIG3 by p53. Nat Genet 30:315–320, 2002

    Google Scholar 

  61. Lin Y, Ma W, Benchimol S: Pidd, a new death-domain-containing protein, is induced by p53 and promotes apoptosis. Nat Genet 26:122–127, 2000

    Google Scholar 

  62. Okamura S, Arakawa H, Tanaka T, Nakanishi H, Ng CC, Taya Y, Monden M, Nakamura Y: p53DINP1, a p53-inducible gene, regu-lates p53-dependent apoptosis. Mol Cell 8:85–94, 2001

    Google Scholar 

  63. Oda K, Arakawa H, Tanaka T, Matsuda K, Tanikawa C, Mori T, Nishimori H, Tamai K, Tokino T, Nakamura Y, Taya Y: p53AIP1, a potential mediator of p53-dependent apoptosis, and its regulation by Ser-46-phosphorylated p53. Cell 102:849–862, 2000

    Google Scholar 

  64. Matsuda K, Yoshida K, Taya Y, Nakamura K, Nakamura Y, Arakawa H: p53AIP1 regulates the mitochondrial apoptotic pathway. Cancer Res 62:2883–2889, 2002

    Google Scholar 

  65. Soengas MS, Alarcon RM, Yoshida H, Giaccia AJ, Hakem R, Mak TW, Lowe SW: Apaf-1 and caspase-9 in p53-dependent apoptosis and tumor inhibition. Science 284:156–159, 1999

    Google Scholar 

  66. Robles AI, Bemmels NA, Foraker AB, Harris CC: APAF-1 is a transcriptional target of p53 in DNA damage-induced apoptosis. Cancer Res 61:6660–6664, 2001

    Google Scholar 

  67. Moroni MC, Hickman ES, Denchi EL, Caprara G, Colli E, Cecconi F, Muller H, Helin K: Apaf-1 is a transcriptional target for E2F and p53. Nat Cell Biol 3:552–558, 2001

    Google Scholar 

  68. Oda E, Ohki R, Murasawa H, Nemoto J, Shibue T, Yamashita T, Tokino T, Taniguchi T, Tanaka N: Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis. Science 288:1053–1058, 2000

    Google Scholar 

  69. Nakano K, Vousden KH: PUMA, a novel proapoptotic gene, is in-duced by p53. Mol Cell 7:683–694, 2001

    Google Scholar 

  70. Wu Y, Mehew JW, Heckman CA, Arcinas M, Boxer LM: Nega-tive regulation of bcl-2 expression by p53 in hematopoietic cells. Oncogene 20:240–251, 2001

    Google Scholar 

  71. Donald SP, Sun XY, Hu CA, Yu J, Mei JM, Valle D, Phang JM: Proline oxidase, encoded by p53-induced gene-6, catalyzes the gen-eration of proline-dependent reactive oxygen species. Cancer Res 61:1810–1815, 2001

    Google Scholar 

  72. Hwang PM, Bunz F, Yu J, Rago C, Chan TA, Murphy MP, Kelso GF, Smith RA, Kinzler KW, Vogelstein B: Ferredoxin reductase af-fects p53-dependent, 5-fluorouracil-induced apoptosis in colorectal cancer cells. Nat Med 7:1111–1117, 2001

    Google Scholar 

  73. Fernandez-Salas E, Suh KS, Speransky VV, Bowers WL, Levy JM, Adams T, Pathak KR, Edwards LE, Hayes DD, Cheng C, Steven AC, Weinberg WC, Yuspa SH: mtCLIC/CLIC4, an organellular chloride channel protein, is increased by DNA damage and partici-pates in the apoptotic response to p53. Mol Cell Biol 22:3610–3620, 2002

    Google Scholar 

  74. Zhou M, Gu L, Li F, Zhu Y, Woods WG, Findley HW: DNA damage induces a novel p53-survivin signaling pathway regulating cell cycle and apoptosis in acute lymphoblastic leukemia cells. J Pharmacol Exp Ther 303:124–131, 2002

    Google Scholar 

  75. Miyashita T, Reed JC: Tumor suppressor p53 is a direct tran-scriptional activator of the human bax gene. Cell 80:293–299, 1995

    Google Scholar 

  76. Sax JK, Fei P, Murphy ME, Bernhard E, Korsmeyer SJ, El-Deiry WS: BID regulation by p53 contributes to chemosensitivity. Nat Cell Biol 4:842–849, 2002

    Google Scholar 

  77. Pohl U, Wagenknecht B, Naumann U, Weller M: p53 enhances BAK and CD95 expression in human malignant glioma cells but does not enhance CD95L-induced apoptosis. Cell Physiol Biochem 9:29–37, 1999

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. CNRS UPRESA 8087, Université de Versailles/St Quentin, LGBC Buffon, 45 Avenue des Etats-Unis, 78035, Versailles, France

    Catherine Brenner & Morgane Le Bras

  2. CNRS UMR 8125, IGR, 39 Rue Camille Desmoulins, 94805, Villejuif Cedex, France

    Guido Kroemer

Authors
  1. Catherine Brenner
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Morgane Le Bras
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Guido Kroemer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Catherine Brenner.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Brenner, C., Le Bras, M. & Kroemer, G. Insights into the Mitochondrial Signaling Pathway: What Lessons for Chemotherapy?. J Clin Immunol 23, 73–80 (2003). https://doi.org/10.1023/A:1022541009662

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1022541009662

Search

Navigation