The Role of Mitochondria in the Activation/Maintenance of SOCE: Store-Operated Ca2+ Entry and Mitochondria

  • András SpätEmail author
  • Gergö Szanda
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 993)


Mitochondria extensively modify virtually all cellular Ca2+ transport processes, and store-operated Ca2+ entry (SOCE) is no exception to this rule. The interaction between SOCE and mitochondria is complex and reciprocal, substantially altering and, ultimately, fine-tuning both capacitative Ca2+ influx and mitochondrial function. Mitochondria, owing to their considerable Ca2+ accumulation ability, extensively buffer the cytosolic Ca2+ in their vicinity. In turn, the accumulated ion is released back into the neighboring cytosol during net Ca2+ efflux. Since store depletion itself and the successive SOCE are both Ca2+-regulated phenomena, mitochondrial Ca2+ handling may have wide-ranging effects on capacitative Ca2+ influx at any given time. In addition, mitochondria may also produce or consume soluble factors known to affect store-operated channels. On the other hand, Ca2+ entering the cell during SOCE is sensed by mitochondria, and the ensuing mitochondrial Ca2+ uptake boosts mitochondrial energy metabolism and, if Ca2+ overload occurs, may even lead to apoptosis or cell death. In several cell types, mitochondria seem to be sterically excluded from the confined space that forms between the plasma membrane (PM) and endoplasmic reticulum (ER) during SOCE. This implies that high-Ca2+ microdomains comparable to those observed between the ER and mitochondria do not form here. In the following chapter, the above aspects of the many-sided SOCE-mitochondrion interplay will be discussed in greater detail.


Store-operated Ca2+ entry Mitochondria Ca2+ uptake Ca2+ release Microdomains NAD(P)H Membrane potential 



G. Szanda was supported by the János Bolyai Research Scholarship of the Hungarian Academy of Sciences.


  1. Acin-Perez R, Salazar E, Kamenetsky M, Buck J, Levin LR, Manfredi G (2009) Cyclic AMP produced inside mitochondria regulates oxidative phosphorylation. Cell Metab 9:265–276PubMedPubMedCentralCrossRefGoogle Scholar
  2. 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 276:29430–29439PubMedCrossRefGoogle Scholar
  3. Bakowski D, Parekh AB (2007) Regulation of store-operated calcium channels by the intermediary metabolite pyruvic acid. Curr Biol 17:1076–1081PubMedCrossRefGoogle Scholar
  4. Baughman JM, Perocchi F, Girgis HS, Plovanich M, Belcher-Timme CA, Sancak Y, Bao XR, 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 476:341–345PubMedPubMedCentralCrossRefGoogle Scholar
  5. 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 351:751–754PubMedCrossRefGoogle Scholar
  6. Bondarenko AI, Parichatikanond W, Madreiter CT, Rost R, Waldeck-Weiermair M, Malli R, Graier WF (2015) UCP2 modulates single-channel properties of a MCU-dependent Ca2+ inward current in mitochondria. Pflugers Arch 467:2509–2518PubMedPubMedCentralCrossRefGoogle Scholar
  7. Brasen JC, Olsen LF, Hallett MB (2010) Cell surface topology creates high Ca2+ signalling microdomains. Cell Calcium 47:339–349PubMedPubMedCentralCrossRefGoogle Scholar
  8. Brown GC (1992) Control of respiration and ATP synthesis in mammalian mitochondria and cells. Biochem J 284(Pt 1):1–13PubMedPubMedCentralCrossRefGoogle Scholar
  9. Carafoli E, Tiozzo R, Lugli G, Crovetti F, Kratzing C (1974) The release of calcium from heart mitochondria by sodium. J Mol Cell Cardiol 6:361–371PubMedCrossRefGoogle Scholar
  10. Chang WC, Nelson C, Parekh AB (2006) Ca2+ influx through CRAC channels activates cytosolic phospholipase A2, leukotriene C4 secretion, and expression of c-fos through ERK-dependent and -independent pathways in mast cells. FASEB J 20:2381–2383PubMedCrossRefGoogle Scholar
  11. Chaudhuri D, Artiga DJ, Abiria SA, Clapham DE (2016) Mitochondrial calcium uniporter regulator 1 (MCUR1) regulates the calcium threshold for the mitochondrial permeability transition. Proc Natl Acad Sci U S A 113:E1872–E1880PubMedPubMedCentralCrossRefGoogle Scholar
  12. Chinopoulos C, Adam-Vizi V (2006) Calcium, mitochondria and oxidative stress in neuronal pathology. Novel aspects of an enduring theme. FEBS J 273:433–450PubMedCrossRefGoogle Scholar
  13. Colegrove SL, Albrecht MA, Friel DD (2000) Dissection of mitochondrial Ca2+ uptake and release fluxes in situ after depolarization-evoked [Ca2+]i elevations in sympathetic neurons. J Gen Physiol 115:351–369PubMedPubMedCentralCrossRefGoogle Scholar
  14. Collins TJ, Lipp P, Berridge MJ, Li WH, Bootman MD (2000) Inositol 1,4,5-trisphosphate-induced Ca2+ release is inhibited by mitochondrial depolarization. Biochem J 347:593–600PubMedPubMedCentralCrossRefGoogle Scholar
  15. Collins TJ, Lipp P, Berridge MJ, Bootman MD (2001) Mitochondrial Ca2+ uptake depends on the spatial and temporal profile of cytosolic Ca2+ signals. J Biol Chem 276:26411–26420PubMedCrossRefGoogle Scholar
  16. Contreras L, Drago I, Zampese E, Pozzan T (2010) Mitochondria: the calcium connection. Biochim Biophys Acta 1797:607–618PubMedCrossRefGoogle Scholar
  17. 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 39:121–132PubMedPubMedCentralCrossRefGoogle Scholar
  18. Csordas G, Golenar T, Seifert EL, Kamer KJ, Sancak Y, Perocchi F, Moffat C, Weaver D, de la Fuente Perez S, Bogorad R, Koteliansky V, Adijanto J, Mootha VK, Hajnoczky G (2013) MICU1 controls both the threshold and cooperative activation of the mitochondrial Ca(2)(+) uniporter. Cell Metab 17:976–987PubMedPubMedCentralCrossRefGoogle Scholar
  19. Davidson SM, Duchen MR (2007) Endothelial mitochondria: contributing to vascular function and disease. Circ Res 100:1128–1141PubMedCrossRefGoogle Scholar
  20. Demaurex N, Poburko D, Frieden M (2009) Regulation of plasma membrane calcium fluxes by mitochondria. Biochim Biophys Acta 1787:1383–1394PubMedCrossRefGoogle Scholar
  21. 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 476:336–340PubMedPubMedCentralCrossRefGoogle Scholar
  22. Di Benedetto G, Scalzotto E, Mongillo M, Pozzan T (2013) Mitochondrial Ca2+ uptake induces cyclic AMP generation in the matrix and modulates organelle ATP levels. Cell Metab 17:965–975PubMedCrossRefGoogle Scholar
  23. Dingsdale H, Haynes L, Lur G, Tepikin A (2012) The role of the ER and ER-plasma membrane junctions in the regulation of SOCE. In: Groschner K, Graier WF, Romanin C (eds) Store-operated Ca2+ entry (SOCE) pathways. Springer, Wien, pp 137–152CrossRefGoogle Scholar
  24. Duchen MR (1992) Ca2+-dependent changes in the mitochondrial energetics in single dissociated mouse sensory neurons. Biochem J 283:41–50PubMedPubMedCentralCrossRefGoogle Scholar
  25. 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 47:525–537PubMedCrossRefGoogle Scholar
  26. Frieden M, James D, Castelbou C, Danckaert A, Martinou JC, Demaurex N (2004) Calcium homeostasis during mitochondria fragmentation and perinuclear clustering induced by hFis1. J Biol Chem 279:22704–22714PubMedCrossRefGoogle Scholar
  27. Frieden M, Arnaudeau S, Castelbou C, Demaurex N (2005) Subplasmalemmal mitochondria modulate the activity of plasma membrane Ca2+-ATPases. J Biol Chem 280:43198–43208PubMedCrossRefGoogle Scholar
  28. 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 38:280–290PubMedCrossRefGoogle Scholar
  29. Gilabert JA, Parekh AB (2000) Respiring mitochondria determine the pattern of activation and inactivation of the store-operated Ca2+ current I(CRAC). EMBO J 19:6401–6407PubMedPubMedCentralCrossRefGoogle Scholar
  30. 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 20:2672–2679PubMedPubMedCentralCrossRefGoogle Scholar
  31. Glitsch MD, Parekh AB (2000) Ca2+ store dynamics determines the pattern of activation of the store-operated Ca2+ current I(CRAC) in response to InsP3 in rat basophilic leukaemia cells. J Physiol 523:283–290PubMedPubMedCentralCrossRefGoogle Scholar
  32. Glitsch MD, Bakowski D, Parekh AB (2002) Store-operated Ca2+ entry depends on mitochondrial Ca2+ uptake. EMBO J 21:6744–6754PubMedPubMedCentralCrossRefGoogle Scholar
  33. Gunter TE, Pfeiffer DR (1990) Mechanisms by which mitochondria transport calcium. Am J Physiol 258:C755–C786PubMedGoogle Scholar
  34. Hajnoczky G, Hager R, Thomas AP (1999) Mitochondria suppress local feedback activation of inositol 1,4, 5-trisphosphate receptors by Ca2+. J Biol Chem 274:14157–14162PubMedCrossRefGoogle Scholar
  35. Hoth M, Fanger CM, Lewis RS (1997) Mitochondrial regulation of store-operated calcium signaling in T lymphocytes. J Cell Biol 137:633–648PubMedPubMedCentralCrossRefGoogle Scholar
  36. 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 97:10607–10612PubMedPubMedCentralCrossRefGoogle Scholar
  37. Ichas F, Mazat JP (1998) From calcium signaling to cell death: two conformations for the mitochondrial permeability transition pore. Switching from low- to high-conductance state. Biochim Biophys Acta 1366:33–50PubMedCrossRefGoogle Scholar
  38. Isshiki M, Ying YS, Fujita T, Anderson RG (2002) A molecular sensor detects signal transduction from caveolae in living cells. J Biol Chem 277:43389–43398PubMedCrossRefGoogle Scholar
  39. Jiang D, Zhao L, Clapham DE (2009) Genome-wide RNAi screen identifies Letm1 as a mitochondrial Ca2+/H+ antiporter. Science 326:144–147PubMedPubMedCentralCrossRefGoogle Scholar
  40. 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 U S A 96:13807–13812PubMedPubMedCentralCrossRefGoogle Scholar
  41. Kamer KJ, Mootha VK (2014) MICU1 and MICU2 play nonredundant roles in the regulation of the mitochondrial calcium uniporter. EMBO Rep 15:299–307PubMedPubMedCentralCrossRefGoogle Scholar
  42. Kamer KJ, Mootha VK (2015) The molecular era of the mitochondrial calcium uniporter. Nat Rev Mol Cell Biol 16:545–553PubMedCrossRefGoogle Scholar
  43. Katona D, Rajki A, Di BG, Pozzan T, Spät A (2015) Calcium-dependent mitochondrial cAMP production enhances aldosterone secretion. Mol Cell Endocrinol 412:196–204PubMedCrossRefGoogle Scholar
  44. Kirichok Y, Krapivinsky G, Clapham DE (2004) The mitochondrial calcium uniporter is a highly selective ion channel. Nature 427:360–364PubMedCrossRefGoogle Scholar
  45. Koncz P, Szanda G, Fülöp L, Rajki A, Spät A (2009) Mitochondrial Ca2+ uptake is inhibited by a concerted action of p38 MAPK and protein kinase D. Cell Calcium 46:122–129PubMedCrossRefGoogle Scholar
  46. Korzeniowski MK, Szanda G, Balla T, Spät A (2009) Store-operated Ca2+ influx and subplasmalemmal mitochondria. Cell Calcium 46:49–55PubMedPubMedCentralCrossRefGoogle Scholar
  47. Lawrie AM, Rizzuto R, Pozzan T, Simpson AWM (1996) A role for calcium influx in the regulation of mitochondrial calcium in endothelial cells. J Biol Chem 271:10753–10759PubMedCrossRefGoogle Scholar
  48. Lenzen S, Hickethier R, Panten U (1986) Interactions between spermine and Mg2+ on mitochondrial Ca2+ transport. J Biol Chem 261:16478–16483PubMedGoogle Scholar
  49. Makowska A, Zablocki K, Duszynski J (2000) The role of mitochondria in the regulation of calcium influx into Jurkat cells. Eur J Biochem 267:877–884PubMedCrossRefGoogle Scholar
  50. Malli R, Frieden M, Osibow K, Zoratti C, Mayer M, Demaurex N, Graier WF (2003) Sustained Ca2+ transfer across mitochondria is essential for mitochondrial Ca2+ buffering, store-operated Ca2+ entry, and Ca2+ store refilling. J Biol Chem 278:44769–44779PubMedCrossRefGoogle Scholar
  51. Malli R, Frieden M, Trenker M, Graier WF (2005) The role of mitochondria for Ca2+ refilling of the endoplasmic reticulum. J Biol Chem 280:12114–12122PubMedCrossRefGoogle Scholar
  52. Mallilankaraman K, Cardenas C, Doonan PJ, Chandramoorthy HC, Irrinki KM, Golenar T, Csordas G, Madireddi P, Yang J, Muller M, Miller R, Kolesar JE, Molgo J, Kaufman B, Hajnoczky G, Foskett JK, Madesh M (2012a) MCUR1 is an essential component of mitochondrial Ca2+ uptake that regulates cellular metabolism. Nat Cell Biol 14:1336–1343PubMedPubMedCentralCrossRefGoogle Scholar
  53. Mallilankaraman K, Doonan P, Cardenas C, Chandramoorthy HC, Muller M, Miller R, Hoffman NE, Gandhirajan RK, Molgo J, Birnbaum MJ, Rothberg BS, Mak DO, Foskett JK, Madesh M (2012b) MICU1 is an essential gatekeeper for MCU-mediated mitochondrial Ca2+ uptake that regulates cell survival. Cell 151:630–644PubMedPubMedCentralCrossRefGoogle Scholar
  54. Marsault R, Murgia M, Pozzan T, Rizzuto R (1997) Domains of high Ca2+ beneath the plasma membrane of living A7r5 cells. EMBO J 16:1575–1581PubMedPubMedCentralCrossRefGoogle Scholar
  55. McCormack JG (1985) Characterization of the effects of Ca2+ on the intramitochondrial Ca2+-sensitive enzymes from rat and within intact rat liver mitochondria. Biochem J 231:581–595PubMedPubMedCentralCrossRefGoogle Scholar
  56. McCormack JG, Halestrap AP, Denton RM (1990) Role of calcium ions in regulation of mammalian intramitochondrial metabolism. Physiol Rev 70:391–425PubMedGoogle Scholar
  57. Mignen O, Brink C, Enfissi A, Nadkarni A, Shuttleworth TJ, Giovannucci DR, Capiod T (2005) Carboxyamidotriazole-induced inhibition of mitochondrial calcium import blocks capacitative calcium entry and cell proliferation in HEK-293 cells. J Cell Sci 118:5615–5623PubMedCrossRefGoogle Scholar
  58. Montalvo GB, Artalejo AR, Gilabert JA (2006) ATP from subplasmalemmal mitochondria controls Ca2+-dependent inactivation of CRAC channels. J Biol Chem 281:35616–35623PubMedCrossRefGoogle Scholar
  59. Motloch LJ, Larbig R, Gebing T, Reda S, Schwaiger A, Leitner J, Wolny M, Eckardt L, Hoppe UC (2016) By regulating mitochondrial Ca2+-uptake UCP2 modulates intracellular Ca2+. PLoS One 11:e0148359PubMedPubMedCentralCrossRefGoogle Scholar
  60. 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 283:8014–8022PubMedCrossRefGoogle Scholar
  61. 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 123:2553–2564PubMedCrossRefGoogle Scholar
  62. Nakahashi Y, Nelson E, Fagan K, Gonzales E, Guillou JL, Cooper DM (1997) Construction of a full-length Ca2+-sensitive adenylyl cyclase/aequorin chimera. J Biol Chem 272:18093–18097PubMedCrossRefGoogle Scholar
  63. Nunes P, Demaurex N (2014) Redox regulation of store-operated Ca2+ entry. Antioxid Redox Signal 21:915–932PubMedPubMedCentralCrossRefGoogle Scholar
  64. Olson ML, Chalmers S, McCarron JG (2010) Mitochondrial Ca2+ uptake increases Ca2+ release from inositol 1,4,5-trisphosphate receptor clusters in smooth muscle cells. J Biol Chem 285:2040–2050PubMedCrossRefGoogle Scholar
  65. Parekh AB (1998) Slow feedback inhibition of calcium release-activated calcium current by calcium entry. J Biol Chem 273:14925–14932PubMedCrossRefGoogle Scholar
  66. Parekh AB (2008) Mitochondrial regulation of store-operated CRAC channels. Cell Calcium 44:6–13PubMedCrossRefGoogle Scholar
  67. Parekh AB (2010) Store-operated CRAC channels: function in health and disease. Nat Rev Drug Discov 9:399–410PubMedCrossRefGoogle Scholar
  68. Park MK, Ashby MC, Erdemli G, Petersen OH, Tepikin AV (2001) Perinuclear, perigranular and sub-plasmalemmal mitochondria have distinct functions in the regulation of cellular calcium transport. EMBO J 20:1863–1874PubMedPubMedCentralCrossRefGoogle Scholar
  69. Park CY, Hoover PJ, Mullins FM, Bachhawat P, Covington ED, Raunser S, Walz T, Garcia KC, Dolmetsch RE, Lewis RS (2009) STIM1 clusters and activates CRAC channels via direct binding of a cytosolic domain to Orai1. Cell 136:876–890PubMedPubMedCentralCrossRefGoogle Scholar
  70. Paupe V, Prudent J, Dassa EP, Rendon OZ, Shoubridge EA (2015) CCDC90A (MCUR1) is a cytochrome c oxidase assembly factor and not a regulator of the mitochondrial calcium uniporter. Cell Metab 21:109–116PubMedCrossRefGoogle Scholar
  71. 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 467:291–296PubMedPubMedCentralCrossRefGoogle Scholar
  72. Petersen OH, Verkhratsky A (2007) Endoplasmic reticulum calcium tunnels integrate signalling in polarised cells. Cell Calcium 42:373–378PubMedCrossRefGoogle Scholar
  73. Pitter JG, Maechler P, Wollheim CB, Spät A (2002) Mitochondria respond to Ca2+ already in the submicromolar range: correlation with redox state. Cell Calcium 31:97–104PubMedCrossRefGoogle Scholar
  74. Pivovarova NB, Hongpaisan J, Andrews SB, Friel DD (1999) Depolarization-induced mitochondrial Ca2+ accumulation in sympathetic neurons: spatial and temporal characteristics. J Neurosci 19:6372–6384PubMedGoogle Scholar
  75. Plovanich M, Bogorad RL, Sancak Y, Kamer KJ, Strittmatter L, Li AA, Girgis HS, Kuchimanchi S, De GJ, 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
  76. Pralong WF, Hunyady L, Varnai P, Wollheim CB, Spät A (1992) Pyridine nucleotide redox state parallels production of aldosterone in potassium-stimulated adrenal glomerulosa cells. Proc Natl Acad Sci U S A 89:132–136PubMedPubMedCentralCrossRefGoogle Scholar
  77. Pralong WF, Spät A, Wollheim CB (1994) Dynamic pacing of cell metabolism by intracellular Ca2+. J Biol Chem 269:27310–27314PubMedGoogle Scholar
  78. Putney JW Jr (2009) Capacitative calcium entry: from concept to molecules. Immunol Rev 231:10–22PubMedCrossRefGoogle Scholar
  79. Quintana A, Schwarz EC, Schwindling C, Lipp P, Kaestner L, Hoth M (2006) Sustained activity of calcium release-activated calcium channels requires translocation of mitochondria to the plasma membrane. J Biol Chem 281:40302–40309PubMedCrossRefGoogle Scholar
  80. Raffaello A, De SD, 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 32:2362–2376PubMedPubMedCentralCrossRefGoogle Scholar
  81. Rao W, Zhang L, Peng C, Hui H, Wang K, Su N, Wang L, Dai SH, Yang YF, Chen T, Luo P, Fei Z (2015) Downregulation of STIM2 improves neuronal survival after traumatic brain injury by alleviating calcium overload and mitochondrial dysfunction. Biochim Biophys Acta 1852:2402–2413PubMedCrossRefGoogle Scholar
  82. Rapizzi E, Pinton P, Szabadkai G, Wieckowski MR, Vandecasteele G, Baird G, Tuft RA, Fogarty KE, Rizzuto R (2002) Recombinant expression of the voltage-dependent anion channel enhances the transfer of Ca2+ microdomains to mitochondria. J Biol Chem 159:613–624Google Scholar
  83. Rizzuto R, Pozzan T (2006) Microdomains of intracellular Ca2+: molecular determinants and functional consequences. Physiol Rev 86:369–408PubMedCrossRefGoogle Scholar
  84. Rohacs T, Nagy G, Spät A (1997a) Cytoplasmic Ca2+ signalling and reduction of mitochondrial pyridine nucleotides in adrenal glomerulosa cells in response to K+, angiotensin II and vasopressin. Biochem J 322:785–792PubMedPubMedCentralCrossRefGoogle Scholar
  85. Rohacs T, Tory K, Dobos A, Spät A (1997b) Intracellular calcium release is more efficient than calcium influx in stimulating mitochondrial NAD(P)H formation in adrenal glomerulosa cells. Biochem J 328:525–528PubMedPubMedCentralCrossRefGoogle Scholar
  86. 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 342:1379–1382PubMedPubMedCentralCrossRefGoogle Scholar
  87. Santo-Domingo J, Demaurex N (2010) Calcium uptake mechanisms of mitochondria. Biochim Biophys Acta 1797:907–912PubMedCrossRefGoogle Scholar
  88. Spät A, Fülöp L, Koncz P, Szanda G (2008a) When is high-Ca2+ microdomain required for mitochondrial Ca2+ uptake? Acta Physiol (Oxf) 195:139–147CrossRefGoogle Scholar
  89. Spät A, Szanda G, Csordas G, Hajnoczky G (2008b) High- and low-calcium-dependent mechanisms of mitochondrial calcium signalling. Cell Calcium 44:51–63PubMedPubMedCentralCrossRefGoogle Scholar
  90. Spät A, Hunyady L, Szanda G (2016) Signaling interactions in the adrenal cortex. Front Endocrinol (Lausanne) 7:17Google Scholar
  91. Spencer T, Bygrave FL (1971) Stimulation by calcium ions of atractyloside-sensitive adenine nucleotide translocation in rat liver mitochondria. Biochem Biophys Res Commun 43:1290–1295PubMedCrossRefGoogle Scholar
  92. Szabadkai G, Pitter JG, Spät A (2001) Cytoplasmic Ca2+ at low submicromolar concentration stimulates mitochondrial metabolism in rat luteal cells. Pflugers Arch 441:678–685PubMedCrossRefGoogle Scholar
  93. Szanda G, Koncz P, Varnai P, Spät A (2006) Mitochondrial Ca2+ uptake with and without the formation of high-Ca2+ microdomains. Cell Calcium 40:527–538PubMedCrossRefGoogle Scholar
  94. Szanda G, Koncz P, Rajki A, Spät A (2008) Participation of p38 MAPK and a novel-type protein kinase C in the control of mitochondrial Ca2+ uptake. Cell Calcium 43:250–259PubMedCrossRefGoogle Scholar
  95. Szanda G, Rajki A, Gallego-Sandin S, Garcia-Sancho J, Spät A (2009) Effect of cytosolic Mg2+ on mitochondrial Ca2+ signaling. Pflugers Arch 457:941–954PubMedCrossRefGoogle Scholar
  96. Tewari SG, Camara AK, Stowe DF, Dash RK (2014) Computational analysis of Ca2+ dynamics in isolated cardiac mitochondria predicts two distinct modes of Ca2+ uptake. J Physiol 592:1917–1930PubMedPubMedCentralCrossRefGoogle Scholar
  97. Thyagarajan B, Malli R, Schmidt K, Graier WF, Groschner K (2002) Nitric oxide inhibits capacitative Ca2+ entry by suppression of mitochondrial Ca2+ handling. Br J Pharmacol 137:821–830PubMedPubMedCentralCrossRefGoogle Scholar
  98. Tinel H, Cancela JM, Mogami H, Gerasimenko JV, Gerasimenko OV, Tepikin AV, Petersen OH (1999) Active mitochondria surrounding the pancreatic acinar granule region prevent spreading of inositol trisphosphate-evoked local cytosolic Ca2+ signals. EMBO J 18:4999–5008PubMedPubMedCentralCrossRefGoogle Scholar
  99. To MS, Aromataris EC, Castro J, Roberts ML, Barritt GJ, Rychkov GY (2010) Mitochondrial uncoupler FCCP activates proton conductance but does not block store-operated Ca2+ current in liver cells. Arch Biochem Biophys 495:152–158PubMedCrossRefGoogle Scholar
  100. 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 9:445–452PubMedPubMedCentralCrossRefGoogle Scholar
  101. Trepakova ES, Cohen RA, Bolotina VM (1999) Nitric oxide inhibits capacitative cation influx in human platelets by promoting sarcoplasmic/endoplasmic reticulum Ca2+-ATPase-dependent refilling of Ca2+ stores. Circ Res 84:201–209PubMedCrossRefGoogle Scholar
  102. Tsai MF, Phillips CB, Ranaghan M, Tsai CW, Wu Y, Willliams C, Miller C (2016) Dual functions of a small regulatory subunit in the mitochondrial calcium uniporter complex. Elife 5:e15545PubMedPubMedCentralGoogle Scholar
  103. Vais H, Tanis JE, Muller M, Payne R, Mallilankaraman K, Foskett JK (2015) MCUR1, CCDC90A, is a regulator of the mitochondrial calcium uniporter. Cell Metab 22:533–535PubMedPubMedCentralCrossRefGoogle Scholar
  104. Vais H, Mallilankaraman K, Mak DO, Hoff H, Payne R, Tanis JE, Foskett JK (2016) EMRE is a matrix Ca2+ sensor that governs gatekeeping of the mitochondrial Ca2+ uniporter. Cell Rep 14:403–410PubMedPubMedCentralCrossRefGoogle Scholar
  105. Varadi A, Cirulli V, Rutter GA (2004) Mitochondrial localization as a determinant of capacitative Ca2+ entry in HeLa cells. Cell Calcium 36:499–508PubMedCrossRefGoogle Scholar
  106. 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 282:29678–29690PubMedCrossRefGoogle Scholar
  107. Waldeck-Weiermair M, Malli R, Naghdi S, Trenker M, Kahn MJ, Graier WF (2010) The contribution of UCP2 and UCP3 to mitochondrial Ca2+ uptake is differentially determined by the source of supplied Ca2+. Cell Calcium 47:433–440PubMedCrossRefGoogle Scholar
  108. 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 Ca(2+). Sci Rep 5:15602PubMedPubMedCentralCrossRefGoogle Scholar
  109. Walsh C, Barrow S, Voronina S, Chvanov M, Petersen OH, Tepikin A (2009) Modulation of calcium signalling by mitochondria. Biochim Biophys Acta 1787:1374–1382PubMedCrossRefGoogle Scholar
  110. Wiederkehr A, Szanda G, Akhmedov D, Mataki C, Heizmann CW, Schoonjans K, Pozzan T, Spät A, Wollheim CB (2011) Mitochondrial matrix calcium is an activating signal for hormone secretion. Cell Metab 13:601–611PubMedCrossRefGoogle Scholar
  111. Won JH, Yule DI (2006) Measurement of Ca2+ signaling dynamics in exocrine cells with total internal reflection microscopy. Am J Physiol Gastrointest Liver Physiol 291:G146–G155PubMedCrossRefGoogle Scholar
  112. Wu MM, Buchanan J, Luik RM, Lewis RS (2006) Ca2+ store depletion causes STIM1 to accumulate in ER regions closely associated with the plasma membrane. J Cell Biol 174:803–813PubMedPubMedCentralCrossRefGoogle Scholar
  113. Yi M, Weaver D, Hajnoczky G (2004) Control of mitochondrial motility and distribution by the calcium signal: a homeostatic circuit. J Cell Biol 167:661–672PubMedPubMedCentralCrossRefGoogle Scholar
  114. Yu WH, Wolfgang W, Forte M (1995) Subcellular localization of human voltage-dependent anion channel isoforms. J Biol Chem 270:13998–14006PubMedCrossRefGoogle Scholar
  115. Zweifach A, Lewis RS (1995) Slow calcium-dependent inactivation of depletion-activated calcium current. Store-dependent and -independent mechanisms. J Biol Chem 270:14445–14451PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Department of PhysiologySemmelweis University Medical SchoolBudapestHungary
  2. 2.Laboratory of Molecular PhysiologyHungarian Academy of SciencesBudapestHungary

Personalised recommendations