The Role of Mitochondria in the Activation/Maintenance of SOCE: The Contribution of Mitochondrial Ca2+ Uptake, Mitochondrial Motility, and Location to Store-Operated Ca2+ Entry

  • Roland Malli
  • Wolfgang F. GraierEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 993)


In most cell types, the depletion of internal Ca2+ stores triggers the activation of Ca2+ entry. This crucial phenomenon is known since the 1980s and referred to as store-operated Ca2+ entry (SOCE). With the discoveries of the stromal-interacting molecules (STIMs) and the Ca2+-permeable Orai channels as the long-awaited molecular constituents of SOCE, the role of mitochondria in controlling the activity of this particular Ca2+ entry pathway is kind of buried in oblivion. However, the capability of mitochondria to locally sequester Ca2+ at sites of Ca2+ release and entry was initially supposed to rule SOCE by facilitating the Ca2+ depletion of the endoplasmic reticulum and removing entering Ca2+ from the Ca2+-inhibitable channels, respectively. Moreover, the central role of these organelles in controlling the cellular energy metabolism has been linked to the activity of SOCE. Nevertheless, the exact molecular mechanisms by which mitochondria actually determine SOCE are still pretty obscure. In this essay we describe the complexity of the mitochondrial Ca2+ uptake machinery and its regulation, molecular components, and properties, which open new ways for scrutinizing the contribution of mitochondria to SOCE. Moreover, data concerning the variability of the morphology and cellular distribution of mitochondria as putative determinants of SOCE activation, maintenance, and termination are summarized.


Mitochondria Endothelial nitric oxide synthase Ca2+ signaling Store-operated Ca2+ entry Mitochondrial Ca2+ uptake Uncoupling protein 2 MICU1 MCU Protein methylation 



The authors thank Karin Osibow for helpful comments and proofreading. Markus Waldeck-Weiermair provided data regarding the impact of Ca2+ on mitochondrial motility. The laboratory of WF Graier and R Malli is supported by the Austrian Science Funds, FWF (DKplus W 1226-B18 and P 28529-B27). Microscopic equipment is part of the Nikon Center of Excellence, Graz, that is supported by the Austrian infrastructure program 2013/2014, Nikon Austria Inc., and BioTechMed.


  1. Abramov AY, Fraley C, Diao CT, Winkfein R, Colicos MA, Duchen MR, French RJ, Pavlov E (2007) Targeted polyphosphatase expression alters mitochondrial metabolism and inhibits calcium-dependent cell death. Proc Natl Acad Sci U S A 104(46):18091–18096PubMedPubMedCentralCrossRefGoogle Scholar
  2. Aichberger KJ, Mittermann I, Reininger R, Seiberler S, Swoboda I, Spitzauer S, Kopp T, Stingl G, Sperr WR, Valent P, Repa A, Bohle B, Kraft D, Valenta R (2005) Hom s 4, an IgE-reactive autoantigen belonging to a new subfamily of calcium-binding proteins, can induce Th cell type 1-mediated autoreactivity. J Immunol 175(2):1286–1294PubMedCrossRefGoogle Scholar
  3. Alam MR, Groschner LN, Parichatikanond W, Kuo L, Bondarenko AI, Rost R, Waldeck-Weiermair M, Malli R, Graier WF (2012) Mitochondrial Ca2+ uptake 1 (MICU1) and mitochondrial Ca2+ uniporter (MCU) contribute to metabolism-secretion coupling in clonal pancreatic β-cells. J Biol Chem 287(41):34445–34454PubMedPubMedCentralCrossRefGoogle Scholar
  4. Arnaudeau S, Kelley WL, Walsh JV Jr, Demaurex N (2001) Mitochondria recycle Ca2+ to the endoplasmic reticulum and prevent the depletion of neighboring endoplasmic reticulum regions. J Biol Chem 276(31):29430–29439PubMedCrossRefGoogle Scholar
  5. Baughman JM, Perocchi F, Girgis HS, Plovanich M, Belcher-Timme CA, Sancak Y, Bao R, Strittmatter L, Goldberger O, Bogorad RL, Koteliansky V, Mootha VK (2011) Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter. Nature 476(7360):341–345PubMedPubMedCentralCrossRefGoogle Scholar
  6. Bernardi P (1999) Mitochondrial transport of cations: channels, exchangers, and permeability transition. Physiol Rev 79(4):1127–1155PubMedGoogle Scholar
  7. Berridge MJ, Lipp P, Bootman MD (2000) The versatility and universality of calcium signalling. Nat Rev Mol Cell Biol 1(1):11–21PubMedCrossRefGoogle Scholar
  8. Bolotina VM (2008) Orai, STIM1 and iPLA2beta: a view from a different perspective. J Physiol (Lond) 586(13):3035–3042CrossRefGoogle Scholar
  9. Bolotina VM, Csutora P (2005) CIF and other mysteries of the store-operated Ca2+-entry pathway. Trends Biochem Sci 30(7):378–387PubMedCrossRefGoogle Scholar
  10. Bondarenko AI, Jean-Quartier C, Malli R, Graier WF (2013) Characterization of distinct single-channel properties of Ca2+ inward currents in mitochondria. Pflugers Arch 465(7):997–1010PubMedPubMedCentralCrossRefGoogle Scholar
  11. Bondarenko AI, Jean-Quartier C, Parichatikanond W, Alam MR, Waldeck-Weiermair M, Malli R, Graier WF (2014) Mitochondrial Ca2+ uniporter (MCU)-dependent and MCU-independent Ca2+ channels coexist in the inner mitochondrial membrane. Pflugers Arch 466(7):1411–1420PubMedCrossRefGoogle Scholar
  12. Bootman MD, Collins TJ, Peppiatt CM, Prothero LS, MacKenzie L, De Smet P, Travers M, Tovey SC, Seo JT, Berridge MJ, Ciccolini F, Lipp P (2001) Calcium signalling—an overview. Semin Cell Dev Biol 12(1):3–10PubMedCrossRefGoogle Scholar
  13. Brandman O, Liou J, Park WS, Meyer T (2007) STIM2 is a feedback regulator that stabilizes basal cytosolic and endoplasmic reticulum Ca2+ levels. Cell 131(7):1327–1339PubMedPubMedCentralCrossRefGoogle Scholar
  14. Braschi E, McBride HM (2010) Mitochondria and the culture of the Borg: understanding the integration of mitochondrial function within the reticulum, the cell, and the organism. Bioessays 32(11):958–966PubMedPubMedCentralCrossRefGoogle Scholar
  15. Carafoli E (2002) Calcium signaling: a tale for all seasons. Proc Natl Acad Sci U S A 99(3):1115–1122PubMedPubMedCentralCrossRefGoogle Scholar
  16. Charoensin S, Eroglu E, Opelt M, Bischof H, Madreiter-Sokolowski CT, Kirsch A, Depaoli MR, Frank S, Schrammel A, Mayer B, Waldeck-Weiermair M, Graier WF, Malli R (2017) Intact mitochondrial Ca2+ uniport is essential for agonist-induced activation of endothelial nitric oxide synthase (eNOS). Free Radic Biol Med 102:248–259PubMedCrossRefGoogle Scholar
  17. Chvanov M, Walsh CM, Haynes LP, Voronina SG, Lur G, Gerasimenko OV, Barraclough R, Rudland PS, Petersen OH, Burgoyne RD, Tepikin AV (2008) ATP depletion induces translocation of STIM1 to puncta and formation of STIM1-ORAI1 clusters: translocation and re-translocation of STIM1 does not require ATP. Pflugers Arch 457(2):505–517PubMedPubMedCentralCrossRefGoogle Scholar
  18. Cosson P, Marchetti A, Ravazzola M, Orci L (2012) Mitofusin-2 independent juxtaposition of endoplasmic reticulum and mitochondria: an ultrastructural study. PLoS One 7:e46293PubMedPubMedCentralCrossRefGoogle Scholar
  19. Csordas G, Renken C, Varnai P, Walter L, Weaver D, Buttle KF, Balla T, Mannella CA, Hajnoczky G (2006) Structural and functional features and significance of the physical linkage between ER and mitochondria. J Cell Biol 174(7):915–921PubMedPubMedCentralCrossRefGoogle Scholar
  20. Csordas G, Varnai P, Golenar T, Roy S, Purkins G, Schneider TG, Balla T, Hajnoczky G (2010) Imaging interorganelle contacts and local calcium dynamics at the ER-mitochondrial interface. Mol Cell 39(1):121–132PubMedPubMedCentralCrossRefGoogle Scholar
  21. Deak AT, Blass S, Khan MJ, Groschner LN, Waldeck-Weiermair M, Hallström S, Graier WF, Malli R (2014) IP3-mediated STIM1 oligomerization requires intact mitochondrial Ca2+ uptake. J Cell Sci 127(Pt 13):2944–2955PubMedPubMedCentralCrossRefGoogle Scholar
  22. de Brito OM, Scorrano L (2008) Mitofusin 2 tethers endoplasmic reticulum to mitochondria. Nature 456(7222):605–610PubMedCrossRefGoogle Scholar
  23. DeHaven WI, Smyth JT, Boyles RR, Putney JW Jr (2007) Calcium inhibition and calcium potentiation of Orai1, Orai2, and Orai3 calcium release-activated calcium channels. J Biol Chem 282(24):17548–17556PubMedCrossRefGoogle Scholar
  24. DeLuca H, Engstrom G (1961) Calcium uptake by rat kidney mitochondria. Proc Natl Acad Sci U S A 47:1744–1750PubMedPubMedCentralCrossRefGoogle Scholar
  25. Demaurex N, Poburko D, Frieden M (2009) Regulation of plasma membrane calcium fluxes by mitochondria. Biochim Biophys Acta 1787(11):1383–1394PubMedCrossRefGoogle Scholar
  26. De Stefani D, Rizzuto R (2015) Structure and function of the mitochondrial calcium uniporter complex. Biochim Biophys Acta 1853(9):2006–2011PubMedPubMedCentralCrossRefGoogle Scholar
  27. De Stefani D, Raffaello A, Teardo E, Szabo I, Rizzuto R (2011) A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter. Nature 476(7360):336–340PubMedPubMedCentralCrossRefGoogle Scholar
  28. Dolmetsch RE, Xu K, Lewis RS (1998) Calcium oscillations increase the efficiency and specificity of gene expression. Nature 392(6679):933–936PubMedCrossRefGoogle Scholar
  29. Duchen MR, Verkhratsky A, Muallem S (2008) Mitochondria and calcium in health and disease. Cell Calcium 44(1):1–5PubMedCrossRefGoogle Scholar
  30. Elustondo PA, Nichols M, Robertson GS, Pavlov EV (2016) Mitochondrial Ca2+ uptake pathways. J Bioenerg Biomembr 49(1):113–119PubMedCrossRefGoogle Scholar
  31. Feldman B, Fedida-Metula S, Nita J, Sekler I, Fishman D (2010) Coupling of mitochondria to store-operated Ca2+-signaling sustains constitutive activation of protein kinase B/Akt and augments survival of malignant melanoma cells. Cell Calcium 47(6):525–537PubMedCrossRefGoogle Scholar
  32. Feske S (2007) Calcium signalling in lymphocyte activation and disease. Nat Rev Immunol 7(9):690–702PubMedCrossRefGoogle Scholar
  33. Fieni F, Lee SB, Jan YN, Kirichok Y (2012) Activity of the mitochondrial calcium uniporter varies greatly between tissues. Nat Commun 3:1317PubMedPubMedCentralCrossRefGoogle Scholar
  34. Filadi R, Greotti E, Turacchio G, Luini A, Pozzan T, Pizzo P (2015) Mitofusin 2 ablation increases endoplasmic reticulum-mitochondria coupling. Proc Natl Acad Sci U S A 112(17):E2174–E2181PubMedPubMedCentralCrossRefGoogle Scholar
  35. Fomina AF, Nowycky MC (1999) A current activated on depletion of intracellular Ca2+ stores can regulate exocytosis in adrenal chromaffin cells. J Neurosci 19(10):3711–3722PubMedGoogle Scholar
  36. Frazier AE, Taylor RD, Mick DU, Warscheid B, Stoepel N, Meyer HE, Ryan MT, Guiard B, Rehling P (2006) Mdm38 interacts with ribosomes and is a component of the mitochondrial protein export machinery. J Cell Biol 172(4):553–564PubMedPubMedCentralCrossRefGoogle Scholar
  37. Frieden M, James D, Castelbou C, Danckaert A, Martinou JC, Demaurex N (2004) Ca2+ homeostasis during mitochondrial fragmentation and perinuclear clustering induced by hFis1. J Biol Chem 279(21):22704–22714PubMedCrossRefGoogle Scholar
  38. Frischauf I, Schindl R, Derler I, Bergsmann J, Fahrner M, Romanin C (2008) The STIM/Orai coupling machinery. Channels (Austin) 2(4):261–268CrossRefGoogle Scholar
  39. Giacomello M, Drago I, Bortolozzi M, Scorzeto M, Gianelle A, Pizzo P, Pozzan T (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(2):280–290PubMedCrossRefGoogle Scholar
  40. Gilabert JA, Parekh AB (2000) Respiring mitochondria determine the pattern of activation and inactivation of the store-operated Ca2+ current ICRAC. EMBO J 19(23):6401–6407PubMedPubMedCentralCrossRefGoogle Scholar
  41. Gilabert JA, Bakowski D, Parekh AB (2001) Energized mitochondria increase the dynamic range over which inositol 1,4,5-trisphosphate activates store-operated calcium influx. EMBO J 20(11):2672–2679PubMedPubMedCentralCrossRefGoogle Scholar
  42. Graier WF, Frieden M, Malli R (2007) Mitochondria and Ca2+ signaling: old guests, new functions. Pflugers Arch 455(3):375–396PubMedPubMedCentralCrossRefGoogle Scholar
  43. Graier W, Trenker M, Malli R (2008) Mitochondrial Ca2+, the secret behind the function of uncoupling proteins 2 and 3? Cell Calcium 44(1):36–50PubMedPubMedCentralCrossRefGoogle Scholar
  44. Gunter TE, Sheu SS (2009) Characteristics and possible functions of mitochondrial Ca2+ transport mechanisms. Biochim Biophys Acta 1787(11):1291–1308PubMedPubMedCentralCrossRefGoogle Scholar
  45. Gunter TE, Buntinas L, Sparagna G, Eliseev R, Gunter K (2000) Mitochondrial calcium transport: mechanisms and functions. Cell Calcium 28(5–6):285–296PubMedCrossRefGoogle Scholar
  46. Hajnoczky G, Csordas G (2010) Calcium signalling: fishing out molecules of mitochondrial calcium transport. Curr Biol 20(20):R888–R891PubMedPubMedCentralCrossRefGoogle Scholar
  47. Hajnoczky G, Hager R, Thomas AP (1999) Mitochondria suppress local feedback activation of inositol 1,4, 5-trisphosphate receptors by Ca2+. J Biol Chem 274(20):14157–14162PubMedCrossRefGoogle Scholar
  48. Hajnoczky G, Csordas G, Das S, Garcia-Perez C, Saotome M, Sinha Roy S, Yi M (2006) Mitochondrial calcium signalling and cell death: approaches for assessing the role of mitochondrial Ca2+ uptake in apoptosis. Cell Calcium 40(5–6):553–560PubMedPubMedCentralCrossRefGoogle Scholar
  49. Han XJ, Lu YF, Li S-A, Kaitsuka T, Sato Y, Tomizawa K, Nairn AC, Takei K, Matsui H, Matsushita M (2008) CaM kinase I alpha-induced phosphorylation of Drp1 regulates mitochondrial morphology. J Cell Biol 182(3):573–585PubMedPubMedCentralCrossRefGoogle Scholar
  50. Hooper R, Samakai E, Kedra J, Soboloff J (2013) Multifaceted roles of STIM proteins. Pflugers Arch 465(10):1383–1396PubMedPubMedCentralCrossRefGoogle Scholar
  51. Hoth M, Fanger CM, Lewis RS (1997) Mitochondrial regulation of store-operated calcium signaling in T lymphocytes. J Cell Biol 137(3):633–648PubMedPubMedCentralCrossRefGoogle Scholar
  52. Hoth M, Button DC, Lewis RS (2000) Mitochondrial control of calcium-channel gating: a mechanism for sustained signaling and transcriptional activation in T lymphocytes. Proc Natl Acad Sci U S A 97(19):10607–10612PubMedPubMedCentralCrossRefGoogle Scholar
  53. Huberts DHEW, van der Klei IJ (2010) Moonlighting proteins: an intriguing mode of multitasking. Biochim Biophys Acta 1803(4):520–525PubMedCrossRefGoogle Scholar
  54. Jiang D, Zhao L, Clapham DE (2009) Genome-wide RNAi screen identifies Letm1 as a mitochondrial Ca2+/H+ antiporter. Science 326(5949):144–147PubMedPubMedCentralCrossRefGoogle Scholar
  55. Kamer KJ, Mootha VK (2014) MICU1 and MICU2 play nonredundant roles in the regulation of the mitochondrial calcium uniporter. EMBO Rep 15(3):299–307PubMedPubMedCentralCrossRefGoogle Scholar
  56. Kamer KJ, Sancak Y, Mootha VK (2014) The uniporter: from newly identified parts to function. Biochem Biophys Res Commun 449(4):370–372PubMedCrossRefGoogle Scholar
  57. Kirichok Y, Krapivinsky G, Clapham DE (2004) The mitochondrial calcium uniporter is a highly selective ion channel. Nature 427(6972):360–364PubMedCrossRefGoogle Scholar
  58. Knot HJ, Laher I, Sobie EA, Guatimosim S, Gomez-Viquez L, Hartmann H, Song LS, Lederer WJ, Graier WF, Malli R, Frieden M, Petersen OH (2005) Twenty years of calcium imaging: cell physiology to dye for. Mol Interv 5(2):112–127PubMedPubMedCentralCrossRefGoogle Scholar
  59. Koziel K, Lebiedzinska M, Szabadkai G, Onopiuk M, Brutkowski W, Wierzbicka K, Wilczynski G, Pinton P, Duszynski J, Zablocki K, Wieckowski MR (2009) Plasma membrane associated membranes (PAM) from Jurkat cells contain STIM1 protein is PAM involved in the capacitative calcium entry? Int J Biochem Cell Biol 41(12):2440–2449PubMedCrossRefGoogle Scholar
  60. Lampe PA, Cornbrooks EB, Juhasz A, Johnson EM, Franklin JL (1995) Suppression of programmed neuronal death by a thapsigargin-induced Ca2+ influx. J Neurobiol 26(2):205–212PubMedCrossRefGoogle Scholar
  61. Lebiedzinska M, Szabadkai G, Jones AWE, Duszynski J, Wieckowski MR (2009) Interactions between the endoplasmic reticulum, mitochondria, plasma membrane and other subcellular organelles. Int J Biochem Cell Biol 41(10):1805–1816PubMedCrossRefGoogle Scholar
  62. Lin S, Fagan KA, Li KX, Shaul PW, Cooper DM, Rodman DM (2000) Sustained endothelial nitric-oxide synthase activation requires capacitative Ca2+ entry. J Biol Chem 275(24):17979–17985PubMedCrossRefGoogle Scholar
  63. Liou J, Kim ML, Heo WD, Jones JT, Myers JW, Ferrell JE Jr, Meyer T (2005) STIM is a Ca2+ sensor essential for Ca2+-store-depletion-triggered Ca2+ influx. Curr Biol 15(13):1235–1241PubMedPubMedCentralCrossRefGoogle Scholar
  64. Liu X, Weaver D, Shirihai O, Hajnoczky G (2009) Mitochondrial ‘kiss-and-run’: interplay between mitochondrial motility and fusion-fission dynamics. EMBO J 28(20):3074–3089PubMedPubMedCentralCrossRefGoogle Scholar
  65. Madreiter-Sokolowski CT, Gottschalk B, Parichatikanond W, Eroglu E, Klec C, Waldeck-Weiermair M, Malli R, Graier WF (2016a) Resveratrol specifically kills cancer cells by a devastating increase in the Ca2+ coupling between the greatly tethered endoplasmic reticulum and mitochondria. Cell Physiol Biochem 39(4):1404–1420PubMedPubMedCentralCrossRefGoogle Scholar
  66. Madreiter-Sokolowski CT, Klec C, Parichatikanond W, Stryeck S, Gottschalk B, Pulido S, Rost R, Eroglu E, Hofmann NA, Bondarenko AI, Madl T, Waldeck-Weiermair M, Malli R, Graier WF (2016b) PRMT1-mediated methylation of MICU1 determines the UCP2/3 dependency of mitochondrial Ca2+ uptake in immortalized cells. Nat Commun 7:12897PubMedPubMedCentralCrossRefGoogle Scholar
  67. Malli R, Graier WF (2010) Mitochondrial Ca2+ channels: great unknowns with important functions. FEBS Lett 584(10):1942–1947PubMedPubMedCentralCrossRefGoogle Scholar
  68. Malli R, Frieden M, Osibow K, Graier WF (2003a) Mitochondria efficiently buffer subplasmalemmal Ca2+ elevation during agonist stimulation. J Biol Chem 278(12):10807–10815PubMedCrossRefGoogle Scholar
  69. Malli R, Frieden M, Osibow K, Zoratti C, Mayer M, Demaurex N, Graier WF (2003b) Sustained Ca2+ transfer across mitochondria is essential for mitochondrial Ca2+ buffering, store-operated Ca2+ entry, and Ca2+ store refilling. J Biol Chem 278(45):44769–44779PubMedCrossRefGoogle Scholar
  70. Malli R, Frieden M, Trenker M, Graier WF (2005) The role of mitochondria for Ca2+ refilling of the endoplasmic reticulum. J Biol Chem 280(13):12114–12122PubMedCrossRefGoogle Scholar
  71. Malli R, Naghdi S, Romanin C, Graier WF (2008) Cytosolic Ca2+ prevents the subplasmalemmal clustering of STIM1: an intrinsic mechanism to avoid Ca2+ overload. J Cell Sci 121(Pt 19):3133–3139PubMedPubMedCentralCrossRefGoogle Scholar
  72. Mallilankaraman K, Cardenas C, Doonan PJ, Chandramoorthy HC, Irrinki KM, Golenar T, Csordas G, Madireddi P, Yang J, Müller M, Miller R, Kolesar JE, Molgo J, Kaufman B, Hajnoczky G, Foskett JK, Madesh M (2012) MCUR1 is an essential component of mitochondrial Ca2+ uptake that regulates cellular metabolism. Nat Cell Biol 14(12):1336–1343PubMedPubMedCentralCrossRefGoogle Scholar
  73. McBride HM, Neuspiel M, Wasiak S (2006) Mitochondria: more than just a powerhouse. Curr Biol 16(14):R551–R560PubMedCrossRefGoogle Scholar
  74. McFadzean I, Gibson A (2002) The developing relationship between receptor-operated and store-operated calcium channels in smooth muscle. Br J Pharmacol 135(1):1–13PubMedPubMedCentralCrossRefGoogle Scholar
  75. Michalak M, Robert Parker JM, Opas M (2002) Ca2+ signaling and calcium binding chaperones of the endoplasmic reticulum. Cell Calcium 32(5–6):269–278PubMedCrossRefGoogle Scholar
  76. Michels G, Khan IF, Endres-Becker J, Rottlaender D, Herzig S, Ruhparwar A, Wahlers T, Hoppe UC (2009) Regulation of the human cardiac mitochondrial Ca2+ uptake by 2 different voltage-gated Ca2+ channels. Circulation 119(18):2435–2443PubMedCrossRefGoogle Scholar
  77. Montalvo GB, Artalejo AR, Gilabert JA (2006) ATP from subplasmalemmal mitochondria controls Ca2+-dependent inactivation of CRAC channels. J Biol Chem 281(47):35616–35623PubMedCrossRefGoogle Scholar
  78. Muik M, Frischauf I, Derler I, Fahrner M, Bergsmann J, Eder P, Schindl R, Hesch C, Polzinger B, Fritsch R, Kahr H, Madl J, Gruber H, Groschner K, Romanin C (2008) Dynamic coupling of the putative coiled-coil domain of ORAI1 with STIM1 mediates ORAI1 channel activation. J Biol Chem 283(12):8014–8022PubMedCrossRefGoogle Scholar
  79. Nagai T, Sawano A, Park ES, Miyawaki A (2001) Circularly permuted green fluorescent proteins engineered to sense Ca2+. Proc Natl Acad Sci U S A 98(6):3197–3202PubMedPubMedCentralCrossRefGoogle Scholar
  80. Naghdi S, Waldeck-Weiermair M, Fertschai I, Poteser M, Graier WF, Malli R (2010) Mitochondrial Ca2+ uptake and not mitochondrial motility is required for STIM1-Orai1-dependent store-operated Ca2+ entry. J Cell Sci 123(Pt 15):2553–2564PubMedCrossRefGoogle Scholar
  81. Nicholls DG (2005) Mitochondria and calcium signaling. Cell Calcium 38(3–4):311–317PubMedCrossRefGoogle Scholar
  82. Nowikovsky K, Froschauer EM, Zsurka G, Samaj J, Reipert S, Kolisek M, Wiesenberger G, Schweyen RJ (2004) The LETM1/YOL027 gene family encodes a factor of the mitochondrial K+ homeostasis with a potential role in the Wolf-Hirschhorn syndrome. J Biol Chem 279(29):30307–30315PubMedCrossRefGoogle Scholar
  83. Osibow K, Frank S, Malli R, Zechner R, Graier WF (2006) Mitochondria maintain maturation and secretion of lipoprotein lipase in the endoplasmic reticulum. Biochem J 396(1):173–182PubMedPubMedCentralCrossRefGoogle Scholar
  84. Palty R, Silverman WF, Hershfinkel M, Caporale T, Sensi SL, Parnis J, Nolte C, Fishman D, Shoshan-Barmatz V, Herrmann S, Khananshvili D, Sekler I (2010) NCLX is an essential component of mitochondrial Na+/Ca2+ exchange. Proc Natl Acad Sci U S A 107(1):436–441PubMedCrossRefGoogle Scholar
  85. Parekh AB (1998) Slow feedback inhibition of calcium release-activated calcium current by calcium entry. J Biol Chem 273(24):14925–14932PubMedCrossRefGoogle Scholar
  86. Parekh AB (2008) Mitochondrial regulation of store-operated CRAC channels. Cell Calcium 44(1):6–13PubMedCrossRefGoogle Scholar
  87. Parekh AB, Putney JW Jr (2005) Store-operated calcium channels. Physiol Rev 85(2):757–810PubMedCrossRefGoogle Scholar
  88. Patron M, Checchetto V, Raffaello A, Teardo E, Vecellio Reane D, Mantoan M, Granatiero V, Szabo I, De Stefani D, Rizzuto R (2014) MICU1 and MICU2 finely tune the mitochondrial Ca2+ uniporter by exerting opposite effects on MCU activity. Mol Cell 53(5):726–737PubMedPubMedCentralCrossRefGoogle Scholar
  89. Penna A, Demuro A, Yeromin AV, Zhang SL, Safrina O, Parker I, Cahalan MD (2008) The CRAC channel consists of a tetramer formed by Stim-induced dimerization of Orai dimers. Nature 456(7218):116–120PubMedPubMedCentralCrossRefGoogle Scholar
  90. Perocchi F, Gohil VM, Girgis HS, Bao XR, McCombs JE, Palmer AE, Mootha VK (2010) MICU1 encodes a mitochondrial EF hand protein required for Ca2+ uptake. Nature 467(7313):291–296PubMedPubMedCentralCrossRefGoogle Scholar
  91. Piao L, Li Y, Kim SJ, Sohn KC, Yang KJ, Park KA, Byun HS, Won M, Hong J, Hur GM, Seok JH, Shong M, Sack R, Brazil DP, Hemmings BA, Park J (2009) Regulation of OPA1-mediated mitochondrial fusion by leucine zipper/EF-hand-containing transmembrane protein-1 plays a role in apoptosis. Cell Signal 21(5):767–777PubMedCrossRefGoogle Scholar
  92. Plovanich M, Bogorad RL, Sancak Y, Kamer KJ, Strittmatter L, Li AA, Girgis HS, Kuchimanchi S, De Groot S, Speciner L, Taneja N, OShea J, Koteliansky V, Mootha VK (2013) MICU2, a paralog of MICU1, resides within the mitochondrial uniporter complex to regulate calcium handling. PLoS One 8:e55785PubMedPubMedCentralCrossRefGoogle Scholar
  93. Potier M, Gonzalez JC, Motiani RK, Abdullaev IF, Bisaillon JM, Singer HA, Trebak M (2009) Evidence for STIM1- and Orai1-dependent store-operated calcium influx through ICRAC in vascular smooth muscle cells: role in proliferation and migration. FASEB J 23(8):2425–2437PubMedPubMedCentralCrossRefGoogle Scholar
  94. Putney JW Jr (1986) A model for receptor-regulated calcium entry. Cell Calcium 7(1):1–12PubMedCrossRefGoogle Scholar
  95. Putney JW Jr (1990) Capacitative calcium entry revisited. Cell Calcium 11(10):611–624PubMedCrossRefGoogle Scholar
  96. Putney JW Jr (1991) The capacitative model for receptor-activated calcium entry. Adv Pharmacol 22:251–269PubMedCrossRefGoogle Scholar
  97. Quintana A, Schwindling C, Wenning AS, Becherer U, Rettig J, Schwarz EC, Hoth M (2007) T cell activation requires mitochondrial translocation to the immunological synapse. Proc Natl Acad Sci U S A 104(36):14418–14423PubMedPubMedCentralCrossRefGoogle Scholar
  98. Raffaello A, De Stefani D, Sabbadin D, Teardo E, Merli G, Picard A, Checchetto V, Moro S, Szabo I, Rizzuto R (2013) The mitochondrial calcium uniporter is a multimer that can include a dominant-negative pore-forming subunit. EMBO J 32(17):2362–2376PubMedPubMedCentralCrossRefGoogle Scholar
  99. Rizzuto R, Simpson AW, Brini M, Pozzan T (1992) Rapid changes of mitochondrial Ca2+ revealed by specifically targeted recombinant aequorin. Nature 358(6384):325–327PubMedCrossRefGoogle Scholar
  100. Rizzuto R, Pinton P, Carrington W, Fay FS, Fogarty KE, Lifshitz LM, Tuft RA, Pozzan T (1998) Close contacts with the endoplasmic reticulum as determinants of mitochondrial Ca2+ responses. Science 280(5370):1763–1766PubMedCrossRefGoogle Scholar
  101. Roos J, DiGregorio PJ, Yeromin AV, Ohlsen K, Lioudyno M, Zhang S, Safrina O, Kozak JA, Wagner SL, Cahalan MD, Velicelebi G, Stauderman KA (2005) STIM1, an essential and conserved component of store-operated Ca2+ channel function. J Cell Biol 169(3):435–445PubMedPubMedCentralCrossRefGoogle Scholar
  102. Sancak Y, Markhard AL, Kitami T, Kovacs-Bogdan E, Kamer KJ, Udeshi ND, Carr SA, Chaudhuri D, Clapham DE, Li AA, Calvo SE, Goldberger O, Mootha VK (2013) EMRE is an essential component of the mitochondrial calcium uniporter complex. Science 342(6164):1379–1382PubMedPubMedCentralCrossRefGoogle Scholar
  103. Saotome M, Safiulina D, Szabadkai G, Das S, Fransson A, Aspenstrom P, Rizzuto R, Hajnoczky G (2008) Bidirectional Ca2+-dependent control of mitochondrial dynamics by the Miro GTPase. Proc Natl Acad Sci U S A 105(52):20728–20733PubMedPubMedCentralCrossRefGoogle Scholar
  104. Scarpa A, Graziotti P (1973) Mechanisms for intracellular calcium regulation in heart. I. Stopped-flow measurements of Ca2+ uptake by cardiac mitochondria. J Gen Physiol 62(6):756–772PubMedPubMedCentralCrossRefGoogle Scholar
  105. Singaravelu K, Nelson C, Bakowski D, Martins de Brito O, Ng SW, Di Capite J, Powell T, Scorrano L, Parekh AB (2011) Mitofusin 2 regulates STIM1 migration from the Ca2+ store to the plasma membrane in cells with depolarised mitochondria. J Biol Chem 286(14):12189–12201PubMedPubMedCentralCrossRefGoogle Scholar
  106. Soboloff J, Rothberg BS, Madesh M, Gill DL (2012) STIM proteins: dynamic calcium signal transducers. Nat Rev Mol Cell Biol 13(9):549–565PubMedPubMedCentralCrossRefGoogle Scholar
  107. Spät A, Szanda G, Csordas G, Hajnoczky G (2008) High- and low-calcium-dependent mechanisms of mitochondrial calcium signalling. Cell Calcium 44(1):51–63PubMedPubMedCentralCrossRefGoogle Scholar
  108. Szabadkai G, Duchen MR (2008) Mitochondria: the hub of cellular Ca2+ signaling. Physiology (Bethesda) 23:84–94CrossRefGoogle Scholar
  109. Tomar D, Dong Z, Shanmughapriya S, Koch DA, Thomas T, Hoffman NE, Timbalia SA, Goldman SJ, Breves SL, Corbally DP, Nemani N, Fairweather JP, Cutri AR, Zhang X, Song J, Jan F, Huang J, Barrero C, Rabinowitz JE, Luongo TS, Schumacher SM, Rockman ME, Dietrich A, Merali S, Caplan J, Stathopulos P, Ahima RS, Cheung JY, Houser SR, Koch WJ, Patel V, Gohil VM, Elrod JW, Rajan S, Madesh M (2016) MCUR1 is a scaffold factor for the MCU complex function and promotes mitochondrial bioenergetics. Cell Rep 15(8):1673–1685PubMedPubMedCentralCrossRefGoogle Scholar
  110. Trenker M, Malli R, Fertschai I, Levak-Frank S, Graier WF (2007) Uncoupling proteins 2 and 3 are fundamental for mitochondrial Ca2+ uniport. Nat Cell Biol 9(4):445–452PubMedPubMedCentralCrossRefGoogle Scholar
  111. Trenker M, Fertschai I, Malli R, Graier WF (2008) UCP2/3—likely to be fundamental for mitochondrial Ca2+ uniport. Nat Cell Biol 10(11):1237–1240CrossRefGoogle Scholar
  112. Varadi A, Cirulli V, Rutter GA (2004) Mitochondrial localization as a determinant of capacitative Ca2+ entry in HeLa cells. Cell Calcium 36(6):499–508PubMedCrossRefGoogle Scholar
  113. Varnai P, Toth B, Toth DJ, Hunyady L, Balla T (2007) Visualization and manipulation of plasma membrane-endoplasmic reticulum contact sites indicates the presence of additional molecular components within the STIM1-Orai1 Complex. J Biol Chem 282(40):29678–29690PubMedCrossRefGoogle Scholar
  114. Varnai P, Hunyady L, Balla T (2009) STIM and Orai: the long-awaited constituents of store-operated calcium entry. Trends Pharmacol Sci 30(3):118–128PubMedPubMedCentralCrossRefGoogle Scholar
  115. Vasington FD, Murphy J (1962) Ca2+ ion uptake by rat kidney mitochondria and its dependence on respiration and phosphorylation. J Biol Chem 237:2670–2677PubMedGoogle Scholar
  116. Waldeck-Weiermair M, Duan X, Naghdi S, Khan MJ, Trenker M, Malli R, Graier WF (2010a) Uncoupling protein 3 adjusts mitochondrial Ca2+ uptake to high and low Ca2+ signals. Cell Calcium 48(5):288–301PubMedPubMedCentralCrossRefGoogle Scholar
  117. Waldeck-Weiermair M, Malli R, Naghdi S, Trenker M, Kahn MJ, Graier WF (2010b) The contribution of UCP2 and UCP3 to mitochondrial Ca2+ uptake is differentially determined by the source of supplied Ca2+. Cell Calcium 47(5):433–440PubMedCrossRefGoogle Scholar
  118. Waldeck-Weiermair M, Jean-Quartier C, Rost R, Khan MJ, Vishnu N, Bondarenko AI, Imamura H, Malli R, Graier WF (2011) The leucine zipper EF hand-containing transmembrane protein 1 (LETM1) and uncoupling proteins 2 and 3 (UCP2/3) contribute to two distinct mitochondrial Ca2+ uptake pathways. J Biol Chem 286(32):28444–28455PubMedPubMedCentralCrossRefGoogle Scholar
  119. Waldeck-Weiermair M, Malli R, Parichatikanond W, Gottschalk B, Madreiter-Sokolowski CT, Klec C, Rost R, Graier WF (2015) Rearrangement of MICU1 multimers for activation of MCU is solely controlled by cytosolic Ca2+. Sci Rep 5:15602PubMedPubMedCentralCrossRefGoogle Scholar
  120. Walsh C, Barrow S, Voronina S, Chvanov M, Petersen OH, Tepikin A (2009) Modulation of calcium signalling by mitochondria. Biochim Biophys Acta 1787(11):1374–1382PubMedCrossRefGoogle Scholar
  121. Wang L, Yang X, Li S, Wang Z, Liu Y, Feng J, Zhu Y, Shen Y (2014) Structural and mechanistic insights into MICU1 regulation of mitochondrial calcium uptake. EMBO J 33(6):594–604PubMedPubMedCentralCrossRefGoogle Scholar
  122. Wang L, Yang X, Shen Y (2015) Molecular mechanism of mitochondrial calcium uptake. Cell Mol Life Sci 72(8):1489–1498PubMedCrossRefGoogle Scholar
  123. Zhang SL, Yu Y, Roos J, Kozak JA, Deerinck TJ, Ellisman MH, Stauderman KA, Cahalan MD (2005) STIM1 is a Ca2+ sensor that activates CRAC channels and migrates from the Ca2+ store to the plasma membrane. Nature 437(7060):902–905PubMedPubMedCentralCrossRefGoogle Scholar
  124. Zweifach A, Lewis RS (1995) Slow calcium-dependent inactivation of depletion-activated calcium current. Store-dependent and -independent mechanisms. J Biol Chem 270(24):14445–14451PubMedCrossRefGoogle Scholar

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© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Institute of Molecular Biology and BiochemistryMedical University of GrazGrazAustria

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