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Calcium and apoptosis: facts and hypotheses

Oncogene volume 22, pages 8619–8627 (2003)Cite this article

Abstract

Although longstanding experimental evidence has associated alterations of calcium homeostasis to cell death, only in the past few years the role of calcium in the signaling of apoptosis has been extensively investigated. In this review, we will summarize the current knowledge, focusing on (i) the effect of the proteins of the Bcl-2 family on ER Ca2+ levels, (ii) the action of the proteolytic enzymes of apoptosis on the Ca2+ signaling machinery, (iii) the ensuing alterations on the signaling patterns of extracellular stimuli, and (iv) the intracellular targets of ‘apoptotic’ Ca2+ signals, with special emphasis on the mitochondria and cytosolic Ca2+-dependent enzymes.

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Abbreviations

AIF:

apoptosis-inducing factor

[Ca2+]c:

cytosolic calcium concentration

[Ca2+]m:

mitochondrial calcium concentration

[Ca2+]ER:

calcium concentration in the endoplasmic reticulum

[Ca2+]Golgi:

calcium concentration in the Golgi apparatus

DAG:

diacylglycerol

drp:

dynamin-like protein

ER:

endoplasmic reticulum

IMM:

inner mitochondrial membrane

IP3:

inositol 1,4,5 trisphosphate

IP3R:

inositol 1,4,5 trisphosphate receptor

OMM:

outer mitochondrial membrane

PTP:

permeability transition pore

ROS:

reactive oxygen species

SERCA:

sarco–endoplasmic reticulum Ca2+ adenosine triphosphatase

References

  • Antonsson B, Conti F, Ciavatta A, Montessuit S, Lewis S, Martinou I, Bernasconi L, Bernard A, Mermod JJ, Mazzei G, Maundrell K, Gambale F, Sadoul R and Martinou JC . (1997). Science, 277, 370–372.

  • Bernardi P . (1999). Physiol. Rev., 79, 1127–1155.

  • Bernardi P, Colonna R, Costantini P, Eriksson O, Fontaine E, Ichas F, Massari S, Nicolli A, Petronilli V and Scorrano L . (1998). Biofactors, 8, 273–281.

  • Berridge MJ, Lipp P and Bootman MD . (2000). Nat. Rev. Mol. Cell Biol., 1, 11–21.

  • Borner C . (2003). Mol. Immunol., 39, 615–647.

  • Breckenridge DG, Stojanovic M, Marcellus RC and Shore GC . (2003). J. Cell Biol., 160, 1115–1127.

  • Brini M, Bano D, Manni S, Rizzuto R and Carafoli E . (2000). EMBO J., 19, 4926–4935.

  • Camello P, Gardner J, Petersen OH and Tepikin AV . (1996). J. Physiol., 490, 585–593.

  • Carafoli E and Molinari M . (1998). Biochem. Biophys. Res. Commun., 247, 193–203.

  • Chan SL and Mattson MP . (1999). J. Neurosci. Res., 58, 167–190.

  • Choi DW . (1992). J. Neurobiol., 23, 1261–1276.

  • Choi DW . (1995). Trends Neurosci., 18, 58–60.

  • Crompton M, Barksby E, Johnson N and Capano M . (2002). Biochimie, 84, 143–152.

  • Csordas G, Madesh M, Antonsson B and Hajnoczky G . (2002). EMBO J., 21, 2198–2206.

  • De Giorgi F, Lartigue L, Bauer MK, Schubert A, Grimm S, Hanson GT, Remington SJ, Youle RJ and Ichas F . (2002). FASEB J..

  • Dempsey EC, Newton AC, Mochly Rosen D, Fields AP, Reyland ME, Insel PA and Messing RO . (2000). Am. J. Physiol. Lung Cell. Mol. Physiol., 279, L429–L438.

  • Duchen MR . (2000). J. Physiol., 529, 57–68.

  • Emoto Y, Manome Y, Meinhardt G, Kisaki H, Kharbanda S, Robertson M, Ghayur T, Wong WW, Kamen R and Weichselbaum R . (1995). EMBO J., 14, 6148–6156.

  • Farrow SN and Brown R . (1996). Curr. Opin. Genet. Dev., 6, 45–49.

  • Fischer H, Koenig U, Eckhart L and Tschachler E . (2002). Biochem. Biophys. Res. Commun., 293, 722–726.

  • Foyouzi-Youssefi R, Arnaudeau S, Borner C, Kelley WL, Tschopp J, Lew DP, Demaurex N and Krause KH . (2000). Proc. Natl. Acad. Sci. USA, 97, 5723–5728.

  • Frank S, Gaume B, Bergmann-Leitner ES, Leitner WW, Robert EG, Catez F, Smith CL and Youle RJ . (2001). Dev. Cell, 1, 515–525.

  • Glazner GW, Chan SL, Lu C and Mattson MP . (2000). J. Neurosci., 20, 3641–3649.

  • Green DR and Evan GI . (2002). Cancer Cell, 1, 19–30.

  • Green DR and Reed JC . (1998). Science, 281, 1309–1312.

  • Hirota J, Furuichi T and Mikoshiba K . (1999). J. Biol. Chem., 274, 34433–34437.

  • Huang C, Ma W, Bowden GT and Dong Z . (1996). J. Biol. Chem., 271, 31262–31268.

  • Jamieson L, Carpenter L, Biden TJ and Fields AP . (1999). J. Biol. Chem., 274, 3927–3930.

  • Jiang S, Chow SC, Nicotera P and Orrenius S . (1994). Exp. Cell Res., 212, 84–92.

  • Karbowski M, Lee YJ, Gaume B, Jeong SY, Frank S, Nechushtan A, Santel A, Fuller M, Smith CL and Youle RJ . (2002). J. Cell Biol., 159, 931–938.

  • Kerr JF, Wyllie AH and Currie AR . (1972). Br. J. Cancer, 26, 239–257.

  • Kobayashi S, Yamashita K, Takeoka T, Ohtsuki T, Suzuki Y, Takahashi R, Yamamoto K, Kaufmann SH, Uchiyama T, Sasada M and Takahashi A . (2002). J. Biol. Chem., 277, 33968–33977.

  • Konishi H, Matsuzaki H, Takaishi H, Yamamoto T, Fukunaga M, Ono Y and Kikkawa U . (1999). Biochem. Biophys. Res. Commun., 264, 840–846.

  • Korsmeyer SJ, McDonnell TJ, Nunez G, Hockenbery D and Young R . (1990). Curr. Top. Microbiol. Immunol., 166, 203–207.

  • Krajewski S, Tanaka S, Takayama S, Schibler MJ, Fenton W and Reed JC . (1993). Cancer Res., 53, 4701–4714.

  • Kroemer G . (1997). Nat. Med., 3, 614–620.

  • Kruman I, Guo Q and Mattson MP . (1998). J. Neurosci. Res., 51, 293–308.

  • Lam M, Dubyak G, Chen L, Nunez G, Miesfeld RL and Distelhorst CW . (1994). Proc. Natl. Acad. Sci. USA, 91, 6569–6573.

  • Lee JY, Hannun YA and Obeid LM . (1996). J. Biol. Chem., 271, 13169–13174.

  • Lee ST, Hoeflich KP, Wasfy GW, Woodgett JR, Leber B, Andrews DW, Hedley DW and Penn LZ . (1999). Oncogene, 18, 3520–3528.

  • Lithgow T, van Driel R, Bertram JF and Strasser A . (1994). Cell Growth Differ., 5, 411–417.

  • Liu Y, Fiskum G and Schubert D . (2002). J. Neurochem., 80, 780–787.

  • Lynch K, Fernandez G, Pappalardo A and Peluso JJ . (2000). Endocrinology, 141, 4209–4217.

  • Ma TS, Mann DL, Lee JH and Gallinghouse GJ . (1999). Cell Calcium, 26, 25–36.

  • Majumder PK, Pandey P, Sun X, Cheng K, Datta R, Saxena S, Kharbanda S and Kufe D . (2000). J. Biol. Chem., 275, 21793–21796.

  • Mandic A, Viktorsson K, Strandberg L, Heiden T, Hansson J, Linder S and Shoshan MC . (2002). Mol. Cell. Biol., 22, 3003–3013.

  • Martikainen P, Kyprianou N, Tucker RW and Isaacs JT . (1991). Cancer Res., 51, 4693–4700.

  • McClintock DS, Santore MT, Lee VY, Brunelle J, Budinger GR, Zong WX, Thompson CB, Hay N and Chandel NS . (2002). Mol. Cell. Biol., 22, 94–104.

  • Mellor H and Parker PJ . (1998). Biochem. J., 332, 281–292.

  • Mikhailov V, Mikhailova M, Pulkrabek DJ, Dong Z, Venkatachalam MA and Saikumar P . (2001). J. Biol. Chem., 276, 18361–18374.

  • Minn AJ, Velez P, Schendel SL, Liang H, Muchmore SW, Fesik SW, Fill M and Thompson CB . (1997). Nature, 385, 353–357.

  • Mizuno K, Noda K, Araki T, Imaoka T, Kobayashi Y, Akita Y, Shimonaka M, Kishi S and Ohno S . (1997). Eur. J. Biochem., 250, 7–18.

  • Nakagawa T and Yuan J . (2000). J. Cell Biol., 150, 887–894.

  • Nakagawa T, Zhu H, Morishima N, Li E, Xu J, Yankner BA and Yuan J . (2000). Nature, 403, 98–103.

  • Nakamura K, Bossy-Wetzel E, Burns K, Fadel MP, Lozyk M, Goping IS, Opas M, Bleackley RC, Green DR and Michalak M . (2000). J. Cell Biol., 150, 731–740.

  • Newmeyer DD and Ferguson-Miller S . (2003). Cell, 112, 481–490.

  • Nicotera P and Orrenius S . (1998). Cell Calcium, 23, 173–180.

  • Nomura M, Shimizu S, Ito T, Narita M, Matsuda H and Tsujimoto Y . (1999). Cancer Res., 59, 5542–5548.

  • Nutt LK, Pataer A, Pahler J, Fang B, Roth J, McConkey DJ and Swisher SG . (2002). J. Biol. Chem., 277, 9219–9225.

  • Oltvai ZN, Milliman CL and Korsmeyer SJ . (1993). Cell, 74, 609–619.

  • Petit PX, Goubern M, Diolez P, Susin SA, Zamzami N and Kroemer G . (1998). FEBS Lett., 426, 111–116.

  • Petronilli V, Nicolli A, Costantini P, Colonna R and Bernardi P . (1994). Biochim. Biophys. Acta, 1187, 255–259.

  • Pinton P, Ferrari D, Magalhaes P, Schulze-Osthoff K, Di Virgilio F, Pozzan T and Rizzuto R . (2000). J. Cell Biol., 148, 857–862.

  • Pinton P, Ferrari D, Rapizzi E, Di Virgilio F, Pozzan T and Rizzuto R . (2001). EMBO J., 20, 2690–2701.

  • Pozzan T, Rizzuto R, Volpe P and Meldolesi J . (1994). Physiol. Rev., 74, 595–636.

  • Rapizzi E, Pinton P, Szabadkai G, Wieckowski MR, Vandecasteele G, Baird G, Tuft RA, Fogarty KE and Rizzuto R . (2002). J. Cell Biol., 159, 613–624.

  • Reed JC . (1994). J. Cell Biol., 124, 1–6.

  • Reed JC, Tsujimoto Y, Alpers JD, Croce CM and Nowell PC . (1987). Science, 236, 1295–1299.

  • Rinkenberger JL and Korsmeyer SJ . (1997). Curr. Opin. Genet. Dev., 7, 589–596.

  • Schendel SL, Montal M and Reed JC . (1998). Cell Death Differ., 5, 372–380.

  • Schwab BL, Guerini D, Didszun C, Bano D, Ferrando-May E, Fava E, Tam J, Xu D, Xanthoudakis S, Nicholson DW, Carafoli E and Nicotera P . (2002). Cell Death Differ., 9, 818–831.

  • Scorrano L, Ashiya M, Buttle K, Weiler S, Oakes SA, Mannella CA and Korsmeyer SJ . (2002). Dev. Cell, 2, 55–67.

  • Scorrano L, Oakes SA, Opferman JT, Cheng EH, Sorcinelli MD, Pozzan T and Korsmeyer SJ . (2003). Science, 300, 135–139.

  • Sentman CL, Shutter JR, Hockenbery D, Kanagawa O and Korsmeyer SJ . (1991). Cell, 67, 879–888.

  • Shchepina LA, Pletjushkina OY, Avetisyan AV, Bakeeva LE, Fetisova EK, Izyumov DS, Saprunova VB, Vyssokikh MY, Chernyak BV and Skulachev VP . (2002). Oncogene, 21, 8149–8157.

  • Shibasaki F and McKeon F . (1995). J. Cell Biol., 131, 735–743.

  • Skarka J and Ostadal B . (2002). Physiol. Res., 51, 425–434.

  • Skulachev VP . (1996). FEBS Lett., 397, 7–10.

  • Staniek K, Gille L, Kozlov AV and Nohl H . (2002). Free Radic. Res., 36, 381–387.

  • Szalai G, Krishnamurthy R and Hajnoczky G . (1999). EMBO J., 18, 6349–6361.

  • Tanaka S, Saito K and Reed JC . (1993). J. Biol. Chem., 268, 10920–10926.

  • Teranishi F, Liu ZQ, Kunimatsu M, Imai K, Takeyama H, Manabe T, Sasaki M and Okamoto T . (2003). Biochem. Biophys. Res. Commun., 303, 940–946.

  • Tidball JG and Spencer MJ . (2000). Int. J. Biochem. Cell Biol., 32, 1–5.

  • Tombal B, Denmeade SR and Isaacs JT . (1999). Cell Calcium, 25, 19–28.

  • Tsujimoto Y, Cossman J, Jaffe E and Croce CM . (1985a). Science, 228, 1440–1443.

  • Tsujimoto Y, Jaffe E, Cossman J, Gorham J, Nowell PC and Croce CM . (1985b). Nature, 315, 340–343.

  • Vieira HL and Kroemer G . (1999). Cell Mol. Life Sci., 56, 971–976.

  • Voehringer DW, Hirschberg DL, Xiao J, Lu Q, Roederer M, Lock CB, Herzenberg LA, Steinman L and Herzenberg LA . (2000). Proc. Natl. Acad. Sci. USA, 97, 2680–2685.

  • Wang HG, Pathan N, Ethell IM, Krajewski S, Yamaguchi Y, Shibasaki F, McKeon F, Bobo T, Franke TF and Reed JC . (1999). Science, 284, 339–343.

  • Wertz IE and Dixit VM . (2000). J. Biol. Chem., 275, 11470–11477.

  • Yoneda T, Imaizumi K, Oono K, Yui D, Gomi F, Katayama T and Tohyama M . (2001). J. Biol. Chem., 276, 13935–13940.

  • Yoon Y and McNiven MA . (2001). Curr. Biol., 11, R67–R70.

  • Zhu W, Cowie A, Wasfy GW, Penn LZ, Leber B and Andrews DW . (1996). EMBO J., 15, 4130–4141.

  • Zirpel L, Lippe WR and Rubel EW . (1998). J. Neurophysiol., 79, 2288–2302.

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Acknowledgements

The original work by the authors has been supported by grants from Italian Telethon, Italian Association for Cancer Research (AIRC), the Italian Ministry of University, the National Research Council, the Human Frontier Science Program, the Italian Space Agency and the European Union.

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Authors and Affiliations

  1. Department of Experimental and Diagnostic Medicine and Center for the Study of Inflammation, University of Ferrara, Italy

    Rosario Rizzuto, Paolo Pinton, Davide Ferrari, Mounia Chami, György Szabadkai & Francesco Di Virgilio

  2. Department of Biomedical Sciences, University of Padova, Italy

    Paulo J Magalhães & Tullio Pozzan

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Rizzuto, R., Pinton, P., Ferrari, D. et al. Calcium and apoptosis: facts and hypotheses. Oncogene 22, 8619–8627 (2003). https://doi.org/10.1038/sj.onc.1207105

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