Pflügers Archiv - European Journal of Physiology

, Volume 470, Issue 8, pp 1149–1163 | Cite as

The role of the mitochondrial calcium uniporter (MCU) complex in cancer

  • Adina Vultur
  • Christine S. Gibhardt
  • Hedwig Stanisz
  • Ivan BogeskiEmail author
Invited Review


The important role of mitochondria in cancer biology is gaining momentum. With their regulation of cell survival, metabolism, basic cell building blocks, and immunity, among other functions, mitochondria affect not only cancer progression but also the response and resistance to current treatments. Calcium ions are constantly shuttled in and out of mitochondria; thus, playing an important role in the regulation of various cellular processes. The mitochondrial calcium uniporter (MCU) channel and its associated regulators transport calcium across the inner mitochondrial membrane to the mitochondrial matrix. Due to this central role and the capacity to affect cell behavior and fate, the MCU complex is being investigated in different cancers and cancer-related conditions. Here, we review current knowledge on the role of the MCU complex in multiple cancer types and models; we also provide a perspective for future research and clinical considerations.


Mitochondria Cancer MCU Calcium ROS Metabolism Redox MICU 


Funding information

This work was supported by the German Research Foundation (DFG) projects: SFB1190 project 17, SFB1027 Project C4, IRTG1816, and BO3643/3-2.


  1. 1.
    Ahuja M, Muallem S (2014) The gatekeepers of mitochondrial calcium influx: MICU1 and MICU2. EMBO Rep 15:205–206PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Akl H, Bultynck G (2013) Altered Ca2+ signaling in cancer cells: proto-oncogenes and tumor suppressors targeting IP3 receptors. Biochim Biophys Acta 1835:180–193PubMedGoogle Scholar
  3. 3.
    Arduino DM, Wettmarshausen J, Vais H, Navas-Navarro P, Cheng YM, Leimpek A, Ma ZM, Delrio-Lorenzo A, Giordano A, Garcia-Perez C, Medard G, Kuster B, Garcia-Sancho J, Mokranjac D, Foskett JK, Alonso MT, Perocchi F (2017) Systematic identification of MCU modulators by orthogonal interspecies chemical screening. Mol Cell 67:711–723.e7PubMedCrossRefPubMedCentralGoogle Scholar
  4. 4.
    Balaban RS (2009) The role of Ca(2+) signaling in the coordination of mitochondrial ATP production with cardiac work. Biochim Biophys Acta 1787:1334–1341PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    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–U111PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Bogeski I, Gulaboski R, Kappl R, Mirceski V, Stefova M, Petreska J, Hoth M (2011) Calcium binding and transport by coenzyme Q. J Am Chem Soc 133:9293–9303PubMedCrossRefGoogle Scholar
  7. 7.
    Bogeski I, Kappl R, Kummerow C, Gulaboski R, Hoth M, Niemeyer BA (2011) Redox regulation of calcium ion channels: chemical and physiological aspects. Cell Calcium 50:407–423PubMedCrossRefGoogle Scholar
  8. 8.
    Booth DM, Enyedi B, Geiszt M, Varnai P, Hajnoczky G (2016) Redox nanodomains are induced by and control calcium signaling at the ER-mitochondrial interface. Mol Cell 63:240–248PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Brookes PS, Yoon YS, Robotham JL, Anders MW, Sheu SS (2004) Calcium, ATP, and ROS: a mitochondrial love-hate triangle. Am J Phys Cell Phys 287:C817–C833CrossRefGoogle Scholar
  10. 10.
    Brookes PS, Parker N, Buckingham JA, Vidal-Puig A, Halestrap AP, Gunter TE, Nicholls DG, Bernardi P, Lemasters JJ, Brand MD (2008) UCPs—unlikely calcium porters. Nat Cell Biol 10:1235–1237; author reply 1237–1240PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Bustos G, Cruz P, Lovy A, Cárdenas C (2017) Endoplasmic reticulum–mitochondria calcium communication and the regulation of mitochondrial metabolism in cancer: a novel potential target. Front Oncol 7:199PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Cardenas C, Muller M, McNeal A, Lovy A, Jana F, Bustos G, Urra F, Smith N, Molgo J, Diehl JA, Ridky TW, Foskett JK (2016) Selective vulnerability of Cancer cells by inhibition of Ca(2+) transfer from endoplasmic reticulum to mitochondria. Cell Rep 14:2313–2324PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Cardenas C, Muller M, McNeal A, Lovy A, Jana F, Bustos G, Urra F, Smith N, Molgo J, Diehl JA, Ridky TW, Foskett JK (2016) Selective vulnerability of cancer cells by inhibition of Ca(2+) transfer from endoplasmic reticulum to mitochondria. Cell Rep 15:219–220PubMedCrossRefGoogle Scholar
  14. 14.
    Chakraborti S, Pramanick A, Saha S, Roy SS, Chaudhuri AR, Das M, Ghosh S, Stewart A, Maity B (2018) Atypical G protein beta5 promotes cardiac oxidative stress, apoptosis, and fibrotic remodeling in response to multiple cancer chemotherapeutics. Cancer Res 78:528–541PubMedCrossRefGoogle Scholar
  15. 15.
    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
  16. 16.
    Chen L, Sun Q, Zhou D, Song W, Yang Q, Ju B, Zhang L, Xie H, Zhou L, Hu Z, Yao H, Zheng S, Wang W (2017) HINT2 triggers mitochondrial Ca(2+) influx by regulating the mitochondrial Ca(2+) uniporter (MCU) complex and enhances gemcitabine apoptotic effect in pancreatic cancer. Cancer Lett 411:106–116PubMedCrossRefGoogle Scholar
  17. 17.
    Cierlitza M, Chauvistre H, Bogeski I, Zhang X, Hauschild A, Herlyn M, Schadendorf D, Vogt T, Roesch A (2015) Mitochondrial oxidative stress as a novel therapeutic target to overcome intrinsic drug resistance in melanoma cell subpopulations. Exp Dermatol 24:155–157PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Clapham DE (2007) Calcium signaling. Cell 131:1047–1058PubMedCrossRefGoogle Scholar
  19. 19.
    Csordas G, Hajnoczky G (2009) SR/ER-mitochondrial local communication: calcium and ROS. BBA-Bioenergetics 1787:1352–1362PubMedCrossRefGoogle Scholar
  20. 20.
    Csordas G, Thomas AP, Hajnoczky G (1999) Quasi-synaptic calcium signal transmission between endoplasmic reticulum and mitochondria. EMBO J 18:96–108PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    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
  22. 22.
    Curry MC, Peters AA, Kenny PA, Roberts-Thomson SJ, Monteith GR (2013) Mitochondrial calcium uniporter silencing potentiates caspase-independent cell death in MDA-MB-231 breast cancer cells. Biochem Biophys Res Commun 434:695–700PubMedCrossRefGoogle Scholar
  23. 23.
    D'Autreaux B, Toledano MB (2007) ROS as signalling molecules: mechanisms that generate specificity in ROS homeostasis. Nat Rev Mol Cell Biol 8:813–824PubMedCrossRefGoogle Scholar
  24. 24.
    Davis FM, Parsonage MT, Cabot PJ, Parat MO, Thompson EW, Roberts-Thomson SJ, Monteith GR (2013) Assessment of gene expression of intracellular calcium channels, pumps and exchangers with epidermal growth factor-induced epithelial-mesenchymal transition in a breast cancer cell line. Cancer Cell Int 13:76PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    De Marchi U, Santo-Domingo J, Castelbou C, Sekler I, Wiederkehr A, Demaurex N (2014) NCLX protein, but not LETM1, mediates mitochondrial Ca2+ extrusion, thereby limiting Ca2+-induced NAD(P)H production and modulating matrix redox state. J Biol Chem 289:20377–20385PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    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–U104PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    De Stefani D, Rizzuto R, Pozzan T (2016) Enjoy the trip: calcium in mitochondria back and forth. Annu Rev Biochem 85, edited by Kornberg RD2016:161–192PubMedCrossRefGoogle Scholar
  28. 28.
    Deluca HF, Engstrom GW (1961) Calcium uptake by rat kidney mitochondria. Proc Natl Acad Sci U S A 47:1744–1750PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Deng Q, Chen S, Fu C, Jiang J, Zou M, Tan Y, Wang X, Xia F, Feng K, Ma K, Bie P (2017) Long noncoding RNA expression profiles in sub-lethal heat-treated hepatoma carcinoma cells. World J Surg Oncol 15(136):136PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Di A, Mehta D, Malik AB (2016) ROS-activated calcium signaling mechanisms regulating endothelial barrier function. Cell Calcium 60:163–171PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Doonan PJ, Chandramoorthy HC, Hoffman NE, Zhang X, Cardenas C, Shanmughapriya S, Rajan S, Vallem S, Chen X, Foskett JK, Cheung JY, Houser SR, Madesh M (2014) LETM1-dependent mitochondrial Ca2+ flux modulates cellular bioenergetics and proliferation. FASEB J 28:4936–4949PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Esterberg R, Linbo T, Pickett SB, Wu P, Ou HC, Rubel EW, Raible DW (2016) Mitochondrial calcium uptake underlies ROS generation during aminoglycoside-induced hair cell death. J Clin Investig 126:3556–3566PubMedCrossRefGoogle Scholar
  33. 33.
    Filadi R, Theurey P, Pizzo P (2017) The endoplasmic reticulum-mitochondria coupling in health and disease: molecules, functions and significance. Cell Calcium 62:1–15PubMedCrossRefGoogle Scholar
  34. 34.
    Foskett JK, Philipson B (2015) The mitochondrial Ca2+ uniporter complex. J Mol Cell Cardiol 78:3–8PubMedCrossRefGoogle Scholar
  35. 35.
    Foskett JK, White C, Cheung KH, Mak DOD (2007) Inositol trisphosphate receptor Ca2+ release channels. Physiol Rev 87:593–658PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Giorgi C, Bonora M, Missiroli S, Poletti F, Ramirez FG, Morciano G, Morganti C, Pandolfi PP, Mammano F, Pinton P (2015) Intravital imaging reveals p53-dependent cancer cell death induced by phototherapy via calcium signaling. Oncotarget 6:1435–1445PubMedGoogle Scholar
  37. 37.
    Giorgi C, Bonora M, Sorrentino G, Missiroli S, Poletti F, Suski JM, Galindo Ramirez F, Rizzuto R, Di Virgilio F, Zito E, Pandolfi PP, Wieckowski MR, Mammano F, Del Sal G, Pinton P (2015) p53 at the endoplasmic reticulum regulates apoptosis in a Ca2+-dependent manner. Proc Natl Acad Sci U S A 112:1779–1784PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Gorlach A, Bertram K, Hudecova S, Krizanova O (2015) Calcium and ROS: a mutual interplay. Redox Biol 6:260–271PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Graier WF, Trenker M, Malli R (2008) Mitochondrial Ca2+, the secret behind the function of uncoupling proteins 2 and 3? Cell Calcium 44:36–50PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Gulaboski R, Bogeski I, Mirceski V, Saul S, Pasieka B, Haeri HH, Stefova M, Stanoeva JP, Mitrev S, Hoth M, Kappl R (2013) Hydroxylated derivatives of dimethoxy-1,4-benzoquinone as redox switchable earth-alkaline metal ligands and radical scavengers. Sci Rep 3:1865PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Hall DD, Wu Y, Domann FE, Spitz DR, Anderson ME (2014) Mitochondrial calcium uniporter activity is dispensable for MDA-MB-231 breast carcinoma cell survival. PLoS One 9:e96866PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Hatzivassiliou G, Song K, Yen I, Brandhuber BJ, Anderson DJ, Alvarado R, Ludlam MJ, Stokoe D, Gloor SL, Vigers G, Morales T, Aliagas I, Liu B, Sideris S, Hoeflich KP, Jaiswal BS, Seshagiri S, Koeppen H, Belvin M, Friedman LS, Malek S (2010) RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature 464:431–435PubMedCrossRefGoogle Scholar
  43. 43.
    Hempel N, Trebak M (2017) Crosstalk between calcium and reactive oxygen species signaling in cancer. Cell Calcium 63:70–96PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Hoffman NE, Chandramoorthy HC, Shanmughapriya S, Zhang XQ, Vallem S, Doonan PJ, Malliankaraman K, Guo S, Rajan S, Elrod JW, Koch WJ, Cheung JY, Madesh M (2014) SLC25A23 augments mitochondrial Ca(2)(+) uptake, interacts with MCU, and induces oxidative stress-mediated cell death. Mol Biol Cell 25:936–947PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Holzmann C, Kilch T, Kappel S, Dorr K, Jung V, Stockle M, Bogeski I, Peinelt C (2015) Differential redox regulation of Ca(2)(+) signaling and viability in normal and malignant prostate cells. Biophys J 109:1410–1419PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Hong Z, Chen KH, DasGupta A, Potus F, Dunham-Snary K, Bonnet S, Tian L, Fu J, Breuils-Bonnet S, Provencher S, Wu D, Mewburn J, Ormiston ML, Archer SL (2017) MicroRNA-138 and MicroRNA-25 down-regulate mitochondrial calcium uniporter, causing the pulmonary arterial hypertension Cancer phenotype. Am J Respir Crit Care Med 195:515–529PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Jiang D, Zhao L, Clish CB, Clapham DE (2013) Letm1, the mitochondrial Ca2+/H+ antiporter, is essential for normal glucose metabolism and alters brain function in Wolf-Hirschhorn syndrome. Proc Natl Acad Sci U S A 110:E2249–E2254PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    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
  49. 49.
    Kamer KJ, Sancak Y, Mootha VK (2014) The uniporter: from newly identified parts to function. Biochem Biophys Res Commun 449:370–372PubMedCrossRefGoogle Scholar
  50. 50.
    Kerkhofs M, Giorgi C, Marchi S, Seitaj B, Parys JB, Pinton P, Bultynck G, Bittremieux M (2017) Alterations in Ca(2+) signalling via ER-mitochondria contact site remodelling in cancer. Adv Exp Med Biol 997:225–254PubMedCrossRefGoogle Scholar
  51. 51.
    Kirichok Y, Krapivinsky G, Clapham DE (2004) The mitochondrial calcium uniporter is a highly selective ion channel. Nature 427:360–364PubMedCrossRefGoogle Scholar
  52. 52.
    Kon N, Murakoshi M, Isobe A, Kagechika K, Miyoshi N, Nagayama T (2017) DS16570511 is a small-molecule inhibitor of the mitochondrial calcium uniporter. Cell Death Discov 3:17045PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Liao Y, Hao Y, Chen H, He Q, Yuan Z, Cheng J (2015) Mitochondrial calcium uniporter protein MCU is involved in oxidative stress-induced cell death. Protein Cell 6:434–442PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Loubiere C, Clavel S, Gilleron J, Harisseh R, Fauconnier J, Ben-Sahra I, Kaminski L, Laurent K, Herkenne S, Lacas-Gervais S, Ambrosetti D, Alcor D, Rocchi S, Cormont M, Michiels JF, Mari B, Mazure NM, Scorrano L, Lacampagne A, Gharib A, Tanti JF, Bost F (2017) The energy disruptor metformin targets mitochondrial integrity via modification of calcium flux in cancer cells. Sci Rep 7(5040):5040PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Lovy A, Foskett JK, Cardenas C (2016) InsP3R, the calcium whisperer: maintaining mitochondrial function in cancer. Mol Cell Oncol 3:e1185563PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Madreiter-Sokolowski CT, Gottschalk B, Parichatikanond W, Eroglu E, Klec C, Waldeck-Weiermair M, Malli R, Graier WF (2016) Resveratrol specifically kills cancer cells by a devastating increase in the Ca2+ coupling between the greatly tethered endoplasmic reticulum and mitochondria. Cell Physiol Biochem 39:1404–1420PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Mallilankaraman K, Cardenas C, Doonan PJ, Chandramoorthy HC, Irrinki KM, Golenar T, Csordas G, Madireddi P, Yang J, Mueller 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 14:1336–1343PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    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 (2012) MICU1 is an essential gatekeeper for MCU-mediated mitochondrial Ca(2+) uptake that regulates cell survival. Cell 151:630–644PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Mammucari C, Gherardi G, Rizzuto R (2017) Structure, activity regulation, and role of the mitochondrial calcium uniporter in health and disease. Front Oncol 7:139PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Marchi S, Pinton P (2013) Mitochondrial calcium uniporter, MiRNA and cancer: live and let die. Commun Integr Biol 6:e23818PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Marchi S, Pinton P (2014) The mitochondrial calcium uniporter complex: molecular components, structure and physiopathological implications. J Physiol Lond 592:829–839PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Marchi S, Lupini L, Patergnani S, Rimessi A, Missiroli S, Bonora M, Bononi A, Corra F, Giorgi C, De Marchi E, Poletti F, Gafa R, Lanza G, Negrini M, Rizzuto R, Pinton P (2013) Downregulation of the mitochondrial calcium uniporter by cancer-related miR-25. Curr Biol 23:58–63PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Martin J, Maurhofer O, Bellance N, Benard G, Graber F, Hahn D, Galinier A, Hora C, Gupta A, Ferrand G, Hoppeler H, Rossignol R, Dufour JF, St-Pierre MV (2013) Disruption of the histidine triad nucleotide-binding hint2 gene in mice affects glycemic control and mitochondrial function. Hepatology 57:2037–2048PubMedCrossRefGoogle Scholar
  64. 64.
    Mishra J, Jhun BS, Hurst S, OU J, Csordas G, Sheu SS (2017) The mitochondrial Ca(2+) uniporter: structure, function, and pharmacology. Handb Exp Pharmacol 240:129–156PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    OU J, Ryu SY, Jhun BS, Hurst S, Sheu SS (2014) Mitochondrial ion channels/transporters as sensors and regulators of cellular redox signaling. Antioxid Redox Signal 21:987–1006CrossRefGoogle Scholar
  66. 66.
    Oxenoid K, Dong Y, Cao C, Cui T, Sancak Y, Markhard AL, Grabarek Z, Kong L, Liu Z, Ouyang B, Cong Y, Mootha VK, Chou JJ (2016) Architecture of the mitochondrial calcium uniporter. Nature 533:269–273PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Paillard M, Csordas G, Szanda G, Golenar T, Debattisti V, Bartok A, Wang N, Moffat C, Seifert EL, Spat A, Hajnoczky G (2017) Tissue-specific mitochondrial decoding of cytoplasmic Ca(2+) signals is controlled by the stoichiometry of MICU1/2 and MCU. Cell Rep 18:2291–2300PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    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 107:436–441PubMedCrossRefGoogle Scholar
  69. 69.
    Parekh AB (2008) Mitochondrial regulation of store-operated CRAC channels. Cell Calcium 44:6–13PubMedCrossRefGoogle Scholar
  70. 70.
    Parekh AB, Putney JW Jr (2005) Store-operated calcium channels. Physiol Rev 85:757–810PubMedCrossRefGoogle Scholar
  71. 71.
    Patron M, Raffaello A, Granatiero V, Tosatto A, Merli G, De Stefani D, Wright L, Pallafacchina G, Terrin A, Mammucari C, Rizzuto R (2013) The mitochondrial calcium uniporter (MCU): molecular identity and physiological roles. J Biol Chem 288:10750–10758PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Patron M, Checchetto V, Raffaello A, Teardo E, Reane DV, 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 53:726–737PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Patron M, Granatiero V, Espino J, Rizzuto R, De Stefani D (2018) MICU3 is a tissue-specific enhancer of mitochondrial calcium uptake. Cell Death Differ.
  74. 74.
    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
  75. 75.
    Pedriali G, Rimessi A, Sbano L, Giorgi C, Wieckowski MR, Previati M, Pinton P (2017) Regulation of endoplasmic reticulum–mitochondria Ca2+ transfer and its importance for anti-cancer therapies. Front Oncol 7:180PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Pendin D, Greotti E, Pozzan T (2014) The elusive importance of being a mitochondrial Ca2+ uniporter. Cell Calcium 55:139–145PubMedCrossRefGoogle Scholar
  77. 77.
    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–U267PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Petrungaro C, Zimmermann KM, Kuttner V, Fischer M, Dengjel J, Bogeski I, Riemer J (2015) The Ca(2+)-dependent release of the Mia40-induced MICU1-MICU2 dimer from MCU regulates mitochondrial Ca(2+) uptake. Cell Metab 22:721–733PubMedCrossRefGoogle Scholar
  79. 79.
    Pinton P, Giorgi C, Siviero R, Zecchini E, Rizzuto R (2008) Calcium and apoptosis: ER-mitochondria Ca2+ transfer in the control of apoptosis. Oncogene 27:6407–6418PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Plovanich M, Bogorad RL, Sancak Y, Kamer KJ, Strittmatter L, Li AA, Girgis HS, Kuchimanchi S, De Groot J, 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
  81. 81.
    Prakriya M, Lewis RS (2015) Store-operated calcium channels. Physiol Rev 95:1383–1436PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    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 104:14418–14423PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    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 32:2362–2376PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Ren T, Zhang H, Wang J, Zhu J, Jin M, Wu Y, Guo X, Ji L, Huang Q, Zhang H, Yang H, Xing J (2017) MCU-dependent mitochondrial Ca(2+) inhibits NAD(+)/SIRT3/SOD2 pathway to promote ROS production and metastasis of HCC cells. Oncogene 36:5897–5909PubMedCrossRefGoogle Scholar
  85. 85.
    Ren T, Wang J, Zhang H, Yuan P, Zhu J, Wu Y, Huang Q, Guo X, Zhang J, Ji L, Li J, Zhang H, Yang H, Xing J (2018) MCUR1-mediated mitochondrial calcium signaling facilitates cell survival of hepatocellular carcinoma via reactive oxygen species-dependent P53 Degradation. Antioxid Redox Signal 28(12):1120–1136PubMedCrossRefGoogle Scholar
  86. 86.
    Rizzuto R, Brini M, Murgia M, Pozzan T (1993) Microdomains with high Ca2+ close to IP(3)-sensitive channels that are sensed by neighboring mitochondria. Science 262:744–747PubMedCrossRefGoogle Scholar
  87. 87.
    Roesch A, Vultur A, Bogeski I, Wang H, Zimmermann KM, Speicher D, Korbel C, Laschke MW, Gimotty PA, Philipp SE, Krause E, Patzold S, Villanueva J, Krepler C, Fukunaga-Kalabis M, Hoth M, Bastian BC, Vogt T, Herlyn M (2013) Overcoming intrinsic multidrug resistance in melanoma by blocking the mitochondrial respiratory chain of slow-cycling JARID1B(high) cells. Cancer Cell 23:811–825PubMedCrossRefGoogle Scholar
  88. 88.
    Samanta K, Mirams GR, Parekh AB (2018) Sequential forward and reverse transport of the Na(+) Ca(2+) exchanger generates Ca(2+) oscillations within mitochondria. Nat Commun 9(156):156PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    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
  90. 90.
    Saul S, Gibhardt CS, Schmidt B, Lis A, Pasieka B, Conrad D, Jung P, Gaupp R, Wonnenberg B, Diler E, Stanisz H, Vogt T, Schwarz EC, Bischoff M, Herrmann M, Tschernig T, Kappl R, Rieger H, Niemeyer BA, Bogeski I (2016) A calcium-redox feedback loop controls human monocyte immune responses: the role of ORAI Ca2+ channels. Sci Signal 9:ra26PubMedCrossRefGoogle Scholar
  91. 91.
    Sena LA, Chandel NS (2012) Physiological roles of mitochondrial reactive oxygen species. Mol Cell 48:158–167PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Song IS, Kim HK, Lee SR, Jeong SH, Kim N, Ko KS, Rhee BD, Han J (2013) Mitochondrial modulation decreases the bortezomib-resistance in multiple myeloma cells. Int J Cancer 133:1357–1367PubMedCrossRefGoogle Scholar
  93. 93.
    De Stefani D, Patron M, Rizzuto R (2015) Structure and function of the mitochondrial calcium uniporter complex. Biochim Biophys Acta 1853:2006–2011PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Takata N, Ohshima Y, Suzuki-Karasaki M, Yoshida Y, Tokuhashi Y, Suzuki-Karasaki Y (2017) Mitochondrial Ca2+ removal amplifies TRAIL cytotoxicity toward apoptosis-resistant tumor cells via promotion of multiple cell death modalities. Int J Oncol 51:193–203PubMedCrossRefGoogle Scholar
  95. 95.
    Tang S, Wang X, Shen Q, Yang X, Yu C, Cai C, Cai G, Meng X, Zou F (2015) Mitochondrial Ca(2)(+) uniporter is critical for store-operated Ca(2)(+) entry-dependent breast cancer cell migration. Biochem Biophys Res Commun 458:186–193PubMedCrossRefGoogle Scholar
  96. 96.
    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, Jana 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 15:1673–1685PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Tosatto A, Sommaggio R, Kummerow C, Bentham RB, Blacker TS, Berecz T, Duchen MR, Rosato A, Bogeski I, Szabadkai G, Rizzuto R, Mammucari C (2016) The mitochondrial calcium uniporter regulates breast cancer progression via HIF-1alpha. EMBO Mol Med 8:569–585PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    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
  99. 99.
    Vyas S, Zaganjor E, Haigis MC (2016) Mitochondria and cancer. Cell 166:555–566PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Warburg O (1956) On the origin of cancer cells. Science 123(3191):309–314PubMedCrossRefGoogle Scholar
  101. 101.
    Wiel C, Lallet-Daher H, Gitenay D, Gras B, Le Calve B, Augert A, Ferrand M, Prevarskaya N, Simonnet H, Vindrieux D, Bernard D (2014) Endoplasmic reticulum calcium release through ITPR2 channels leads to mitochondrial calcium accumulation and senescence. Nat Commun 5:3792PubMedCrossRefGoogle Scholar
  102. 102.
    Wu Y, Sarkissyan M, Vadgama JV (2016) Epithelial-mesenchymal transition and breast cancer. J Clin Med 5(2).
  103. 103.
    Yoon MJ, Lee AR, Jeong SA, Kim YS, Kim JY, Kwon YJ, Choi KS (2014) Release of Ca2+ from the endoplasmic reticulum and its subsequent influx into mitochondria trigger celastrol-induced paraptosis in cancer cells. Oncotarget 5:6816–6831PubMedPubMedCentralGoogle Scholar
  104. 104.
    Yu C, Wang Y, Peng J, Shen Q, Chen M, Tang W, Li X, Cai C, Wang B, Cai S, Meng X, Zou F (2017) Mitochondrial calcium uniporter as a target of microRNA-340 and promoter of metastasis via enhancing the Warburg effect. Oncotarget 8:83831–83844PubMedPubMedCentralGoogle Scholar
  105. 105.
    Zhou X, Ren Y, Kong L, Cai G, Sun S, Song W, Wang Y, Jin R, Qi L, Mei M, Wang X, Kang C, Li M, Zhang L (2015) Targeting EZH2 regulates tumor growth and apoptosis through modulating mitochondria dependent cell-death pathway in HNSCC. Oncotarget 6:33720–33732PubMedPubMedCentralGoogle Scholar
  106. 106.
    Zorov DB, Juhaszova M, Sollott SJ (2014) Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release. Physiol Rev 94:909–950PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Molecular Physiology, Institute of Cardiovascular Physiology, University Medical CenterGeorg-August-UniversityGöttingenGermany
  2. 2.Department of Dermatology, Venereology and Allergology, University Medical CenterGeorg-August-UniversityGöttingenGermany

Personalised recommendations