IP3 Receptor Properties and Function at Membrane Contact Sites

  • Gemma Roest
  • Rita M. La Rovere
  • Geert Bultynck
  • Jan B. Parys
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 981)


The inositol 1,4,5-trisphosphate (IP3) receptor (IP3R) is a ubiquitously expressed Ca2+-release channel localized in the endoplasmic reticulum (ER). The intracellular Ca2+ signals originating from the activation of the IP3R regulate multiple cellular processes including the control of cell death versus cell survival via their action on apoptosis and autophagy. The exact role of the IP3Rs in these two processes does not only depend on their activity, which is modulated by the cytosolic composition (Ca2+, ATP, redox status, …) and by various types of regulatory proteins, including kinases and phosphatases as well as by a number of oncogenes and tumor suppressors, but also on their intracellular localization, especially at the ER-mitochondrial and ER-lysosomal interfaces. At these interfaces, Ca2+ microdomains are formed, in which the Ca2+ concentration is finely regulated by the different ER, mitochondrial and lysosomal Ca2+-transport systems and also depends on the functional and structural interactions existing between them. In this review, we therefore discuss the most recent insights in the role of Ca2+ signaling in general, and of the IP3R in particular, in the control of basal mitochondrial bioenergetics, apoptosis, and autophagy at the level of inter-organellar contact sites.


Apoptosis Autophagy Ca2+ microdomains Cell death Cell survival Endoplasmic reticulum IP3 receptor Lysosomes Membrane contact sites Mitochondria 



Amyotrophic lateral sclerosis


AMP-activated kinase




Bcl-2/IP3R disruptor-2 peptide


Ca2+-induced Ca2+ release


cAMP response element-binding protein


DT40 IP3R triple knock-out


Endoplasmic reticulum


Fission 1 homologue


Glucose-regulated protein 75


Glucose-regulated protein 78


Glycogen synthase kinase-3β


Inner mitochondrial membrane


IP3-binding core


Inositol 1,4,5-trisphosphate


IP3 receptor


Microtubule-associated protein light chain 3


Leucine-rich repeat kinase 2


Mitochondria-associated ER membrane


Mitochondrial Ca2+ uniporter




Mitochondrial permeabilization transition pore


Mechanistic target of rapamycin complex 1


Outer mitochondrial membrane


Nicotinic acid adenine dinucleotide phosphate


Phosphofurin acidic cluster sorting protein 2


Protein kinase RNA-like ER kinase


Phosphatidylinositol 3,4,5-trisphosphate


Protein kinase B


Promyelocytic leukemia


Phosphatase and tensin homolog


Protein tyrosine phosphatase-interacting protein-51


Reactive oxygen species


Ryanodine receptor


Sarco-/endoplasmic reticulum Ca2+ ATPase


Tricarboxylic acid


Transcription factor EB


Thioredoxin-like transmembrane protein


Two-pore channel


Transient receptor potential mucolipin


Atg1/Unc-51-like kinase 1/2


Unfolded protein response


Vesicle-associated protein B


Voltage-dependent anion channel



GR is recipient of a Ph.D. fellowship of the Research Fund—Flanders (FWO). Work performed in the laboratory of the authors was supported by research grants of the FWO, the Research Council of the KU Leuven and the Interuniversity Attraction Poles Programmes (Belgian Science Policy).


  1. 1.
    Berridge MJ, Lipp P, Bootman MD (2000) The versatility and universality of calcium signalling. Nat Rev Mol Cell Biol 1:11–21. Scholar
  2. 2.
    Berridge MJ, Bootman MD, Roderick HL (2003) Calcium signalling: dynamics, homeostasis and remodelling. Nat Rev Mol Cell Biol 4:517–529. Scholar
  3. 3.
    Vandecaetsbeek I, Vangheluwe P, Raeymaekers L et al (2011) The Ca2+ pumps of the endoplasmic reticulum and Golgi apparatus. Cold Spring Harb Perspect Biol 3:a004184. Scholar
  4. 4.
    Prins D, Michalak M (2011) Organellar calcium buffers. Cold Spring Harb Perspect Biol 3:a004069. Scholar
  5. 5.
    Lanner JT (2012) Ryanodine receptor physiology and its role in disease. Adv Exp Med Biol 740:217–234. Scholar
  6. 6.
    Vermassen E, Parys JB, Mauger J-P (2004) Subcellular distribution of the inositol 1,4,5-trisphosphate receptors: functional relevance and molecular determinants. Biol Cell 96:3–17. Scholar
  7. 7.
    Fedorenko OA, Popugaeva E, Enomoto M et al (2014) Intracellular calcium channels: inositol-1,4,5-trisphosphate receptors. Eur J Pharmacol 739:39–48. Scholar
  8. 8.
    Foskett JK, White C, Cheung K-H, Mak D-OD (2007) Inositol trisphosphate receptor Ca2+ release channels. Physiol Rev 87:593–658. Scholar
  9. 9.
    Mikoshiba K (2015) Role of IP3 receptor signaling in cell functions and diseases. Adv Biol Regul 57:217–227. Scholar
  10. 10.
    Parys JB, De Smedt H (2012) Inositol 1,4,5-trisphosphate and its receptors. Adv Exp Med Biol 740:255–279. Scholar
  11. 11.
    Taylor CW, Genazzani AA, Morris SA (1999) Expression of inositol trisphosphate receptors. Cell Calcium 26:237–251. Scholar
  12. 12.
    Bittremieux M, Parys JB, Pinton P, Bultynck G (2016) ER functions of oncogenes and tumor suppressors: Modulators of intracellular Ca2+ signaling. Biochim Biophys Acta 1863:1364–1378. Scholar
  13. 13.
    Bosanac I, Michikawa T, Mikoshiba K, Ikura M (2004) Structural insights into the regulatory mechanism of IP3 receptor. Biochim Biophys Acta 1742:89–102. Scholar
  14. 14.
    Uchida K, Miyauchi H, Furuichi T et al (2003) Critical regions for activation gating of the inositol 1,4,5-trisphosphate receptor. J Biol Chem 278:16551–16560. Scholar
  15. 15.
    Bosanac I, Alattia J-R, Mal TK et al (2002) Structure of the inositol 1,4,5-trisphosphate receptor binding core in complex with its ligand. Nature 420:696–700. Scholar
  16. 16.
    Bosanac I, Yamazaki H, Matsu-Ura T et al (2005) Crystal structure of the ligand binding suppressor domain of type 1 inositol 1,4,5-trisphosphate receptor. Mol Cell 17:193–203. Scholar
  17. 17.
    Lin C-C, Baek K, Lu Z (2011) Apo and InsP3-bound crystal structures of the ligand-binding domain of an InsP3 receptor. Nat Struct Mol Biol 18:1172–1174. Scholar
  18. 18.
    Seo M-D, Velamakanni S, Ishiyama N et al (2012) Structural and functional conservation of key domains in InsP3 and ryanodine receptors. Nature 483:108–112. Scholar
  19. 19.
    Hamada K, Miyatake H, Terauchi A, Mikoshiba K (2017) IP3-mediated gating mechanism of the IP3 receptor revealed by mutagenesis and X-ray crystallography. Proc Natl Acad Sci USA 114:4661–4666. Scholar
  20. 20.
    Fan G, Baker ML, Wang Z et al (2015) Gating machinery of InsP3R channels revealed by electron cryomicroscopy. Nature 527:336–341. Scholar
  21. 21.
    Serysheva II, Baker M, Fan G (2018) Structural insights into IP3R function. Adv Exp Med Biol 981Google Scholar
  22. 22.
    Alzayady KJ, Wang L, Chandrasekhar R et al (2016) Defining the stoichiometry of inositol 1,4,5-trisphosphate binding required to initiate Ca2+ release. Sci Signal 9:ra35. Scholar
  23. 23.
    Taylor CW, Konieczny V (2016) IP3 receptors: take four IP3 to open. Sci Signal 9:pe1. Scholar
  24. 24.
    Takahashi M, Kagasaki T, Hosoya T, Takahashi S (1993) Adenophostins A and B: potent agonists of inositol-1,4,5-trisphosphate receptor produced by Penicillium brevicompactum. Taxonomy, fermentation, isolation, physico-chemical and biological properties. J Antibiot (Tokyo) 46:1643–1647CrossRefGoogle Scholar
  25. 25.
    Bezprozvanny I, Watras J, Ehrlich BE (1991) Bell-shaped calcium-response curves of Ins(1,4,5)P3- and calcium-gated channels from endoplasmic reticulum of cerebellum. Nature 351:751–754. Scholar
  26. 26.
    Finch EA, Turner TJ, Goldin SM (1991) Calcium as a coagonist of inositol 1,4,5-trisphosphate-induced calcium release. Science 252:443–446CrossRefPubMedGoogle Scholar
  27. 27.
    Iino M (1990) Biphasic Ca2+ dependence of inositol 1,4,5-trisphosphate-induced Ca2+ release in smooth muscle cells of the guinea pig taenia caeci. J Gen Physiol 95:1103–1122CrossRefPubMedGoogle Scholar
  28. 28.
    Parys JB, Sernett SW, DeLisle S et al (1992) Isolation, characterization, and localization of the inositol 1,4,5-trisphosphate receptor protein in Xenopus laevis oocytes. J Biol Chem 267:18776–18782PubMedGoogle Scholar
  29. 29.
    Bezprozvanny I, Ehrlich BE (1993) ATP modulates the function of inositol 1,4,5-trisphosphate-gated channels at two sites. Neuron 10:1175–1184CrossRefPubMedGoogle Scholar
  30. 30.
    Bootman MD, Taylor CW, Berridge MJ (1992) The thiol reagent, thimerosal, evokes Ca2+ spikes in HeLa cells by sensitizing the inositol 1,4,5-trisphosphate receptor. J Biol Chem 267:25113–25119PubMedGoogle Scholar
  31. 31.
    Parys JB, Missiaen L, De Smedt H et al (1993) Bell-shaped activation of inositol-1,4,5-trisphosphate-induced Ca2+ release by thimerosal in permeabilized A7r5 smooth-muscle cells. Pflugers Arch 424:516–522CrossRefPubMedGoogle Scholar
  32. 32.
    Tovey SC, Dedos SG, Taylor EJA et al (2008) Selective coupling of type 6 adenylyl cyclase with type 2 IP3 receptors mediates direct sensitization of IP3 receptors by cAMP. J Cell Biol 183:297–311. Scholar
  33. 33.
    Tovey SC, Dedos SG, Rahman T et al (2010) Regulation of inositol 1,4,5-trisphosphate receptors by cAMP independent of cAMP-dependent protein kinase. J Biol Chem 285:12979–12989. Scholar
  34. 34.
    Konieczny V, Tovey SC, Mataragka S et al (2017) Cyclic AMP recruits a discrete intracellular Ca2+ store by unmasking hypersensitive IP3 receptors. Cell Rep 18:711–722. Scholar
  35. 35.
    Patterson RL, Boehning D, Snyder SH (2004) Inositol 1,4,5-trisphosphate receptors as signal integrators. Annu Rev Biochem 73:437–465CrossRefPubMedGoogle Scholar
  36. 36.
    Vervloessem T, Yule DI, Bultynck G, Parys JB (2015) The type 2 inositol 1,4,5-trisphosphate receptor, emerging functions for an intriguing Ca2+-release channel. Biochim Biophys Acta 1853:1992–2005. Scholar
  37. 37.
    Iwai M, Michikawa T, Bosanac I et al (2007) Molecular basis of the isoform-specific ligand-binding affinity of inositol 1,4,5-trisphosphate receptors. J Biol Chem 282:12755–12764. Scholar
  38. 38.
    Miyakawa T, Maeda A, Yamazawa T et al (1999) Encoding of Ca2+ signals by differential expression of IP3 receptor subtypes. EMBO J 18:1303–1308. Scholar
  39. 39.
    Newton CL, Mignery GA, Südhof TC (1994) Co-expression in vertebrate tissues and cell lines of multiple inositol 1,4,5-trisphosphate (InsP3) receptors with distinct affinities for InsP3. J Biol Chem 269:28613–28619PubMedGoogle Scholar
  40. 40.
    Tu H, Wang Z, Nosyreva E et al (2005) Functional characterization of mammalian inositol 1,4,5-trisphosphate receptor isoforms. Biophys J 88:1046–1055. Scholar
  41. 41.
    Vanlingen S, Sipma H, De Smet P et al (2000) Ca2+ and calmodulin differentially modulate myo-inositol 1,4, 5-trisphosphate (IP3)-binding to the recombinant ligand-binding domains of the various IP3 receptor isoforms. Biochem J 346:275–280CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Mak DO, McBride S, Foskett JK (2001) Regulation by Ca2+ and inositol 1,4,5-trisphosphate (InsP3) of single recombinant type 3 InsP3 receptor channels. Ca2+ activation uniquely distinguishes types 1 and 3 InsP3 receptors. J Gen Physiol 117:435–446CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Mak D-OD, McBride SMJ, Petrenko NB, Foskett JK (2003) Novel regulation of calcium inhibition of the inositol 1,4,5-trisphosphate receptor calcium-release channel. J Gen Physiol 122:569–581. Scholar
  44. 44.
    Tu H, Wang Z, Bezprozvanny I (2005) Modulation of mammalian inositol 1,4,5-trisphosphate receptor isoforms by calcium: a role of calcium sensor region. Biophys J 88:1056–1069. Scholar
  45. 45.
    Betzenhauser MJ, Wagner LE, Iwai M et al (2008) ATP modulation of Ca2+ release by type-2 and type-3 inositol (1, 4, 5)-triphosphate receptors. Differing ATP sensitivities and molecular determinants of action. J Biol Chem 283:21579–21587. Scholar
  46. 46.
    Missiaen L, Parys JB, Sienaert I et al (1998) Functional properties of the type-3 InsP3 receptor in 16HBE14o- bronchial mucosal cells. J Biol Chem 273:8983–8986CrossRefPubMedGoogle Scholar
  47. 47.
    Maes K, Missiaen L, De Smet P et al (2000) Differential modulation of inositol 1,4,5-trisphosphate receptor type 1 and type 3 by ATP. Cell Calcium 27:257–267. Scholar
  48. 48.
    Alzayady KJ, Wagner LE, Chandrasekhar R et al (2013) Functional inositol 1,4,5-trisphosphate receptors assembled from concatenated homo- and heteromeric subunits. J Biol Chem 288:29772–29784. Scholar
  49. 49.
    Bultynck G, Szlufcik K, Kasri NN et al (2004) Thimerosal stimulates Ca2+ flux through inositol 1,4,5-trisphosphate receptor type 1, but not type 3, via modulation of an isoform-specific Ca2+-dependent intramolecular interaction. Biochem J 381:87–96. Scholar
  50. 50.
    Bultynck G, Sienaert I, Parys JB et al (2003) Pharmacology of inositol trisphosphate receptors. Pflugers Arch 445:629–642. Scholar
  51. 51.
    Saleem H, Tovey SC, Molinski TF, Taylor CW (2014) Interactions of antagonists with subtypes of inositol 1,4,5-trisphosphate (IP3) receptor. Br J Pharmacol 171:3298–3312. Scholar
  52. 52.
    Swarbrick JM, Riley AM, Mills SJ, Potter BVL (2015) Designer small molecules to target calcium signalling. Biochem Soc Trans 43:417–425. Scholar
  53. 53.
    Fredericks GJ, Hoffmann FW, Rose AH et al (2014) Stable expression and function of the inositol 1,4,5-triphosphate receptor requires palmitoylation by a DHHC6/selenoprotein K complex. Proc Natl Acad Sci USA 111:16478–16483. Scholar
  54. 54.
    Hamada K, Terauchi A, Nakamura K et al (2014) Aberrant calcium signaling by transglutaminase-mediated posttranslational modification of inositol 1,4,5-trisphosphate receptors. Proc Natl Acad Sci USA 111:E3966–E3975. Scholar
  55. 55.
    Bultynck G, Vermassen E, Szlufcik K et al (2003) Calcineurin and intracellular Ca2+-release channels: regulation or association? Biochem Biophys Res Commun 311:1181–1193CrossRefPubMedGoogle Scholar
  56. 56.
    Vanderheyden V, Devogelaere B, Missiaen L et al (2009) Regulation of inositol 1,4,5-trisphosphate-induced Ca2+ release by reversible phosphorylation and dephosphorylation. Biochim Biophys Acta 1793:959–970. Scholar
  57. 57.
    Prole DL, Taylor CW (2016) Inositol 1,4,5-trisphosphate receptors and their protein partners as signalling hubs. J Physiol 594:2849–2866. Scholar
  58. 58.
    Ando H, Mizutani A, Kiefer H et al (2006) IRBIT suppresses IP3 receptor activity by competing with IP3 for the common binding site on the IP3 receptor. Mol Cell 22:795–806. Scholar
  59. 59.
    Devogelaere B, Beullens M, Sammels E et al (2007) Protein phosphatase-1 is a novel regulator of the interaction between IRBIT and the inositol 1,4,5-trisphosphate receptor. Biochem J 407:303–311. Scholar
  60. 60.
    Michikawa T, Hirota J, Kawano S et al (1999) Calmodulin mediates calcium-dependent inactivation of the cerebellar type 1 inositol 1,4,5-trisphosphate receptor. Neuron 23:799–808CrossRefPubMedGoogle Scholar
  61. 61.
    Missiaen L, Parys JB, Weidema AF et al (1999) The bell-shaped Ca2+ dependence of the inositol 1,4, 5-trisphosphate-induced Ca2+ release is modulated by Ca2+/calmodulin. J Biol Chem 274:13748–13751CrossRefPubMedGoogle Scholar
  62. 62.
    Patel S, Morris SA, Adkins CE et al (1997) Ca2+-independent inhibition of inositol trisphosphate receptors by calmodulin: redistribution of calmodulin as a possible means of regulating Ca2+ mobilization. Proc Natl Acad Sci USA 94:11627–11632CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Sienaert I, Nadif Kasri N, Vanlingen S et al (2002) Localization and function of a calmodulin-apocalmodulin-binding domain in the N-terminal part of the type 1 inositol 1,4,5-trisphosphate receptor. Biochem J 365:269–277. Scholar
  64. 64.
    Yamada M, Miyawaki A, Saito K et al (1995) The calmodulin-binding domain in the mouse type 1 inositol 1,4,5-trisphosphate receptor. Biochem J 308:83–88CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Haynes LP, Tepikin AV, Burgoyne RD (2004) Calcium-binding protein 1 is an inhibitor of agonist-evoked, inositol 1,4,5-trisphosphate-mediated calcium signaling. J Biol Chem 279:547–555. Scholar
  66. 66.
    Kasri NN, Holmes AM, Bultynck G et al (2004) Regulation of InsP3 receptor activity by neuronal Ca2+-binding proteins. EMBO J 23:312–321. Scholar
  67. 67.
    Yang J, McBride S, Mak D-OD et al (2002) Identification of a family of calcium sensors as protein ligands of inositol trisphosphate receptor Ca2+ release channels. Proc Natl Acad Sci USA 99:7711–7716. Scholar
  68. 68.
    Chen R, Valencia I, Zhong F et al (2004) 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 166:193–203. Scholar
  69. 69.
    Eckenrode EF, Yang J, Velmurugan GV et al (2010) Apoptosis protection by Mcl-1 and Bcl-2 modulation of inositol 1,4,5-trisphosphate receptor-dependent Ca2+ signaling. J Biol Chem 285:13678–13684. Scholar
  70. 70.
    Rong Y-P, Bultynck G, Aromolaran AS et al (2009) The BH4 domain of Bcl-2 inhibits ER calcium release and apoptosis by binding the regulatory and coupling domain of the IP3 receptor. Proc Natl Acad Sci USA 106:14397–14402. Scholar
  71. 71.
    White C, Li C, Yang J et al (2005) The endoplasmic reticulum gateway to apoptosis by Bcl-XL modulation of the InsP3R. Nat Cell Biol 7:1021–1028. Scholar
  72. 72.
    Xu S, Xu Y, Chen L et al (2017) RCN1 suppresses ER stress-induced apoptosis via calcium homeostasis and PERK-CHOP signaling. Oncogenesis 6:e304. Scholar
  73. 73.
    Decuypere J-P, Welkenhuyzen K, Luyten T et al (2011) Ins(1,4,5)P3 receptor-mediated Ca2+ signaling and autophagy induction are interrelated. Autophagy 7:1472–1489CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Vicencio JM, Ortiz C, Criollo A et al (2009) The inositol 1,4,5-trisphosphate receptor regulates autophagy through its interaction with Beclin 1. Cell Death Differ 16:1006–1017. Scholar
  75. 75.
    Higo T, Hattori M, Nakamura T et al (2005) Subtype-specific and ER lumenal environment-dependent regulation of inositol 1,4,5-trisphosphate receptor type 1 by ERp44. Cell 120:85–98. Scholar
  76. 76.
    Higo T, Hamada K, Hisatsune C et al (2010) Mechanism of ER stress-induced brain damage by IP3 receptor. Neuron 68:865–878. Scholar
  77. 77.
    Hayashi T, Su TP (2001) Regulating ankyrin dynamics: Roles of sigma-1 receptors. Proc Natl Acad Sci USA 98:491–496. Scholar
  78. 78.
    Boehning D, Patterson RL, Sedaghat L et al (2003) Cytochrome c binds to inositol (1,4,5) trisphosphate receptors, amplifying calcium-dependent apoptosis. Nat Cell Biol 5:1051–1061. Scholar
  79. 79.
    Akl H, Bultynck G (2013) Altered Ca2+ signaling in cancer cells: proto-oncogenes and tumor suppressors targeting IP3 receptors. Biochim Biophys Acta 1835:180–193. Scholar
  80. 80.
    Ivanova H, Kerkhofs M, La Rovere R, Bultynck G (2017) Endoplasmic reticulum–mitochondrial Ca2+ fluxes underlying cancer cell survival. Front Oncol 7:Article 70. Scholar
  81. 81.
    Decrock E, De Bock M, Wang N et al (2013) IP3, a small molecule with a powerful message. Biochim Biophys Acta 1833:1772–1786. Scholar
  82. 82.
    Distelhorst CW, Bootman MD (2011) Bcl-2 interaction with the inositol 1,4,5-trisphosphate receptor: role in Ca2+ signaling and disease. Cell Calcium 50:234–241. Scholar
  83. 83.
    Ivanova H, Vervliet T, Missiaen L et al (2014) Inositol 1,4,5-trisphosphate receptor-isoform diversity in cell death and survival. Biochim Biophys Acta 1843:2164–2183. Scholar
  84. 84.
    Joseph SK, Hajnóczky G (2007) IP3 receptors in cell survival and apoptosis: Ca2+ release and beyond. Apoptosis 12:951–968. Scholar
  85. 85.
    La Rovere RML, Roest G, Bultynck G, Parys JB (2016) Intracellular Ca2+ signaling and Ca2+ microdomains in the control of cell survival, apoptosis and autophagy. Cell Calcium 60:74–87. Scholar
  86. 86.
    Smaili SS, Pereira GJS, Costa MM et al (2013) The role of calcium stores in apoptosis and autophagy. Curr Mol Med 13:252–265CrossRefPubMedGoogle Scholar
  87. 87.
    Bootman MD, Chehab T, Bultynck G, et al (2018) Autophagy and calcium signalling: do we have a consensus? Cell Calcium.
  88. 88.
    Ghislat G, Knecht E (2013) Ca2+-sensor proteins in the autophagic and endocytic traffic. Curr Protein Pept Sci 14:97–110CrossRefPubMedPubMedCentralGoogle Scholar
  89. 89.
    Parys JB, Decuypere J-P, Bultynck G (2012) Role of the inositol 1,4,5-trisphosphate receptor/Ca2+-release channel in autophagy. Cell Commun Signal CCS 10:17. Scholar
  90. 90.
    Sun F, Xu X, Wang X, Zhang B (2016) Regulation of autophagy by Ca2+. Tumour Biol 37(12):15467–15476. Scholar
  91. 91.
    Czabotar PE, Lessene G, Strasser A, Adams JM (2014) Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy. Nat Rev Mol Cell Biol 15:49–63. Scholar
  92. 92.
    Letai AG (2008) Diagnosing and exploiting cancer’s addiction to blocks in apoptosis. Nat Rev Cancer 8:121–132. Scholar
  93. 93.
    Tait SWG, Green DR (2013) Mitochondrial regulation of cell death. Cold Spring Harb Perspect Biol 5:a008706. Scholar
  94. 94.
    Pinton P, Giorgi C, Siviero R et al (2008) Calcium and apoptosis: ER-mitochondria Ca2+ transfer in the control of apoptosis. Oncogene 27:6407–6418. Scholar
  95. 95.
    Hwang M-S, Schwall CT, Pazarentzos E et al (2014) Mitochondrial Ca2+ influx targets cardiolipin to disintegrate respiratory chain complex II for cell death induction. Cell Death Differ 21:1733–1745. Scholar
  96. 96.
    Bonora M, Bononi A, De Marchi E et al (2013) Role of the c subunit of the F0 ATP synthase in mitochondrial permeability transition. Cell Cycle 12:674–683. Scholar
  97. 97.
    Giorgio V, von Stockum S, Antoniel M et al (2013) Dimers of mitochondrial ATP synthase form the permeability transition pore. Proc Natl Acad Sci USA 110:5887–5892. Scholar
  98. 98.
    Giorgio V, Guo L, Bassot C, et al (2018) Calcium and regulation of the mitochondrial permeability transition. Cell Calcium.
  99. 99.
    Giorgio V, Burchell V, Schiavone M et al (2017) Ca2+ binding to F-ATP synthase β subunit triggers the mitochondrial permeability transition. EMBO Rep 18(7):1065–1076CrossRefPubMedGoogle Scholar
  100. 100.
    Bender T, Martinou J-C (2013) Where killers meet--permeabilization of the outer mitochondrial membrane during apoptosis. Cold Spring Harb Perspect Biol 5:a011106. Scholar
  101. 101.
    Wang HG, Pathan N, Ethell IM et al (1999) Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD. Science 284:339–343CrossRefPubMedGoogle Scholar
  102. 102.
    Sano R, Reed JC (2013) ER stress-induced cell death mechanisms. Biochim Biophys Acta 1833:3460–3470. Scholar
  103. 103.
    Urra H, Dufey E, Lisbona F et al (2013) When ER stress reaches a dead end. Biochim Biophys Acta 1833:3507–3517. Scholar
  104. 104.
    Ravikumar B, Sarkar S, Davies JE et al (2010) Regulation of mammalian autophagy in physiology and pathophysiology. Physiol Rev 90:1383–1435. Scholar
  105. 105.
    Liu Y, Levine B (2015) Autosis and autophagic cell death: the dark side of autophagy. Cell Death Differ 22:367–376. Scholar
  106. 106.
    Liu Y, Shoji-Kawata S, Sumpter RM et al (2013) Autosis is a Na+,K+-ATPase-regulated form of cell death triggered by autophagy-inducing peptides, starvation, and hypoxia-ischemia. Proc Natl Acad Sci USA 110:20364–20371. Scholar
  107. 107.
    Bento CF, Renna M, Ghislat G et al (2016) Mammalian autophagy: how does it work? Annu Rev Biochem 85:685–713. Scholar
  108. 108.
    Wesselborg S, Stork B (2015) Autophagy signal transduction by ATG proteins: from hierarchies to networks. Cell Mol Life Sci 72:4721–4757. Scholar
  109. 109.
    Hamasaki M, Furuta N, Matsuda A et al (2013) Autophagosomes form at ER-mitochondria contact sites. Nature 495:389–393. Scholar
  110. 110.
    Hayashi-Nishino M, Fujita N, Noda T et al (2009) A subdomain of the endoplasmic reticulum forms a cradle for autophagosome formation. Nat Cell Biol 11:1433–1437. Scholar
  111. 111.
    Ylä-Anttila P, Vihinen H, Jokitalo E, Eskelinen E-L (2009) 3D tomography reveals connections between the phagophore and endoplasmic reticulum. Autophagy 5:1180–1185CrossRefPubMedGoogle Scholar
  112. 112.
    Roberts R, Ktistakis NT (2013) Omegasomes: PI3P platforms that manufacture autophagosomes. Essays Biochem 55:17–27. Scholar
  113. 113.
    Proikas-Cezanne T, Takacs Z, Dönnes P, Kohlbacher O (2015) WIPI proteins: essential PtdIns3P effectors at the nascent autophagosome. J Cell Sci 128:207–217. Scholar
  114. 114.
    Decuypere J-P, Kindt D, Luyten T et al (2013) mTOR-controlled autophagy requires intracellular Ca2+ signaling. PloS One 8:e61020. Scholar
  115. 115.
    Grotemeier A, Alers S, Pfisterer SG et al (2010) AMPK-independent induction of autophagy by cytosolic Ca2+ increase. Cell Signal 22:914–925. Scholar
  116. 116.
    Høyer-Hansen M, Bastholm L, Szyniarowski P et al (2007) Control of macroautophagy by calcium, calmodulin-dependent kinase kinase-beta, and Bcl-2. Mol Cell 25:193–205. Scholar
  117. 117.
    Luyten T, Welkenhuyzen K, Roest G et al (2017) Resveratrol-induced autophagy is dependent on IP3Rs and on cytosolic Ca2+. Biochim Biophys Acta 1864:947–956. Scholar
  118. 118.
    Messai Y, Noman MZ, Hasmim M et al (2014) ITPR1 protects renal cancer cells against natural killer cells by inducing autophagy. Cancer Res 74:6820–6832. Scholar
  119. 119.
    Engedal N, Torgersen ML, Guldvik IJ et al (2013) Modulation of intracellular calcium homeostasis blocks autophagosome formation. Autophagy 9:1475–1490. Scholar
  120. 120.
    Gulati P, Gaspers LD, Dann SG et al (2008) Amino acids activate mTOR complex 1 via Ca2+/CaM signaling to hVps34. Cell Metab 7:456–465. Scholar
  121. 121.
    Khan MT, Joseph SK (2010) Role of inositol trisphosphate receptors in autophagy in DT40 cells. J Biol Chem 285:16912–16920. Scholar
  122. 122.
    Sarkar S, Floto RA, Berger Z et al (2005) Lithium induces autophagy by inhibiting inositol monophosphatase. J Cell Biol 170:1101–1111. Scholar
  123. 123.
    Cárdenas C, Foskett JK (2012) Mitochondrial Ca2+signals in autophagy. Cell Calcium 52:44–51. Scholar
  124. 124.
    Decuypere J-P, Bultynck G, Parys JB (2011) A dual role for Ca2+ in autophagy regulation. Cell Calcium 50:242–250. Scholar
  125. 125.
    East DA, Campanella M (2013) Ca2+ in quality control: an unresolved riddle critical to autophagy and mitophagy. Autophagy 9:1710–1719. Scholar
  126. 126.
    Rimessi A, Bonora M, Marchi S et al (2013) Perturbed mitochondrial Ca2+ signals as causes or consequences of mitophagy induction. Autophagy 9:1677–1686. Scholar
  127. 127.
    Vicencio JM, Lavandero S, Szabadkai G (2010) Ca2+, autophagy and protein degradation: thrown off balance in neurodegenerative disease. Cell Calcium 47:112–121. Scholar
  128. 128.
    Decuypere J-P, Monaco G, Bultynck G et al (2011) The IP3 receptor-mitochondria connection in apoptosis and autophagy. Biochim Biophys Acta 1813:1003–1013. Scholar
  129. 129.
    Rizzuto R, De Stefani D, Raffaello A, Mammucari C (2012) Mitochondria as sensors and regulators of calcium signalling. Nat Rev Mol Cell Biol 13:566–578. Scholar
  130. 130.
    Giacomello M, Pellegrini L (2016) The coming of age of the mitochondria-ER contact: a matter of thickness. Cell Death Differ 23:1417–1427. Scholar
  131. 131.
    Danese A, Patergnani S, Bonora M et al (2017) Calcium regulates cell death in cancer: Roles of the mitochondria and mitochondria-associated membranes (MAMs). Biochim Biophys Acta 1858(8):615–627. Scholar
  132. 132.
    Giorgi C, Missiroli S, Patergnani S et al (2015) Mitochondria-associated membranes: composition, molecular mechanisms, and physiopathological implications. Antioxid Redox Signal 22:995–1019. Scholar
  133. 133.
    Herrera-Cruz MS, Simmen T (2017) Of yeast, mice and men: MAMs come in two flavors. Biol Direct 12:3. Scholar
  134. 134.
    Naon D, Scorrano L (2014) At the right distance: ER-mitochondria juxtaposition in cell life and death. Biochim Biophys Acta 1843:2184–2194. Scholar
  135. 135.
    van Vliet AR, Verfaillie T, Agostinis P (2014) New functions of mitochondria associated membranes in cellular signaling. Biochim Biophys Acta 1843:2253–2262. Scholar
  136. 136.
    Vervliet T, Clerix E, Seitaj B et al (2017) Modulation of Ca2+ signaling by anti-apoptotic B-cell lymphoma 2 proteins at the endoplasmic reticulum–mitochondrial interface. Front Oncol 7:Article 75. Scholar
  137. 137.
    Csordás G, Renken C, Várnai P et al (2006) Structural and functional features and significance of the physical linkage between ER and mitochondria. J Cell Biol 174:915–921. Scholar
  138. 138.
    Filadi R, Theurey P, Pizzo P (2017) The endoplasmic reticulum-mitochondria coupling in health and disease: Molecules, functions and significance. Cell Calcium 62:1–15. Scholar
  139. 139.
    Paillusson S, Stoica R, Gómez-Suaga P et al (2016) There’s something wrong with my MAM; the ER-mitochondria axis and neurodegenerative diseases. Trends Neurosci 39:146–157. Scholar
  140. 140.
    Szabadkai G, Bianchi K, Várnai P et al (2006) Chaperone-mediated coupling of endoplasmic reticulum and mitochondrial Ca2+ channels. J Cell Biol 175:901–911. Scholar
  141. 141.
    Csordás G, Thomas AP, Hajnóczky G (1999) Quasi-synaptic calcium signal transmission between endoplasmic reticulum and mitochondria. EMBO J 18:96–108. Scholar
  142. 142.
    Csordás G, Várnai P, Golenár T et al (2010) Imaging interorganelle contacts and local calcium dynamics at the ER-mitochondrial interface. Mol Cell 39:121–132. Scholar
  143. 143.
    Giacomello M, Drago I, Bortolozzi M et al (2010) Ca2+ hot spots on the mitochondrial surface are generated by Ca2+ mobilization from stores, but not by activation of store-operated Ca2+ channels. Mol Cell 38:280–290. Scholar
  144. 144.
    Murgia M, Rizzuto R (2015) Molecular diversity and pleiotropic role of the mitochondrial calcium uniporter. Cell Calcium 58:11–17. Scholar
  145. 145.
    de Brito OM, Scorrano L (2008) Mitofusin 2 tethers endoplasmic reticulum to mitochondria. Nature 456:605–610. Scholar
  146. 146.
    Naon D, Zaninello M, Giacomello M et al (2016) Critical reappraisal confirms that Mitofusin 2 is an endoplasmic reticulum-mitochondria tether. Proc Natl Acad Sci USA 113:11249–11254. Scholar
  147. 147.
    Cerqua C, Anesti V, Pyakurel A et al (2010) Trichoplein/mitostatin regulates endoplasmic reticulum-mitochondria juxtaposition. EMBO Rep 11:854–860. Scholar
  148. 148.
    Sugiura A, Nagashima S, Tokuyama T et al (2013) MITOL regulates endoplasmic reticulum-mitochondria contacts via Mitofusin2. Mol Cell 51:20–34. Scholar
  149. 149.
    Cosson P, Marchetti A, Ravazzola M, Orci L (2012) Mitofusin-2 independent juxtaposition of endoplasmic reticulum and mitochondria: an ultrastructural study. PloS One 7:e46293. Scholar
  150. 150.
    Filadi R, Greotti E, Turacchio G et al (2015) Mitofusin 2 ablation increases endoplasmic reticulum-mitochondria coupling. Proc Natl Acad Sci USA 112:E2174–E2181. Scholar
  151. 151.
    Leal NS, Schreiner B, Pinho CM et al (2016) Mitofusin-2 knockdown increases ER-mitochondria contact and decreases amyloid β-peptide production. J Cell Mol Med 20:1686–1695. Scholar
  152. 152.
    Wang PTC, Garcin PO, Fu M et al (2015) Distinct mechanisms controlling rough and smooth endoplasmic reticulum contacts with mitochondria. J Cell Sci 128:2759–2765. Scholar
  153. 153.
    Filadi R, Greotti E, Turacchio G et al (2017) On the role of Mitofusin 2 in endoplasmic reticulum-mitochondria tethering. Proc Natl Acad Sci USA 114:E2266–E2267. Scholar
  154. 154.
    Naon D, Zaninello M, Giacomello M et al (2017) Reply to Filadi et al.: does Mitofusin 2 tether or separate endoplasmic reticulum and mitochondria? Proc Natl Acad Sci USA 114:E2268–E2269. Scholar
  155. 155.
    Walker AK, Atkin JD (2011) Stress signaling from the endoplasmic reticulum: a central player in the pathogenesis of amyotrophic lateral sclerosis. IUBMB Life 63:754–763. Scholar
  156. 156.
    De Vos KJ, Mórotz GM, Stoica R et al (2012) VAPB interacts with the mitochondrial protein PTPIP51 to regulate calcium homeostasis. Hum Mol Genet 21:1299–1311. Scholar
  157. 157.
    Nishimura AL, Mitne-Neto M, Silva HC et al (2004) A mutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis. Am J Hum Genet 75:822–831CrossRefPubMedPubMedCentralGoogle Scholar
  158. 158.
    Iwasawa R, Mahul-Mellier A-L, Datler C et al (2011) Fis1 and Bap31 bridge the mitochondria-ER interface to establish a platform for apoptosis induction. EMBO J 30:556–568. Scholar
  159. 159.
    Breckenridge DG, Stojanovic M, Marcellus RC, Shore GC (2003) Caspase cleavage product of BAP31 induces mitochondrial fission through endoplasmic reticulum calcium signals, enhancing cytochrome c release to the cytosol. J Cell Biol 160:1115–1127. Scholar
  160. 160.
    Simmen T, Aslan JE, Blagoveshchenskaya AD et al (2005) PACS-2 controls endoplasmic reticulum-mitochondria communication and Bid-mediated apoptosis. EMBO J 24:717–729. Scholar
  161. 161.
    Verfaillie T, Rubio N, Garg AD et al (2012) PERK is required at the ER-mitochondrial contact sites to convey apoptosis after ROS-based ER stress. Cell Death Differ 19:1880–1891. Scholar
  162. 162.
    Gellerich FN, Gizatullina Z, Gainutdinov T et al (2013) The control of brain mitochondrial energization by cytosolic calcium: the mitochondrial gas pedal. IUBMB Life 65:180–190. Scholar
  163. 163.
    McCormack JG, Halestrap AP, Denton RM (1990) Role of calcium ions in regulation of mammalian intramitochondrial metabolism. Physiol Rev 70:391–425CrossRefPubMedGoogle Scholar
  164. 164.
    Glancy B, Balaban RS (2012) Role of mitochondrial Ca2+ in the regulation of cellular energetics. Biochemistry (Mosc) 51:2959–2973. Scholar
  165. 165.
    Shanmughapriya S, Rajan S, Hoffman NE et al (2015) Ca2+ signals regulate mitochondrial metabolism by stimulating CREB-mediated expression of the mitochondrial Ca2+ uniporter gene MCU. Sci Signal 8:ra23. Scholar
  166. 166.
    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 16:3078–3088CrossRefPubMedPubMedCentralGoogle Scholar
  167. 167.
    Wen H, Xu WJ, Jin X et al (2015) The roles of IP3 receptor in energy metabolic pathways and reactive oxygen species homeostasis revealed by metabolomic and biochemical studies. Biochim Biophys Acta 1853:2937–2944. Scholar
  168. 168.
    Cárdenas C, Miller RA, Smith I et al (2010) Essential regulation of cell bioenergetics by constitutive InsP3 receptor Ca2+ transfer to mitochondria. Cell 142:270–283. Scholar
  169. 169.
    Gómez-Suaga P, Paillusson S, Stoica R et al (2017) The ER-mitochondria tethering complex VAPB-PTPIP51 regulates autophagy. Curr Biol 27:371–385. Scholar
  170. 170.
    Bultynck G (2016) Onco-IP3Rs feed cancerous cravings for mitochondrial Ca2+. Trends Biochem Sci 41:390–393. Scholar
  171. 171.
    Cárdenas C, Müller M, McNeal A et al (2016) Selective vulnerability of cancer cells by inhibition of Ca2+ transfer from endoplasmic reticulum to mitochondria. Cell Rep 15:219–220. Scholar
  172. 172.
    Krols M, Bultynck G, Janssens S (2016) ER-Mitochondria contact sites: a new regulator of cellular calcium flux comes into play. J Cell Biol 214:367–370. Scholar
  173. 173.
    Raturi A, Gutiérrez T, Ortiz-Sandoval C et al (2016) TMX1 determines cancer cell metabolism as a thiol-based modulator of ER-mitochondria Ca2+ flux. J Cell Biol 214:433–444. Scholar
  174. 174.
    Granatiero V, Giorgio V, Calì T et al (2016) Reduced mitochondrial Ca2+ transients stimulate autophagy in human fibroblasts carrying the 13514A>G mutation of the ND5 subunit of NADH dehydrogenase. Cell Death Differ 23:231–241. Scholar
  175. 175.
    MacVicar TDB, Mannack LVJC, Lees RM, Lane JD (2015) Targeted siRNA screens identify ER-to-mitochondrial calcium exchange in autophagy and mitophagy responses in RPE1 cells. Int J Mol Sci 16:13356–13380. Scholar
  176. 176.
    Hayashi T, Su T-P (2007) Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca2+ signaling and cell survival. Cell 131:596–610. Scholar
  177. 177.
    Chan J, Yamazaki H, Ishiyama N et al (2010) Structural studies of inositol 1,4,5-trisphosphate receptor: coupling ligand binding to channel gating. J Biol Chem 285:36092–36099. Scholar
  178. 178.
    Williams A, Hayashi T, Wolozny D et al (2016) The non-apoptotic action of Bcl-xL: regulating Ca2+ signaling and bioenergetics at the ER-mitochondrion interface. J Bioenerg Biomembr 48:211–225. Scholar
  179. 179.
    Yang J, Vais H, Gu W, Foskett JK (2016) Biphasic regulation of InsP3 receptor gating by dual Ca2+ release channel BH3-like domains mediates Bcl-XL control of cell viability. Proc Natl Acad Sci USA 113:E1953–E1962. Scholar
  180. 180.
    Sung PJ, Tsai FD, Vais H et al (2013) Phosphorylated K-Ras limits cell survival by blocking Bcl-xL sensitization of inositol trisphosphate receptors. Proc Natl Acad Sci USA 110:20593–20598. Scholar
  181. 181.
    Mendes CCP, Gomes DA, Thompson M 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. Scholar
  182. 182.
    De Stefani D, Bononi A, Romagnoli A et al (2012) VDAC1 selectively transfers apoptotic Ca2+ signals to mitochondria. Cell Death Differ 19:267–273. Scholar
  183. 183.
    Akl H, Monaco G, La Rovere R et al (2013) IP3R2 levels dictate the apoptotic sensitivity of diffuse large B-cell lymphoma cells to an IP3R-derived peptide targeting the BH4 domain of Bcl-2. Cell Death Dis 4:e632. Scholar
  184. 184.
    Jayaraman T, Marks AR (1997) T cells deficient in inositol 1,4,5-trisphosphate receptor are resistant to apoptosis. Mol Cell Biol 17:3005–3012CrossRefPubMedPubMedCentralGoogle Scholar
  185. 185.
    Csordás G, Hajnóczky G (2001) Sorting of calcium signals at the junctions of endoplasmic reticulum and mitochondria. Cell Calcium 29:249–262. Scholar
  186. 186.
    Chami M, Oulès B, Szabadkai G et al (2008) Role of SERCA1 truncated isoform in the proapoptotic calcium transfer from ER to mitochondria during ER stress. Mol Cell 32:641–651. Scholar
  187. 187.
    Akl H, Vervloessem T, Kiviluoto S et al (2014) A dual role for the anti-apoptotic Bcl-2 protein in cancer: mitochondria versus endoplasmic reticulum. Biochim Biophys Acta 1843:2240–2252. Scholar
  188. 188.
    Greenberg EF, Lavik AR, Distelhorst CW (2014) Bcl-2 regulation of the inositol 1,4,5-trisphosphate receptor and calcium signaling in normal and malignant lymphocytes: potential new target for cancer treatment. Biochim Biophys Acta 1843:2205–2210. Scholar
  189. 189.
    Lewis A, Hayashi T, Su T-P, Betenbaugh MJ (2014) Bcl-2 family in inter-organelle modulation of calcium signaling; roles in bioenergetics and cell survival. J Bioenerg Biomembr 46:1–15. Scholar
  190. 190.
    Parys JB (2014) The IP3 receptor as a hub for Bcl-2 family proteins in cell death control and beyond. Sci Signal 7:pe4. Scholar
  191. 191.
    Vervliet T, Parys JB, Bultynck G (2016) Bcl-2 proteins and calcium signaling: complexity beneath the surface. Oncogene 35:5079–5092. Scholar
  192. 192.
    Rong Y-P, Aromolaran AS, Bultynck G et al (2008) Targeting Bcl-2-IP3 receptor interaction to reverse Bcl-2’s inhibition of apoptotic calcium signals. Mol Cell 31:255–265. Scholar
  193. 193.
    Monaco G, Decrock E, Akl H et al (2012) Selective regulation of IP3-receptor-mediated Ca2+ signaling and apoptosis by the BH4 domain of Bcl-2 versus Bcl-XL. Cell Death Differ 19:295–309. Scholar
  194. 194.
    Monaco G, Decrock E, Arbel N et al (2015) The BH4 domain of anti-apoptotic Bcl-XL, but not that of the related Bcl-2, limits the voltage-dependent anion channel 1 (VDAC1)-mediated transfer of pro-apoptotic Ca22+ signals to mitochondria. J Biol Chem 290:9150–9161. Scholar
  195. 195.
    Zhong F, Harr MW, Bultynck G et al (2011) Induction of Ca2+-driven apoptosis in chronic lymphocytic leukemia cells by peptide-mediated disruption of Bcl-2-IP3 receptor interaction. Blood 117:2924–2934. Scholar
  196. 196.
    Lavik AR, Zhong F, Chang M-J et al (2015) A synthetic peptide targeting the BH4 domain of Bcl-2 induces apoptosis in multiple myeloma and follicular lymphoma cells alone or in combination with agents targeting the BH3-binding pocket of Bcl-2. Oncotarget 6:27388–27402. Scholar
  197. 197.
    Greenberg EF, McColl KS, Zhong F et al (2015) Synergistic killing of human small cell lung cancer cells by the Bcl-2-inositol 1,4,5-trisphosphate receptor disruptor BIRD-2 and the BH3-mimetic ABT-263. Cell Death Dis 6:e2034. Scholar
  198. 198.
    Khan MT, Wagner L, Yule DI et al (2006) Akt kinase phosphorylation of inositol 1,4,5-trisphosphate receptors. J Biol Chem 281:3731–3737. Scholar
  199. 199.
    Marchi S, Rimessi A, Giorgi C et al (2008) Akt kinase reducing endoplasmic reticulum Ca2+ release protects cells from Ca2+-dependent apoptotic stimuli. Biochem Biophys Res Commun 375:501–505. Scholar
  200. 200.
    Szado T, Vanderheyden V, Parys JB 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. Scholar
  201. 201.
    Marchi S, Marinello M, Bononi A et al (2012) Selective modulation of subtype III IP3R by Akt regulates ER Ca2+ release and apoptosis. Cell Death Dis 3:e304. Scholar
  202. 202.
    Bononi A, Bonora M, Marchi S et al (2013) Identification of PTEN at the ER and MAMs and its regulation of Ca2+ signaling and apoptosis in a protein phosphatase-dependent manner. Cell Death Differ 20:1631–1643. Scholar
  203. 203.
    Kuchay S, Giorgi C, Simoneschi D et al (2017) PTEN counteracts FBXL2 to promote IP3R3- and Ca2+-mediated apoptosis limiting tumour growth. Nature 546:554–558. Scholar
  204. 204.
    Ilyin GP, Rialland M, Glaise D, Guguen-Guillouzo C (1999) Identification of a novel Skp2-like mammalian protein containing F-box and leucine-rich repeats. FEBS Lett 459:75–79CrossRefPubMedGoogle Scholar
  205. 205.
    Chen BB, Glasser JR, Coon TA, Mallampalli RK (2011) FBXL2 is a ubiquitin E3 ligase subunit that triggers mitotic arrest. Cell Cycle 10:3487–3494. Scholar
  206. 206.
    Chen BB, Glasser JR, Coon TA, Mallampalli RK (2012) F-box protein FBXL2 exerts human lung tumor suppressor-like activity by ubiquitin-mediated degradation of cyclin D3 resulting in cell cycle arrest. Oncogene 31:2566–2579. Scholar
  207. 207.
    Giorgi C, Ito K, Lin H-K et al (2010) PML regulates apoptosis at endoplasmic reticulum by modulating calcium release. Science 330:1247–1251. Scholar
  208. 208.
    Paillard M, Tubbs E, Thiebaut P-A et al (2013) Depressing mitochondria-reticulum interactions protects cardiomyocytes from lethal hypoxia-reoxygenation injury. Circulation 128:1555–1565. Scholar
  209. 209.
    Gomez L, Thiebaut P-A, Paillard M et al (2016) The SR/ER-mitochondria calcium crosstalk is regulated by GSK3β during reperfusion injury. Cell Death Differ 23:313–322. Scholar
  210. 210.
    Wiel C, Lallet-Daher H, Gitenay D et al (2014) Endoplasmic reticulum calcium release through ITPR2 channels leads to mitochondrial calcium accumulation and senescence. Nat Commun 5:3792. Scholar
  211. 211.
    Morgan AJ (2016) Ca2+ dialogue between acidic vesicles and ER. Biochem Soc Trans 44:546–553. Scholar
  212. 212.
    Morgan AJ, Platt FM, Lloyd-Evans E, Galione A (2011) Molecular mechanisms of endolysosomal Ca2+ signalling in health and disease. Biochem J 439:349–374. Scholar
  213. 213.
    Penny CJ, Kilpatrick BS, Eden ER, Patel S (2015) Coupling acidic organelles with the ER through Ca2+ microdomains at membrane contact sites. Cell Calcium 58:387–396. Scholar
  214. 214.
    Xu H, Ren D (2015) Lysosomal physiology. Annu Rev Physiol 77:57–80. Scholar
  215. 215.
    Melchionda M, Pittman JK, Mayor R, Patel S (2016) Ca2+/H+ exchange by acidic organelles regulates cell migration in vivo. J Cell Biol 212:803–813. Scholar
  216. 216.
    Patel S, Cai X (2015) Evolution of acidic Ca2+ stores and their resident Ca2+-permeable channels. Cell Calcium 57:222–230. Scholar
  217. 217.
    Galione A (2015) A primer of NAADP-mediated Ca2+ signalling: From sea urchin eggs to mammalian cells. Cell Calcium 58:27–47. Scholar
  218. 218.
    Morgan AJ, Davis LC, Ruas M, Galione A (2015) TPC: the NAADP discovery channel? Biochem Soc Trans 43:384–389. Scholar
  219. 219.
    Patel S (2015) Function and dysfunction of two-pore channels. Sci Signal 8:re7. Scholar
  220. 220.
    Allbritton NL, Meyer T, Stryer L (1992) Range of messenger action of calcium ion and inositol 1,4,5-trisphosphate. Science 258:1812–1815CrossRefPubMedGoogle Scholar
  221. 221.
    Sukumaran P, Schaar A, Sun Y, Singh BB (2016) Functional role of TRP channels in modulating ER stress and autophagy. Cell Calcium 60:123–132. Scholar
  222. 222.
    Waller-Evans H, Lloyd-Evans E (2015) Regulation of TRPML1 function. Biochem Soc Trans 43:442–446. Scholar
  223. 223.
    Wang W, Zhang X, Gao Q, Xu H (2014) TRPML1: an ion channel in the lysosome. Handb Exp Pharmacol 222:631–645. Scholar
  224. 224.
    Galione A (2011) NAADP receptors. Cold Spring Harb Perspect Biol 3:a004036. Scholar
  225. 225.
    Grimm C, Chen C-C, Wahl-Schott C, Biel M (2017) Two-pore channels: catalyzers of endolysosomal transport and function. Front Pharmacol 8:45. Scholar
  226. 226.
    Kilpatrick BS, Eden ER, Schapira AH et al (2013) Direct mobilisation of lysosomal Ca2+ triggers complex Ca2+ signals. J Cell Sci 126:60–66. Scholar
  227. 227.
    Fameli N, Ogunbayo OA, van Breemen C, Evans AM (2014) Cytoplasmic nanojunctions between lysosomes and sarcoplasmic reticulum are required for specific calcium signaling. F1000Research 3:93. Scholar
  228. 228.
    Lam AKM, Galione A (2013) The endoplasmic reticulum and junctional membrane communication during calcium signaling. Biochim Biophys Acta 1833:2542–2559. Scholar
  229. 229.
    Raiborg C, Wenzel EM, Stenmark H (2015) ER-endosome contact sites: molecular compositions and functions. EMBO J 34:1848–1858. Scholar
  230. 230.
    Cancela JM, Churchill GC, Galione A (1999) Coordination of agonist-induced Ca2+-signalling patterns by NAADP in pancreatic acinar cells. Nature 398:74–76. Scholar
  231. 231.
    Churchill GC, Galione A (2001) NAADP induces Ca2+ oscillations via a two-pool mechanism by priming IP3- and cADPR-sensitive Ca2+ stores. EMBO J 20:2666–2671. Scholar
  232. 232.
    Gerasimenko JV, Charlesworth RM, Sherwood MW et al (2015) Both RyRs and TPCs are required for NAADP-induced intracellular Ca2+ release. Cell Calcium 58:237–245. Scholar
  233. 233.
    Morgan AJ, Davis LC, Wagner SKTY et al (2013) Bidirectional Ca2+ signaling occurs between the endoplasmic reticulum and acidic organelles. J Cell Biol 200:789–805. Scholar
  234. 234.
    López Sanjurjo CI, Tovey SC, Taylor CW (2014) Rapid recycling of Ca2+ between IP3-sensitive stores and lysosomes. PloS One 9:e111275. Scholar
  235. 235.
    López-Sanjurjo CI, Tovey SC, Prole DL, Taylor CW (2013) Lysosomes shape Ins(1,4,5)P3-evoked Ca2+ signals by selectively sequestering Ca2+ released from the endoplasmic reticulum. J Cell Sci 126:289–300. Scholar
  236. 236.
    Kilpatrick BS, Yates E, Grimm C et al (2016) Endo-lysosomal TRP mucolipin-1 channels trigger global ER Ca2+ release and Ca2+ influx. J Cell Sci 129:3859–3867. Scholar
  237. 237.
    Decuypere J-P, Parys JB, Bultynck G (2015) ITPRs/inositol 1,4,5-trisphosphate receptors in autophagy: From enemy to ally. Autophagy 11:1944–1948. Scholar
  238. 238.
    Penny CJ, Kilpatrick BS, Han JM et al (2014) A computational model of lysosome-ER Ca2+ microdomains. J Cell Sci 127:2934–2943. Scholar
  239. 239.
    Raffaello A, Mammucari C, Gherardi G, Rizzuto R (2016) Calcium at the center of cell signaling: Interplay between endoplasmic reticulum, mitochondria, and lysosomes. Trends Biochem Sci 41:1035–1049. Scholar
  240. 240.
    Ronco V, Potenza DM, Denti F et al (2015) A novel Ca2+-mediated cross-talk between endoplasmic reticulum and acidic organelles: implications for NAADP-dependent Ca2+ signalling. Cell Calcium 57:89–100. Scholar
  241. 241.
    Gómez-Suaga P, Luzón-Toro B, Churamani D et al (2012) Leucine-rich repeat kinase 2 regulates autophagy through a calcium-dependent pathway involving NAADP. Hum Mol Genet 21:511–525. Scholar
  242. 242.
    Pereira GJS, Hirata H, Fimia GM et al (2011) Nicotinic acid adenine dinucleotide phosphate (NAADP) regulates autophagy in cultured astrocytes. J Biol Chem 286:27875–27881. Scholar
  243. 243.
    Lin P-H, Duann P, Komazaki S et al (2015) Lysosomal two-pore channel subtype 2 (TPC2) regulates skeletal muscle autophagic signaling. J Biol Chem 290:3377–3389. Scholar
  244. 244.
    Lu Y, Hao B-X, Graeff R et al (2013) Two pore channel 2 (TPC2) inhibits autophagosomal-lysosomal fusion by alkalinizing lysosomal pH. J Biol Chem 288:24247–24263. Scholar
  245. 245.
    Wong C-O, Li R, Montell C, Venkatachalam K (2012) Drosophila TRPML is required for TORC1 activation. Curr Biol 22:1616–1621. Scholar
  246. 246.
    Wang W, Gao Q, Yang M et al (2015) Up-regulation of lysosomal TRPML1 channels is essential for lysosomal adaptation to nutrient starvation. Proc Natl Acad Sci USA 112:E1373–E1381. Scholar
  247. 247.
    Li X, Rydzewski N, Hider A et al (2016) A molecular mechanism to regulate lysosome motility for lysosome positioning and tubulation. Nat Cell Biol 18:404–417. Scholar
  248. 248.
    García-Rúa V, Feijóo-Bandín S, Rodríguez-Penas D et al (2016) Endolysosomal two-pore channels regulate autophagy in cardiomyocytes. J Physiol 594:3061–3077. Scholar
  249. 249.
    Manzoni C (2017) The LRRK2-macroautophagy axis and its relevance to Parkinson’s disease. Biochem Soc Trans 45:155–162. Scholar
  250. 250.
    Hockey LN, Kilpatrick BS, Eden ER et al (2015) Dysregulation of lysosomal morphology by pathogenic LRRK2 is corrected by TPC2 inhibition. J Cell Sci 128:232–238. Scholar
  251. 251.
    Medina DL, Di Paola S, Peluso I et al (2015) Lysosomal calcium signalling regulates autophagy through calcineurin and TFEB. Nat Cell Biol 17:288–299. Scholar
  252. 252.
    Settembre C, Di Malta C, Polito VA et al (2011) TFEB links autophagy to lysosomal biogenesis. Science 332:1429–1433. Scholar
  253. 253.
    Medina DL, Fraldi A, Bouche V et al (2011) Transcriptional activation of lysosomal exocytosis promotes cellular clearance. Dev Cell 21:421–430. Scholar
  254. 254.
    Sardiello M, Palmieri M, di Ronza A et al (2009) A gene network regulating lysosomal biogenesis and function. Science 325:473–477. Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2017

Authors and Affiliations

  1. 1.Laboratory for Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine & Leuven Kanker InstituutKU LeuvenLeuvenBelgium

Personalised recommendations