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Calcium and apoptosis: ER-mitochondria Ca2+ transfer in the control of apoptosis

Abstract

There is a growing consensus that the various forms of cell death (necrosis, apoptosis and autophagy) are not separated by strict boundaries, but rather share molecular effectors and signaling routes. Among the latter, a clear role is played by calcium (Ca2+), the ubiquitous second messenger involved in the control of a broad variety of physiological events. Fine tuning of intracellular Ca2+ homeostasis by anti- and proapoptotic proteins shapes the Ca2+ signal to which mitochondria and other cellular effectors are exposed, and hence the efficiency of various cell death inducers. Here, we will review: (i) the evidence linking calcium homeostasis to the regulation of apoptotic, and more recently autophagic cell death, (ii) the discussion of mitochondria as a critical, although not unique checkpoint and (iii) the molecular and functional elucidation of ER/mitochondria contacts, corresponding to the mitochondria-associated membrane (MAM) subfraction and proposed to be a specialized signaling microdomain.

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Abbreviations

AIF:

apoptosis-inducing factor

APAF-1:

apoptosis protease-activating factor-1

Calcium concentrations: [Ca2+]c:

cytosolic

[Ca2+]m:

mitochondrial

[Ca2+]ER:

in the endoplasmic reticulum

CASPASE:

cysteinyl/aspartate-specific protease

DAG:

diacylglycerol

DRP:

dynamin-like protein

GRP75:

glucose-regulated protein 75

ER:

endoplasmic reticulum

IP3:

inositol 1,4,5 trisphosphate

IP3R:

inositol 1,4,5 trisphosphate receptor

MAM:

mitochondrial-associated membrane

Mefs:

mouse embryonic fibroblasts

mPTP:

mitochondrial permeability transition pore

PACS-2:

cytosolic sorting protein-2

PK:

protein kinase

PMCA:

plasma membrane Ca2+ ATP-ase

SERCA:

sarco–endoplasmic reticulum Ca2+ ATPase

VDAC:

voltage anion-dependent channel

References

  • Alnemri ES, Livingston DJ, Nicholson DW, Salvesen G, Thornberry NA, Wong WW et al. (1996). Human ICE/CED-3 protease nomenclature. Cell 87: 171.

    CAS  PubMed  Google Scholar 

  • Assefa Z, Bultynck G, Szlufcik K, Nadif KN, Vermassen E, Goris J et al. (2004). Caspase-3-induced truncation of type 1 inositol trisphosphate receptor accelerates apoptotic cell death and induces inositol trisphosphate-independent calcium release during apoptosis. J Biol Chem 279: 43227–43236.

    CAS  PubMed  Google Scholar 

  • Baehrecke EH . (2005). Autophagy: dual roles in life and death? Nat Rev Mol Cell Biol 6: 505–510.

    CAS  PubMed  Google Scholar 

  • Baffy G, Miyashita T, Williamson JR, Reed JC . (1993). Apoptosis induced by withdrawal of interleukin-3 (IL-3) from an IL-3- dependent hematopoietic cell line is associated with repartitioning of intracellular calcium and is blocked by enforced Bcl-2 oncoprotein production. J Biol Chem 268: 6511–6519.

    CAS  PubMed  Google Scholar 

  • Baines CP, Kaiser RA, Purcell NH, Blair NS, Osinska H, Hambleton MA et al. (2005). Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death. Nature 434: 658–662.

    CAS  PubMed  Google Scholar 

  • Bano D, Young KW, Guerin CJ, Lefeuvre R, Rothwell NJ, Naldini L et al. (2005). Cleavage of the plasma membrane Na+/Ca2+ exchanger in excitotoxicity. Cell 120: 275–285.

    CAS  PubMed  Google Scholar 

  • Basso E, Fante L, Fowlkes J, Petronilli V, Forte MA, Bernardi P . (2005). Properties of the permeability transition pore in mitochondria devoid of cyclophilin D. J Biol Chem 280: 18558–18561.

    CAS  PubMed  Google Scholar 

  • Bastianutto C, Clementi E, Codazzi F, Podini P, De Giorgi F, Rizzuto R et al. (1995). Overexpression of calreticulin increases the Ca2+ capacity of rapidly exchanging Ca2+ stores and reveals aspects of their lumenal microenvironment and function. J Cell Biol 130: 847–855.

    CAS  PubMed  Google Scholar 

  • Bernardi P, Krauskopf A, Basso E, Petronilli V, Blachly-Dyson E, Di Lisa F et al. (2006). The mitochondrial permeability transition from in vitro artifact to disease target. FEBS J 273: 2077–2099.

    CAS  PubMed  Google Scholar 

  • Berridge MJ . (2002). The endoplasmic reticulum: a multifunctional signaling organelle. Cell Calcium 32: 235–249.

    CAS  PubMed  Google Scholar 

  • Berridge MJ, Bootman MD, Roderick HL . (2003). Calcium signalling: dynamics, homeostasis and remodelling. Nat Rev Mol Cell Biol 4: 517–529.

    CAS  PubMed  Google Scholar 

  • Berridge MJ, Lipp P, Bootman MD . (2000). The versatility and universality of calcium signalling. Nat Rev Mol Cell Biol 1: 11–21.

    CAS  PubMed  Google Scholar 

  • Biagioli M, Pifferi S, Ragghianti M, Bucci S, Rizzuto R, Pinton P . (2008). Endoplasmic reticulum stress and alteration in calcium homeostasis are involved in cadmium-induced apoptosis. Cell Calcium 43: 184–195.

    CAS  PubMed  Google Scholar 

  • Blackshaw S, Sawa A, Sharp AH, Ross CA, Snyder SH, Khan AA . (2000). Type 3 inositol 1,4,5-trisphosphate receptor modulates cell death. FASEB J 14: 1375–1379.

    CAS  PubMed  Google Scholar 

  • Boehning D, Patterson RL, Sedaghat L, Glebova NO, Kurosaki T, Snyder SH . (2003). Cytochrome c binds to inositol (1,4,5) trisphosphate receptors, amplifying calcium-dependent apoptosis. Nat Cell Biol 5: 1051–1061.

    CAS  PubMed  Google Scholar 

  • Brini M, Bano D, Manni S, Rizzuto R, Carafoli E . (2000). Effects of PMCA and SERCA pump overexpression on the kinetics of cell Ca(2+) signalling. EMBO J 19: 4926–4935.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Budd SL, Nicholls DG . (1996). A reevaluation of the role of mitochondria in neuronal Ca2+ homeostasis. J Neurochem 66: 403–411.

    CAS  PubMed  Google Scholar 

  • Camello P, Gardner J, Petersen OH, Tepikin AV . (1996). Calcium dependence of calcium extrusion and calcium uptake in mouse pancreatic acinar cells. J Physiol 490 (Pt 3): 585–593.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Campanella M, de Jong AS, Lanke KW, Melchers WJ, Willems PH, Pinton P et al. (2004). The coxsackievirus 2B protein suppresses apoptotic host cell responses by manipulating intracellular Ca2+ homeostasis. J Biolo Chem 279: 18440–18450.

    CAS  Google Scholar 

  • Carafoli E, Molinari M . (1998). Calpain: a protease in search of a function? Biochem Biophys Res Commun 247: 193–203.

    CAS  PubMed  Google Scholar 

  • Chami M, Ferrari D, Nicotera P, Paterlini-Brechot P, Rizzuto R . (2003). Caspase-dependent alterations of Ca2+ signaling in the induction of apoptosis by hepatitis B virus X protein. J Biol Chem 278: 31745–31755.

    CAS  PubMed  Google Scholar 

  • Chami M, Gozuacik D, Saigo K, Capiod T, Falson P, Lecoeur H et al. (2000). Hepatitis B virus-related insertional mutagenesis implicates SERCA1 gene in the control of apoptosis. Oncogene 19: 2877–2886.

    CAS  PubMed  Google Scholar 

  • Chami M, Prandini A, Campanella M, Pinton P, Szabadkai G, Reed JC et al. (2004). Bcl-2 and Bax exert opposing effects on Ca2+ signalling, which do not depend on their putative pore-forming region. J Biol Chem 279: 54581–54589.

    CAS  PubMed  Google Scholar 

  • Chan SL, Mattson MP . (1999). Caspase and calpain substrates: roles in synaptic plasticity and cell death. J Neurosci Res 58: 167–190.

    CAS  PubMed  Google Scholar 

  • Clapham DE . (2007). Calcium signaling. Cell 131: 1047–1058.

    CAS  PubMed  Google Scholar 

  • Csordas G, Thomas AP, Hajnoczky G . (1999). Quasi-synaptic calcium signal transmission between endoplasmic reticulum and mitochondria. EMBO J 18: 96–108.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Danial NN, Korsmeyer SJ . (2004). Cell death: critical control points. Cell 116: 205–219.

    CAS  PubMed  Google Scholar 

  • Demaurex N, Distelhorst C . (2003). Cell biology. Apoptosis—the calcium connection. Science 300: 65–67.

    CAS  PubMed  Google Scholar 

  • Fariss MW, Pascoe GA, Reed DJ . (1985). Vitamin E reversal of the effect of extracellular calcium on chemically induced toxicity in hepatocytes. Science 227: 751–754.

    CAS  PubMed  Google Scholar 

  • Foyouzi-Youssefi R, Arnaudeau S, Borner C, Kelley WL, Tschopp J, Lew DP et al. (2000). Bcl-2 decreases the free Ca2+ concentration within the endoplasmic reticulum. Proc Natl Acad Sci USA 97: 5723–5728.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Garrido C, Galluzzi L, Brunet M, Puig PE, Didelot C, Kroemer G . (2006). Mechanisms of cytochrome c release from mitochondria. Cell Death Differ 13: 1423–1433.

    CAS  PubMed  Google Scholar 

  • Giorgi C, Romagnoli A, Pinton P, Rizzuto R . (2008). Ca2+ signaling, mitochondria and cell death. Curr Mol Med 8: 119–130.

    CAS  PubMed  Google Scholar 

  • Giorgio M, Migliaccio E, Orsini F, Paolucci D, Moroni M, Contursi C et al. (2005). Electron transfer between cytochrome c and p66Shc generates reactive oxygen species that trigger mitochondrial apoptosis. Cell 122: 221–233.

    CAS  PubMed  Google Scholar 

  • Glazner GW, Chan SL, Lu C, Mattson MP . (2000). Caspase-mediated degradation of AMPA receptor subunits: a mechanism for preventing excitotoxic necrosis and ensuring apoptosis. J Neurosci 20: 3641–3649.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Griner EM, Kazanietz MG . (2007). Protein kinase C and other diacylglycerol effectors in cancer. Nat Rev Cancer 7: 281–294.

    CAS  PubMed  Google Scholar 

  • Hajnoczky G, Davies E, Madesh M . (2003). Calcium signaling and apoptosis. Biochem Biophys Res Commun 304: 445–454.

    CAS  PubMed  Google Scholar 

  • Hajnoczky G, Robb-Gaspers LD, Seitz MB, Thomas AP . (1995). Decoding of cytosolic calcium oscillations in the mitochondria. Cell 82: 415–424.

    CAS  PubMed  Google Scholar 

  • Hayashi T, Su TP . (2007). Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca(2+) signaling and cell survival. Cell 131: 596–610.

    CAS  PubMed  Google Scholar 

  • Hetts SW . (1998). To die or not to die: an overview of apoptosis and its role in disease. JAMA 279: 300–307.

    CAS  PubMed  Google Scholar 

  • Hill MM, Adrain C, Martin SJ . (2003). Portrait of a killer: the mitochondrial apoptosome emerges from the shadows. Mol Interv 3: 19–26.

    CAS  PubMed  Google Scholar 

  • Hirota J, Furuichi T, Mikoshiba K . (1999). Inositol 1,4,5-trisphosphate receptor type 1 is a substrate for caspase-3 and is cleaved during apoptosis in a caspase-3-dependent manner. J Biol Chem 274: 34433–34437.

    CAS  PubMed  Google Scholar 

  • Hofer AM, Fasolato C, Pozzan T . (1998). Capacitative Ca2+ entry is closely linked to the filling state of internal Ca2+ stores: a study using simultaneous measurements of ICRAC and intraluminal [Ca2+]. J Cell Biol 140: 325–334.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hoyer-Hansen M, Bastholm L, Szyniarowski P, Campanella M, Szabadkai G, Farkas T et al. (2007). Control of macroautophagy by calcium, calmodulin-dependent kinase kinase-beta, and Bcl-2. Mol Cell 25: 193–205.

    PubMed  Google Scholar 

  • Jayaraman T, Marks AR . (1997). T cells deficient in inositol 1,4,5-trisphosphate receptor are resistant to apoptosis. Mol Cell Biol 17: 3005–3012.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Jouaville LS, Pinton P, Bastianutto C, Rutter GA, Rizzuto R . (1999). Regulation of mitochondrial ATP synthesis by calcium: evidence for a long-term metabolic priming. Proc Natl Acad Sci USA 96: 13807–13812.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kerr JF, Wyllie AH, Currie AR . (1972). Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 26: 239–257.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Khan AA, Soloski MJ, Sharp AH, Schilling G, Sabatini DM, Li SH et al. (1996). Lymphocyte apoptosis: mediation by increased type 3 inositol 1,4,5- trisphosphate receptor. Science 273: 503–507.

    CAS  PubMed  Google Scholar 

  • Khan MT, Wagner L, Yule DI, Bhanumathy C, Joseph SK . (2006). Akt kinase phosphorylation of inositol 1,4,5-trisphosphate receptors. J Biol Chem 281: 3731–3737.

    CAS  PubMed  Google Scholar 

  • Kobayashi S, Yamashita K, Takeoka T, Ohtsuki T, Suzuki Y, Takahashi R et al. (2002). Calpain-mediated X-linked inhibitor of apoptosis degradation in neutrophil apoptosis and its impairment in chronic neutrophilic leukemia. J Biol Chem 277: 33968–33977.

    CAS  PubMed  Google Scholar 

  • Kroemer G, El-Deiry WS, Golstein P, Peter ME, Vaux D, Vandenabeele P et al. (2005). Classification of cell death: recommendations of the Nomenclature Committee on Cell Death. Cell Death Differ 12 (Suppl 2): 1463–1467.

    CAS  PubMed  Google Scholar 

  • Kroemer G, Galluzzi L, Brenner C . (2007). Mitochondrial membrane permeabilization in cell death. Physiol Rev 87: 99–163.

    CAS  PubMed  Google Scholar 

  • Kruman I, Guo Q, Mattson MP . (1998). Calcium and reactive oxygen species mediate staurosporine-induced mitochondrial dysfunction and apoptosis in PC12 cells. J Neurosci Res 51: 293–308.

    CAS  PubMed  Google Scholar 

  • Lam M, Dubyak G, Chen L, Nunez G, Miesfeld RL, Distelhorst CW . (1994). Evidence that BCL-2 represses apoptosis by regulating endoplasmic reticulum-associated Ca2+ fluxes. Proc Natl Acad Sci USA 91: 6569–6573.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lasorsa FM, Pinton P, Palmieri L, Fiermonte G, Rizzuto R, Palmieri F . (2003). Recombinant expression of the Ca(2+)-sensitive aspartate/glutamate carrier increases mitochondrial ATP production in agonist-stimulated Chinese hamster ovary cells. J Biol Chem 278: 38686–38692.

    CAS  PubMed  Google Scholar 

  • Lavin MF, Watters D, Song Q . (1996). Role of protein kinase activity in apoptosis. Experientia 52: 979–994.

    CAS  PubMed  Google Scholar 

  • Li C, Wang X, Vais H, Thompson CB, Foskett JK, White C . (2007). Apoptosis regulation by Bcl-x(L) modulation of mammalian inositol 1,4,5-trisphosphate receptor channel isoform gating. Proc Natl Acad Sci USA 104: 12565–12570.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Liu Y, Fiskum G, Schubert D . (2002). Generation of reactive oxygen species by the mitochondrial electron transport chain. J Neurochem 80: 780–787.

    CAS  PubMed  Google Scholar 

  • Lum JJ, Bauer DE, Kong M, Harris MH, Li C, Lindsten T et al. (2005). Growth factor regulation of autophagy and cell survival in the absence of apoptosis. Cell 120: 237–248.

    CAS  PubMed  Google Scholar 

  • Lynch K, Fernandez G, Pappalardo A, Peluso JJ . (2000). Basic fibroblast growth factor inhibits apoptosis of spontaneously immortalized granulosa cells by regulating intracellular free calcium levels through a protein kinase Cdelta-dependent pathway. Endocrinology 141: 4209–4217.

    CAS  PubMed  Google Scholar 

  • Ma TS, Mann DL, Lee JH, Gallinghouse GJ . (1999). SR compartment calcium and cell apoptosis in SERCA overexpression. Cell Calcium 26: 25–36.

    CAS  PubMed  Google Scholar 

  • Mandic A, Viktorsson K, Strandberg L, Heiden T, Hansson J, Linder S et al. (2002). Calpain-mediated Bid cleavage and calpain-independent Bak modulation: two separate pathways in cisplatin-induced apoptosis. Mol Cell Biol 22: 3003–3013.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Marsh BJ, Mastronarde DN, Buttle KF, Howell KE, McIntosh JR . (2001). Organellar relationships in the Golgi region of the pancreatic beta cell line, HIT-T15, visualized by high resolution electron tomography. Proc Natl Acad Sci USA 98: 2399–2406.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Mendes CC, Gomes DA, Thompson M, Souto NC, Goes TS, Goes AM et al. (2005). The type III inositol 1,4,5-trisphosphate receptor preferentially transmits apoptotic Ca2+ signals into mitochondria. J Biol Chem 280: 40892–40900.

    CAS  PubMed  Google Scholar 

  • Montero M, Lobaton CD, Moreno A, Alvarez J . (2002). A novel regulatory mechanism of the mitochondrial Ca2+ uniporter revealed by the p38 mitogen-activated protein kinase inhibitor SB202190. FASEB J 16: 1955–1957.

    CAS  PubMed  Google Scholar 

  • Nakagawa T, Shimizu S, Watanabe T, Yamaguchi O, Otsu K, Yamagata H et al. (2005). Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death. Nature 434: 652–658.

    CAS  PubMed  Google Scholar 

  • Nakagawa T, Yuan J . (2000). Cross-talk between two cysteine protease families. Activation of caspase-12 by calpain in apoptosis. J Cell Biol 150: 887–894.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Nakagawa T, Zhu H, Morishima N, Li E, Xu J, Yankner BA et al. (2000). Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta. Nature 403: 98–103.

    CAS  PubMed  Google Scholar 

  • Nakamura K, Bossy-Wetzel E, Burns K, Fadel MP, Lozyk M, Goping IS et al. (2000). Changes in endoplasmic reticulum luminal environment affect cell sensitivity to apoptosis. J Cell Biol 150: 731–740.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Nicholson DW . (1999). Caspase structure, proteolytic substrates, and function during apoptotic cell death. Cell Death Differ 6: 1028–1042.

    CAS  PubMed  Google Scholar 

  • Nicholson DW, Thornberry NA . (1997). Caspases: killer proteases. Trends Biochem Sci 22: 299–306.

    CAS  PubMed  Google Scholar 

  • Nicotera P, Orrenius S . (1998). The role of calcium in apoptosis. Cell Calcium 23: 173–180.

    CAS  PubMed  Google Scholar 

  • Oakes SA, Scorrano L, Opferman JT, Bassik MC, Nishino M, Pozzan T et al. (2005). Proapoptotic BAX and BAK regulate the type 1 inositol trisphosphate receptor and calcium leak from the endoplasmic reticulum. Proc Natl Acad Sci USA 102: 105–110.

    CAS  PubMed  Google Scholar 

  • Orrenius S, Zhivotovsky B, Nicotera P . (2003). Regulation of cell death: the calcium-apoptosis link. Nat Rev Mol Cell Biol 4: 552–565.

    CAS  PubMed  Google Scholar 

  • Palmer AE, Jin C, Reed JC, Tsien RY . (2004). Bcl-2-mediated alterations in endoplasmic reticulum Ca2+ analyzed with an improved genetically encoded fluorescent sensor. Proc Natl Acad Sci USA 101: 17404–17409.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Parker PJ, Murray-Rust J . (2004). PKC at a glance. J Cell Sci 117: 131–132.

    CAS  PubMed  Google Scholar 

  • Pattingre S, Tassa A, Qu X, Garuti R, Liang XH, Mizushima N et al. (2005). Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell 122: 927–939.

    CAS  PubMed  Google Scholar 

  • Perry G, Nunomura A, Lucassen P, Lassmann H, Smith MA . (1998). Apoptosis and Alzheimer's disease. Science 282: 1268–1269.

    CAS  PubMed  Google Scholar 

  • Piccini M, Vitelli F, Bruttini M, Pober BR, Jonsson JJ, Villanova M et al. (1998). FACL4, a new gene encoding long-chain acyl-CoA synthetase 4, is deleted in a family with Alport syndrome, elliptocytosis, and mental retardation. Genomics 47: 350–358.

    CAS  PubMed  Google Scholar 

  • Pinton P, Brini M, Bastianutto C, Tuft RA, Pozzan T, Rizzuto R . (1998). New light on mitochondrial calcium. Biofactors 8: 243–253.

    CAS  PubMed  Google Scholar 

  • Pinton P, Ferrari D, Di Virgilio F, Pozzan T, Rizzuto R . (2001a). Molecular machinery and signalling events in apoptosis. Drug Dev Res 52: 558–570.

    CAS  Google Scholar 

  • Pinton P, Ferrari D, Magalhaes P, Schulze-Osthoff K, Di Virgilio F, Pozzan T et al. (2000). Reduced loading of intracellular Ca(2+) stores and downregulation of capacitative Ca(2+) influx in Bcl-2-overexpressing cells. J Cell Biol 148: 857–862.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Pinton P, Ferrari D, Rapizzi E, Di Virgilio F, Pozzan T, Rizzuto R . (2002). A role for calcium in Bcl-2 action? Biochimie 84: 195–201.

    CAS  PubMed  Google Scholar 

  • Pinton P, Ferrari D, Rapizzi E, Di Virgilio FD, Pozzan T, Rizzuto R . (2001b). The Ca2+ concentration of the endoplasmic reticulum is a key determinant of ceramide-induced apoptosis: significance for the molecular mechanism of Bcl-2 action. EMBO J 20: 2690–2701.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Pinton P, Leo S, Wieckowski MR, Di Benedetto G, Rizzuto R . (2004). Long-term modulation of mitochondrial Ca2+ signals by protein kinase C isozymes. J Cell Biol 165: 223–232.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Pinton P, Rimessi A, Marchi S, Orsini F, Migliaccio E, Giorgio M et al. (2007a). Protein kinase C beta and prolyl isomerase 1 regulate mitochondrial effects of the life-span determinant p66Shc. Science 315: 659–663.

    CAS  PubMed  Google Scholar 

  • Pinton P, Rimessi A, Romagnoli A, Prandini A, Rizzuto R . (2007b). Biosensors for the detection of calcium and pH. Methods Cell Biol 80: 297–325.

    CAS  PubMed  Google Scholar 

  • Pinton P, Rizzuto R . (2006). Bcl-2 and Ca2+ homeostasis in the endoplasmic reticulum. Cell Death Differ 13: 1409–1418.

    CAS  PubMed  Google Scholar 

  • Pinton P, Rizzuto R . (2008). p66Shc, oxidative stress and aging: importing a lifespan determinant into mitochondria. Cell Cycle 7: 304–308.

    CAS  PubMed  Google Scholar 

  • Pozzan T, Rizzuto R, Volpe P, Meldolesi J . (1994). Molecular and cellular physiology of intracellular calcium stores. Physiol Rev 74: 595–636.

    CAS  PubMed  Google Scholar 

  • Pressman BC . (1976). Biological applications of ionophores. Annu Rev Biochem 45: 501–530.

    CAS  PubMed  Google Scholar 

  • Putney Jr JW . (1990). Capacitative calcium entry revisited. Cell Calcium 11: 611–624.

    CAS  PubMed  Google Scholar 

  • Rapizzi E, Pinton P, Szabadkai G, Wieckowski MR, Vandecasteele G, Baird GS et al. (2002). Recombinant expression of the voltage-dependent anion channel enhances the transfer of Ca2+ microdomains to mitochondria. J Cell Biol 159: 613–624.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ravagnan L, Roumier T, Kroemer G . (2002). Mitochondria, the killer organelles and their weapons. J Cell Physiol 192: 131–137.

    CAS  PubMed  Google Scholar 

  • Rimessi A, Giorgi C, Pinton P, Rizzuto R . (2008). The versatility of mitochondrial calcium signals: from stimulation of cell metabolism to induction of cell death. Biochim Biophys Acta 1777: 808–816.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Rippo MR, Malisan F, Ravagnan L, Tomassini B, Condo I, Costantini P et al. (2000). GD3 ganglioside directly targets mitochondria in a bcl-2-controlled fashion. FASEB J 14: 2047–2054.

    CAS  PubMed  Google Scholar 

  • Rizzuto R, Pinton P, Carrington W, Fay FS, Fogarty KE, Lifshitz LM et al. (1998). Close contacts with the endoplasmic reticulum as determinants of mitochondrial Ca2+ responses. Science 280: 1763–1766.

    CAS  PubMed  Google Scholar 

  • Rizzuto R, Pinton P, Ferrari D, Chami M, Szabadkai G, Magalhaes PJ et al. (2003). Calcium and apoptosis: facts and hypotheses. Oncogene 22: 8619–8627.

    CAS  PubMed  Google Scholar 

  • Rizzuto R, Pozzan T . (2006). Microdomains of intracellular Ca2+: molecular determinants and functional consequences. Physiol Rev 86: 369–408.

    CAS  PubMed  Google Scholar 

  • Saeki K, Yuo A, Okuma E, Yazaki Y, Susin SA, Kroemer G et al. (2000). Bcl-2 down-regulation causes autophagy in a caspase-independent manner in human leukemic HL60 cells. Cell Death Differ 7: 1263–1269.

    CAS  PubMed  Google Scholar 

  • Schwab BL, Guerini D, Didszun C, Bano D, Ferrando-May E, Fava E et al. (2002). Cleavage of plasma membrane calcium pumps by caspases: a link between apoptosis and necrosis. Cell Death Differ 9: 818–831.

    CAS  PubMed  Google Scholar 

  • Scorrano L, Oakes SA, Opferman JT, Cheng EH, Sorcinelli MD, Pozzan T et al. (2003). BAX and BAK regulation of endoplasmic reticulum Ca2+: a control point for apoptosis. Science 300: 135–139.

    CAS  PubMed  Google Scholar 

  • Shibasaki F, McKeon F . (1995). Calcineurin functions in Ca(2+)-activated cell death in mammalian cells. J Cell Biol 131: 735–743.

    CAS  PubMed  Google Scholar 

  • Simmen T, Aslan JE, Blagoveshchenskaya AD, Thomas L, Wan L, Xiang Y et al. (2005). PACS-2 controls endoplasmic reticulum-mitochondria communication and Bid-mediated apoptosis. EMBO J 24: 717–729.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Stone SJ, Vance JE . (2000). Phosphatidylserine synthase-1 and -2 are localized to mitochondria-associated membranes. J Biol Chem 275: 34534–34540.

    CAS  PubMed  Google Scholar 

  • Sugawara H, Kurosaki M, Takata M, Kurosaki T . (1997). Genetic evidence for involvement of type 1, type 2 and type 3 inositol 1,4,5-trisphosphate receptors in signal transduction through the B-cell antigen receptor. EMBO J 16: 3078–3088.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Szabadkai G, Bianchi K, Varnai P, De Stefani D, Wieckowski MR, Cavagna D et al. (2006). Chaperone-mediated coupling of endoplasmic reticulum and mitochondrial Ca2+ channels. JCell Biol 175: 901–911.

    CAS  Google Scholar 

  • Szabadkai G, Simoni AM, Chami M, Wieckowski MR, Youle RJ, Rizzuto R . (2004). Drp-1-dependent division of the mitochondrial network blocks intraorganellar Ca2+ waves and protects against Ca2+-mediated apoptosis. Mol Cell 16: 59–68.

    CAS  PubMed  Google Scholar 

  • Szado T, Vanderheyden V, Parys JB, De Smedt H, Rietdorf K, Kotelevets L et al. (2008). Phosphorylation of inositol 1,4,5-trisphosphate receptors by protein kinase B/Akt inhibits Ca2+ release and apoptosis. Proc Natl Acad Sci USA 105: 2427–2432.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Szalai G, Krishnamurthy R, Hajnoczky G . (1999). Apoptosis driven by IP(3)-linked mitochondrial calcium signals. EMBO J 18: 6349–6361.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Teranishi F, Liu ZQ, Kunimatsu M, Imai K, Takeyama H, Manabe T et al. (2003). Calpain is involved in the HIV replication from the latently infected OM10.1 cells. Biochem Biophys Res Commun 303: 940–946.

    CAS  PubMed  Google Scholar 

  • Thompson CB . (1995). Apoptosis in the pathogenesis and treatment of disease. Science 267: 1456–1462.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Tombal B, Denmeade SR, Isaacs JT . (1999). Assessment and validation of a microinjection method for kinetic analysis of [Ca2+]i in individual cells undergoing apoptosis. Cell Calcium 25: 19–28.

    CAS  PubMed  Google Scholar 

  • Tsujimoto Y, Shimizu S . (2005). Another way to die: autophagic programmed cell death. Cell Death Differ 12 (Suppl 2): 1528–1534.

    CAS  PubMed  Google Scholar 

  • Turrens JF . (2003). Mitochondrial formation of reactive oxygen species. J Physiol 552: 335–344.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Twomey C, McCarthy JV . (2005). Pathways of apoptosis and importance in development. J Cell Mol Med 9: 345–359.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Vance JE . (1990). Phospholipid synthesis in a membrane fraction associated with mitochondria. J Biol Chem 265: 7248–7256.

    CAS  PubMed  Google Scholar 

  • Vanden Abeele F, Skryma R, Shuba Y, Van Coppenolle F, Slomianny C, Roudbaraki M et al. (2002). Bcl-2-dependent modulation of Ca(2+) homeostasis and store-operated channels in prostate cancer cells. Cancer Cell 1: 169–179.

    CAS  PubMed  Google Scholar 

  • Vanoverberghe K, Vanden Abeele F, Mariot P, Lepage G, Roudbaraki M, Bonnal JL et al. (2004). Ca2+ homeostasis and apoptotic resistance of neuroendocrine-differentiated prostate cancer cells. Cell Death Differ 11: 321–330.

    CAS  PubMed  Google Scholar 

  • Voeltz GK, Rolls MM, Rapoport TA . (2002). Structural organization of the endoplasmic reticulum. EMBO Rep 3: 944–950.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wang HG, Pathan N, Ethell IM, Krajewski S, Yamaguchi Y, Shibasaki F et al. (1999). Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD. Science 284: 339–343.

    CAS  PubMed  Google Scholar 

  • Wang NS, Unkila MT, Reineks EZ, Distelhorst CW . (2001). Transient expression of wild-type or mitochondrially targeted Bcl-2 induces apoptosis, whereas transient expression of endoplasmic reticulum-targeted Bcl-2 is protective against Bax-induced cell death. J Biol Chem 276: 44117–44128.

    CAS  PubMed  Google Scholar 

  • White C, Li C, Yang J, Petrenko NB, Madesh M, Thompson CB et al. (2005). The endoplasmic reticulum gateway to apoptosis by Bcl-X(L) modulation of the InsP3R. Nat Cell Biol 7: 1021–1028.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wieckowski MR, Szabadkai G, Wasilewski M, Pinton P, Duszynski J, Rizzuto R . (2006). Overexpression of adenine nucleotide translocase reduces Ca2+ signal transmission between the ER and mitochondria. Biochem Biophys Res Commun 348: 393–399.

    CAS  PubMed  Google Scholar 

  • Xu XZ, Moebius F, Gill DL, Montell C . (2001). Regulation of melastatin, a TRP-related protein, through interaction with a cytoplasmic isoform. Proc Natl Acad Sci USA 98: 10692–10697.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yoneda T, Imaizumi K, Oono K, Yui D, Gomi F, Katayama T et al. (2001). Activation of caspase-12, an endoplastic reticulum (ER) resident caspase, through tumor necrosis factor receptor-associated factor 2- dependent mechanism in response to the ER stress. J Biol Chem 276: 13935–13940.

    CAS  PubMed  Google Scholar 

  • Youle RJ, Karbowski M . (2005). Mitochondrial fission in apoptosis. Nat Rev Mol Cell Biol 6: 657–663.

    CAS  PubMed  Google Scholar 

  • Zhang J, Alter N, Reed JC, Borner C, Obeid LM, Hannun YA . (1996). Bcl-2 interrupts the ceramide-mediated pathway of cell death. Proc Natl Acad Sci USA 93: 5325–5328.

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We are deeply indebted to past and present collaborators. This work was supported by the Italian Association for Cancer Research (AIRC), Telethon, local funds from the University of Ferrara, the Italian University Ministry, the PRRIITT program of the Emilia Romagna Region, the Italian Space Agency (ASI), NIH (Grant no.1P01AG025532-01A1) and the United Mitochondrial Disease Foundation (UMDF).

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Correspondence to R Rizzuto.

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Pinton, P., Giorgi, C., Siviero, R. et al. Calcium and apoptosis: ER-mitochondria Ca2+ transfer in the control of apoptosis. Oncogene 27, 6407–6418 (2008). https://doi.org/10.1038/onc.2008.308

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