Enjoy the Trip: Calcium in Mitochondria Back and Forth

Annual Review of Biochemistry

Volumn 85, Issue , 2016, Pages 161-192

  De Stefani, Diego ^a   Rizzuto, Rosario ^a,b   Pozzan, Tullio ^a,b,c  

^a UNIVERSITY OF PADOVA   (Italy)

^b CNR   (Italy)

^c VENETIAN INSTITUTE OF MOLECULAR MEDICINE   (Italy)

Author keywords

Ca2+ signaling; MCU complex; NCLX

Indexed keywords

CALCIUM; CALCIUM CHANNEL; MITOCHONDRIAL CALCIUM UNIPORTER; SLC24A6 PROTEIN, HUMAN; SODIUM CALCIUM EXCHANGE PROTEIN;

ARTICLE; CALCIUM HOMEOSTASIS; CALCIUM TRANSPORT; CELL FUNCTION; CELL ORGANELLE; GENETIC MANIPULATION; HUMAN; MITOCHONDRIAL MEMBRANE; MITOCHONDRION; MOLECULAR DYNAMICS; NONHUMAN; PRIORITY JOURNAL; THERMODYNAMICS; ANIMAL; CALCIUM SIGNALING; CHEMISTRY; GENE EXPRESSION REGULATION; GENETICS; HOMEOSTASIS; ION TRANSPORT; KINETICS; METABOLISM; MOLECULAR MODEL; ULTRASTRUCTURE;

ANIMALS; CALCIUM; CALCIUM CHANNELS; CALCIUM SIGNALING; GENE EXPRESSION REGULATION; HOMEOSTASIS; HUMANS; ION TRANSPORT; KINETICS; MITOCHONDRIA; MITOCHONDRIAL MEMBRANES; MODELS, MOLECULAR; SODIUM-CALCIUM EXCHANGER; THERMODYNAMICS;

EID: 84974666820     PISSN: 00664154     EISSN: 15454509     Source Type: Book Series    
DOI: 10.1146/annurev-biochem-060614-034216     Document Type: Article

References (178)

1. Palty R, Silverman WF, Hershfinkel M, Caporale T, Sensi SL, et al. 2010. NCLX is an essential component of mitochondrial Na+/Ca2+ exchange. PNAS 107:436-41
2. Perocchi F, Gohil VM, Girgis HS, Bao XR, McCombs JE, et al. 2010. MICU1 encodes a mitochondrial EF hand protein required for Ca2+ uptake. Nature 467:291-96
3. 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 476:336-40
4. Baughman JM, Perocchi F, Girgis HS, Plovanich M, Belcher-Timme CA, et al. 2011. Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter. Nature 476:341-45
5. Raffaello A, De Stefani D, Sabbadin D, Teardo E, Merli G, et al. 2013. The mitochondrial calcium uniporter is a multimer that can include a dominant-negative pore-forming subunit. EMBO J. 32:2362-76
6. Plovanich M, Bogorad RL, Sancak Y, Kamer KJ, Strittmatter L, et al. 2013. MICU2, a paralog of MICU1, resides within the mitochondrial uniporter complex to regulate calcium handling. PLOS ONE 8:e55785
7. Mallilankaraman K, Cardenas C, Doonan PJ, Chandramoorthy HC, Irrinki KM, et al. 2012. MCUR1 is an essential component of mitochondrial Ca2+ uptake that regulates cellular metabolism. Nat. Cell Biol. 14:1336-43
8. Sancak Y, Markhard AL, Kitami T, Kovacs-Bogdan E, Kamer KJ, et al. 2013. EMRE is an essential component of the mitochondrial calcium uniporter complex. Science 342:1379-82
9. Hoffman NE, Chandramoorthy HC, Shanmughapriya S, Zhang XQ, Vallem S, et al. 2014. SLC25A23 augments mitochondrial Ca2+ uptake, interacts with MCU, and induces oxidative stress-mediated cell death. Mol. Biol. Cell 25:936-47
10. Deluca HF, Engstrom GW. 1961. Calcium uptake by rat kidney mitochondria. PNAS 47:1744-50
11. Vasington F, Murphy JV. 1962. Ca2+ uptake by rat kidney mitochondria and its dependence on respiration and phosphorylation. J. Biol. Chem. 237:2670-77
12. MacLennan DH, Wong TS. 1971. Isolation of a calcium sequestering protein from sarcoplasmic reticulum. PNAS 68:1231-35
13. BrandMD, Chen CH, Lehninger AL. 1976. Stoichiometry ofH+ ejection during respiration-dependent accumulation of Ca2+ by rat liver mitochondria. J. Biol. Chem. 251:968-74
14. Pozzan T, Bragadin M, Azzone GF. 1977. Disequilibrium between steady-state Ca2+ accumulation ratio and membrane potential in mitochondria. Pathway and role of Ca2+ efflux. Biochemistry 16:5618-25
15. Rossi CS, Vasington FD, Carafoli E. 1973. The effect of ruthenium red on the uptake and release of Ca2+ by mitochondria. Biochem. Biophys. Res. Commun. 50:846-52
16. Pozzan T, Azzone GF. 1976. The coupling of electrical ion fluxes in rat liver mitochondria. FEBS Lett. 72:62-66
17. Crompton M, KunziM, Carafoli E. 1977. The calcium-induced and sodium-induced effluxes of calcium from heart mitochondria. Evidence for a sodium-calcium carrier. Eur. J. Biochem. 79:549-58
18. Nicholls DG. 1978. The regulation of extramitochondrial free calcium ion concentration by rat liver mitochondria. Biochem. J. 176:463-74
19. Nowikovsky K, Pozzan T, Rizzuto R, Scorrano L, Bernardi P. 2012. The pathophysiology of LETM1. J. Gen. Physiol. 139:445-54
20. Rizzuto R, Pinton P, CarringtonW, Fay FS, Fogarty KE, et al. 1998. Close contactswith the endoplasmic reticulum as determinants of mitochondrial Ca2+ responses. Science 280:1763-66
21. Rizzuto R, Brini M, Murgia M, Pozzan T. 1993. Microdomains with high Ca2+ close to IP3-sensitive channels that are sensed by neighboring mitochondria. Science 262:744-47
22. Rizzuto R, Bernardi P, Pozzan T. 2000. Mitochondria as all-round players of the calcium game. J. Physiol. 529(Pt 1):37-47
23. Rizzuto R, Pinton P, Brini M, Chiesa A, Filippin L, Pozzan T. 1999. Mitochondria as biosensors of calcium microdomains. Cell Calcium 26:193-99
24. Rizzuto R, Pozzan T. 2006. Microdomains of intracellular Ca2+: molecular determinants and functional consequences. Physiol. Rev. 86:369-408
25. Montero M, Alonso MT, Carnicero E, Cuchillo-Ibáñez I, Albillos A, et al. 2000. Chromaffin-cell stimulation triggers fast millimolar mitochondrial Ca2+ transients that modulate secretion. Nat. Cell Biol. 2:57-61
26. Nicolli A, Basso E, Petronilli V, Wenger RM, Bernardi P. 1996. Interactions of cyclophilin with the mitochondrial inner membrane and regulation of the permeability transition pore, and cyclosporin Asensitive channel. J. Biol. Chem. 271:2185-92
27. BidenTJ, PrentkiM, IrvineRF, BerridgeMJ, WollheimCB. 1984. Inositol 1, 4, 5-trisphosphatemobilizes intracellular Ca2+ from permeabilized insulin-secreting cells. Biochem. J. 223:467-73
28. Bernardi P. 1999. Mitochondrial transport of cations: channels, exchangers, and permeability transition. Physiol. Rev. 79:1127-55
29. Miyata H, Silverman HS, Sollott SJ, Lakatta EG, Stern MD, Hansford RG. 1991. Measurement of mitochondrial free Ca2+ concentration in living single rat cardiac myocytes. Am. J. Physiol. 261:H1123-34
30. Pozzan T, Rudolf R. 2009. Measurements of mitochondrial calcium in vivo. Biochim. Biophys. Acta 1787:1317-23
31. Rudolf R, Mongillo M, Rizzuto R, Pozzan T. 2003. Looking forward to seeing calcium. Nat. Rev. Mol. Cell Biol. 4:579-86
32. Zacharias DA, BairdGS, TsienRY. 2000. Recent advances in technology formeasuring andmanipulating cell signals. Curr. Opin. Neurobiol. 10:416-21
33. Granatiero V, Patron M, Tosatto A, Merli G, Rizzuto R. 2014. The use of aequorin and its variants for Ca2+ measurements. Cold Spring Harb. Protoc. 2014:9-16
34. Paredes RM, Etzler JC, Watts LT, Zheng W, Lechleiter JD. 2008. Chemical calcium indicators. Methods 46:143-51
35. Kotlikoff MI. 2007. Genetically encoded Ca2+ indicators: using genetics and molecular design to understand complex physiology. J. Physiol. 578:55-67
36. Simpson AW. 2006. Fluorescent measurement of [Ca2+]c: basic practical considerations. Methods Mol. Biol. 312:3-36
37. Demaurex N. 2005. Calcium measurements in organelles with Ca2+-sensitive fluorescent proteins. Cell Calcium 38:213-22
38. Gerasimenko O, Tepikin A. 2005. How to measure Ca2+ in cellular organelles? Cell Calcium 38:201-11
39. Petersen OH, Michalak M, Verkhratsky A. 2005. Calcium signalling: past, present and futurE. Cell Calcium 38:161-69
40. Rizzuto R, Simpson AW, Brini M, Pozzan T. 1992. Rapid changes of mitochondrial Ca2+ revealed by specifically targeted recombinant aequorin. Nature 358:325-27
41. Filippin L, Abad MC, Gastaldello S, Magalhães PJ, Sandonà D, Pozzan T. 2005. Improved strategies for the delivery of GFP-based Ca2+ sensors into the mitochondrial matrix. Cell Calcium 37:129-36
42. Rutter GA, Burnett P, Rizzuto R, BriniM, MurgiaM, et al. 1996. Subcellular imaging of intramitochondrial Ca2+ with recombinant targeted aequorin: significance for the regulation of pyruvate dehydrogenase activity. PNAS 93:5489-94
43. Nunez L, Senovilla L, Sanz-Blasco S, Chamero P, Alonso MT, et al. 2007. Bioluminescence imaging of mitochondrial Ca2+ dynamics in soma and neurites of individual adult mouse sympathetic neurons. J. Physiol. 580:385-95
44. Manjarres IM, Chamero P, Domingo B, Molina F, Llopis J, et al. 2008. Red and green aequorins for simultaneous monitoring of Ca2+ signals from two different organelles. Pflügers Arch. 455:961-70
45. Brandenburger Y, Arrighi J-F, Rossier MF, Maturana A, Vallotton MB, Capponi AM. 1999. Measurement of perimitochondrial Ca2+ concentration in bovine adrenal glomerulosa cells with aequorin targeted to the outer mitochondrial membrane. Biochem. J. 341:745-53
46. Giacomello M, Drago I, Bortolozzi M, Scorzeto M, Gianelle A, et al. 2010. Ca2+ hot spots on the mitochondrial surface are generated by Ca2+ mobilization from stores, but not by activation of storeoperated Ca2+ channels. Mol. Cell 38:280-90
47. Csordas G, Varnai P, Golenar T, Roy S, Purkins G, et al. 2010. Imaging interorganelle contacts and local calcium dynamics at the ER-mitochondrial interface. Mol. Cell 39:121-32
48. Pendin D, Greotti E, Pozzan T. 2014. The elusive importance of being a mitochondrial Ca2+ uniporter. Cell Calcium 55:139-45
49. Marchi S, Pinton P. 2014. Themitochondrial calcium uniporter complex:molecular components, structure and physiopathological implications. J. Physiol. 592:829-39
50. Kamer KJ, Sancak Y, Mootha VK. 2014. The uniporter: from newly identified parts to function. Biochem. Biophys. Res. Commun. 449:370-72
51. Foskett JK, Philipson B. 2015. The mitochondrial Ca2+ uniporter complex. J. Mol. Cell. Cardiol. 78:3-8
52. Ahuja M, Muallem S. 2014. The gatekeepers of mitochondrial calcium influx: MICU1 and MICU2. EMBO Rep. 15:205-6
53. Bick AG, Calvo SE, Mootha VK. 2012. Evolutionary diversity of the mitochondrial calcium uniporter. Science 336:886
54. Cheng Y, Perocchi F. 2015. ProtPhylo: Identification of protein-phenotype and protein-protein functional associations via phylogenetic profiling. Nucleic Acids Res. 43:W160-8
55. Martell JD, Deerinck TJ, Sancak Y, Poulos TL, Mootha VK, et al. 2012. Engineered ascorbate peroxidase as a genetically encoded reporter for electron microscopy. Nat. Biotechnol. 30:1143-48
56. Chaudhuri D, Sancak Y, Mootha VK, Clapham DE. 2013. MCU encodes the pore conducting mitochondrial calcium currents. ELife 2:e00704
57. Drago I, De Stefani D, Rizzuto R, Pozzan T. 2012. Mitochondrial Ca2+ uptake contributes to buffering cytoplasmic Ca2+ peaks in cardiomyocytes. PNAS 109:12986-91
58. Tarasov AI, Semplici F, Ravier MA, Bellomo EA, Pullen TJ, et al. 2012. The mitochondrial Ca2+ uniporter MCU is essential for glucose-induced ATP increases in pancreatic cells. PLOS ONE 7:e39722
59. Alam MR, Groschner LN, Parichatikanond W, Kuo L, Bondarenko AI, et al. 2012. Mitochondrial Ca2+ uptake 1 (MICU1) and mitochondrial Ca2+ uniporter (MCU) contribute to metabolism-secretion coupling in clonal pancreatic cells. J. Biol. Chem. 287:34445-54
60. Qiu J, Tan YW, Hagenston AM, Martel MA, Kneisel N, et al. 2013. Mitochondrial calcium uniporter Mcu controls excitotoxicity and is transcriptionally repressed by neuroprotective nuclear calcium signals. Nat. Commun. 4:2034
61. 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. 434:695-700
62. Hall DD, Wu Y, Domann FE, Spitz DR, AndersonME. 2014. Mitochondrial calcium uniporter activity is dispensable for MDA-MB-231 breast carcinoma cell survival. PLOS ONE 9:e96866
63. Pan X, Liu J, Nguyen T, Liu C, Sun J, et al. 2013. The physiological role of mitochondrial calcium revealed by mice lacking the mitochondrial calcium uniporter. Nat. Cell Biol. 15:1464-72
64. Kirichok Y, KrapivinskyG, Clapham DE. 2004. Themitochondrial calcium uniporter is a highly selective ion channel. Nature 427:360-64
65. Michels G, Khan IF, Endres-Becker J, Rottlaender D, Herzig S, et al. 2009. Regulation of the human cardiac mitochondrial Ca2+ uptake by 2 different voltage-gated Ca2+ channels. Circulation 119:2435-43
66. Fieni F, Lee SB, Jan YN, Kirichok Y. 2012. Activity of themitochondrial calcium uniporter varies greatly between tissues. Nat. Commun. 3:1317
67. Barel O, Shalev SA, Ofir R, Cohen A, Zlotogora J, et al. 2008. Maternally inherited Birk Barel mental retardation dysmorphism syndrome caused by a mutation in the genomically imprinted potassium channel KCNK9. Am. J. Hum. Genet. 83:193-99
68. Jeanguenin L, Alcon C, Duby G, Boeglin M, Cherel I, et al. 2011. AtKC1 is a general modulator of Arabidopsis inward Shaker channel activity. Plant J. 67:570-82
69. Cambridge SB, Gnad F, Nguyen C, Bermejo JL, Kruger M, Mann M. 2011. Systems-wide proteomic analysis in mammalian cells reveals conserved, functional protein turnover. J. Proteome Res. 10:5275-84
70. Patron M, Checchetto V, Raffaello A, Teardo E, Vecellio Reane D, et al. 2014. MICU1 and MICU2 finely tune the mitochondrial Ca2+ uniporter by exerting opposite effects on MCU activity. Mol. Cell 53:726-37
71. Kovacs-Bogdan E, Sancak Y, Kamer KJ, Plovanich M, Jambhekar A, et al. 2014. Reconstitution of the mitochondrial calcium uniporter in yeast. PNAS 111:8985-90
72. Hung V, Zou P, Rhee HW, Udeshi ND, Cracan V, et al. 2014. Proteomic mapping of the human mitochondrial intermembrane space in live cells via ratiometric APEX tagging. Mol. Cell 55:332-41
73. Mallilankaraman K, Doonan P, Cardenas C, Chandramoorthy HC, Muller M, et al. 2012. MICU1 is an essential gatekeeper for MCU-mediated mitochondrial Ca2+ uptake that regulates cell survival. Cell 151:630-44
74. Csordás G, Golenár T, Seifert EL, Kamer KJ, Sancak Y, et al. 2013. MICU1 controls both the threshold and cooperative activation of the mitochondrial Ca2+ uniporter. Cell Metab. 17(6):976-87
75. 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 themitochondrial calcium uniporter. CellMetab. 21:109-16
76. Bassi MT, Manzoni M, Bresciani R, Pizzo MT, Della Monica A, et al. 2005. Cellular expression and alternative splicing of SLC25A23, a member of the mitochondrial Ca2+-dependent solute carrier gene family. Gene 345:173-82
77. Rueda CB, Llorente-Folch I, Amigo I, Contreras L, Gonzalez-Sanchez P, et al. 2014. Ca2+ regulation of mitochondrial function in neurons. Biochim. Biophys. Acta 1837:1617-24
78. Bragadin M, Pozzan T, Azzone GF. 1979. Kinetics of Ca2+ carrier in rat liver mitochondria. Biochemistry 18:5972-78
79. Corry B, Allen TW, Kuyucak S, Chung SH. 2001. Mechanisms of permeation and selectivity in calcium channels. Biophys. J. 80:195-214
80. Joiner ML, Koval OM, Li J, He BJ, Allamargot C, et al. 2012. CaMKII determines mitochondrial stress responses in heart. Nature 491:269-73
81. Lee Y, Min CK, Kim TG, Song HK, Lim Y, et al. 2015. Structure and function of the N-terminal domain of the human mitochondrial calcium uniporter. EMBO Rep. 16:1318-33
82. Wang L, Yang X, Li S, Wang Z, Liu Y, et al. 2014. Structural and mechanistic insights into MICU1 regulation of mitochondrial calcium uptake. EMBO J. 33:594-604
83. Rizzuto R, Duchen MR, Pozzan T. 2004. Flirting in little space: The ER/mitochondria Ca2+ liaison. Sci. Signal Transduct. Knowl. Environ. 2004:re1
84. Shanmughapriya S, Rajan S, Hoffman NE, Zhang X, Guo S, et al. 2015. Ca2+ signals regulate mitochondrial metabolism by stimulating CREB-mediated expression of the mitochondrial Ca2+ uniporter gene MCU. Sci. Signal. 8:ra23
85. Shaywitz AJ, Greenberg ME. 1999. CREB: A stimulus-induced transcription factor activated by a diverse array of extracellular signals. Annu. Rev. Biochem. 68:821-61
86. Rizzuto R, Pinton P, Ferrari D, Chami M, Szabadkai G, et al. 2003. Calcium and apoptosis: facts and hypotheses. Oncogene 22:8619-27
87. Marchi S, Lupini L, Patergnani S, Rimessi A, Missiroli S, et al. 2013. Downregulation of the mitochondrial calcium uniporter by cancer-related miR-25. Curr. Biol. 23:58-63
88. Marchi S, Pinton P. 2013. Mitochondrial calcium uniporter, MiRNA and cancer: live and let diE. Commun. Integr. Biol. 6:e23818
89. Lanza G, Ferracin M, Gafa R, Veronese A, Spizzo R, et al. 2007. mRNA/microRNA gene expression profile in microsatellite unstable colorectal cancer. Mol. Cancer 6:54
90. SparagnaGC, Gunter KK, Sheu SS, Gunter TE. 1995. Mitochondrial calcium uptake from physiologicaltype pulses of calcium. A description of the rapid uptake mode. J. Biol. Chem. 270:27510-15
91. Buntinas L, Gunter KK, Sparagna GC, Gunter TE. 2001. The rapid mode of calcium uptake into heart mitochondria (RaM): comparison to RaM in liver mitochondria. Biochim. Biophys. Acta 1504:248-61
92. Bondarenko AI, Jean-Quartier C, Malli R, GraierWF. 2013. Characterization of distinct single-channel properties of Ca2+ inward currents in mitochondria. Pflügers Arch. 465:997-1010
93. Wei AC, LiuT, Winslow RL, O'Rourke B. 2012. Dynamics of matrix-free Ca2+ in cardiac mitochondria: Two components of Ca2+ uptake and role of phosphate buffering. J. Gen. Physiol. 139:465-78
94. BeutnerG, Sharma VK, Giovannucci DR, Yule DI, Sheu SS. 2001. Identification of a ryanodine receptor in rat heart mitochondria. J. Biol. Chem. 276:21482-88
95. 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. 9:445-52
96. Jiang D, Zhao L, Clapham DE. 2009. Genome-wide RNAi screen identifies Letm1 as a mitochondrial Ca2+/H+ antiporter. Science 326:144-47
97. Nowikovsky K, Bernardi P. 2014. LETM1 in mitochondrial cation transport. Front. Physiol. 5:83
98. Brookes PS, ParkerN, Buckingham JA, Vidal-Puig A, Halestrap AP, et al. 2008. UCPs-unlikely calcium porters. Nat. Cell Biol. 10:1235-37; author reply 1237-40
99. Tsai MF, Jiang D, Zhao L, Clapham D, Miller C. 2014. Functional reconstitution of the mitochondrial Ca2+/H+ antiporter Letm1. J. Gen. Physiol. 143:67-73
100. McQuibban AG, Joza N, Megighian A, Scorzeto M, Zanini D, et al. 2010. A Drosophila mutant of LETM1, a candidate gene for seizures inWolf-Hirschhorn syndrome. Hum. Mol. Genet. 19:987-1000
101. Paucek P, Jaburek M. 2004. Kinetics and ion specificity of Na+/Ca2+ exchange mediated by the reconstituted beef heart mitochondrial Na+/Ca2+ antiporter. Biochim. Biophys. Acta 1659:83-91
102. Carafoli E, Tiozzo R, Lugli G, Crovetti F, Kratzing C. 1974. The release of calcium from heart mitochondria by sodium. J. Mol. Cell. Cardiol. 6:361-71
103. Sekler I. 2015. Standing of giants shoulders the story of themitochondrial Na+Ca2+ exchanger. Biochem. Biophys. Res. Commun. 460:50-52
104. Nita II, Hershfinkel M, Lewis EC, Sekler I. 2015. A crosstalk between Na+ channels, Na+/K+ pump and mitochondrial Na+ transporters controls glucose-dependent cytosolic and mitochondrial Na+ signals. Cell Calcium 57:69-75
105. Nita II, Hershfinkel M, Kantor C, Rutter GA, Lewis EC, Sekler I. 2014. Pancreatic cellNa+ channels control global Ca2+ signaling and oxidative metabolism by inducing Na+ and Ca2+ responses that are propagated into mitochondria. FASEB J. 28:3301-12
106. Takeuchi A, Kim B, Matsuoka S. 2013. The mitochondrial Na+-Ca2+ exchanger, NCLX, regulates automaticity of HL-1 cardiomyocytes. Sci. Rep. 3:2766
107. Parnis J, Montana V, Delgado-Martinez I, Matyash V, Parpura V, et al. 2013. Mitochondrial exchanger NCLX plays a major role in the intracellular Ca2+ signaling, gliotransmission, and proliferation of astrocytes. J. Neurosci. 33:7206-19
108. Liao J, Li H, Zeng W, Sauer DB, Belmares R, Jiang Y. 2012. Structural insight into the ion-exchange mechanism of the sodium/calcium exchanger. Science 335:686-90
109. Marinelli F, Almagor L, Hiller R, Giladi M, Khananshvili D, Faraldo-Gomez JD. 2014. Sodium recognition by the Na+/Ca2+ exchanger in the outward-facing conformation. PNAS 111:E5354-62
110. Arslan P, Di Virgilio F, Beltrame M, Tsien RY, Pozzan T. 1985. Cytosolic Ca2+ homeostasis in Ehrlich and Yoshida carcinomas. A new, membrane-permeant chelator of heavy metals reveals that these ascites tumor cell lines have normal cytosolic free Ca2+. J. Biol. Chem. 260:2719-27
111. Plesner L, Plesner IW. 1991. Kinetics of oligomycin inhibition and activation of Na+/K+-ATPase. Biochim. Biophys. Acta 1076:421-26
112. Robinson JD. 1971. Effects of oligomycin on the (Na+ + K+)-dependent adenosine triphosphatase. Mol. Pharmacol. 7:238-46
113. Ruiz A, Alberdi E, Matute C. 2014. CGP37157, an inhibitor of the mitochondrial Na+/Ca2+ exchanger, protects neurons from excitotoxicity by blocking voltage-gated Ca2+ channels. Cell Death Dis. 5:e1156
114. Hajnóczky G, Csordás G, Das S, Garcia-Perez C, Saotome M, et al. 2006. Mitochondrial calcium signalling and cell death: Approaches for assessing the role of mitochondrial Ca2+ uptake in apoptosis. Cell Calcium 40:553-60
115. McCormack JG, Halestrap AP, Denton RM. 1990. Role of calcium ions in regulation of mammalian intramitochondrial metabolism. Physiol. Rev. 70:391-425
116. Denton RM, Randle PJ, Martin BR. 1972. Stimulation by calcium ions of pyruvate dehydrogenase phosphate phosphatase. Biochem. J. 128:161-63
117. Rutter GA, Denton RM. 1988. Regulation ofNAD+-linked isocitrate dehydrogenase and 2-oxoglutarate dehydrogenase by Ca2+ ions within toluene-permeabilized rat heart mitochondria. Interactions with regulation by adenine nucleotides and NADH/NAD+ ratios. Biochem. J. 252:181-89
118. Denton RM. 2009. Regulation of mitochondrial dehydrogenases by calcium ions. Biochim. Biophys. Acta 1787:1309-16
119. Spat A, Hunyady L. 2004. Control of aldosterone secretion: Amodel for convergence in cellular signaling pathways. Physiol. Rev. 84:489-539
120. Maechler P, WollheimCB. 1999. Mitochondrial glutamate acts as a messenger in glucose-induced insulin exocytosis. Nature 402:685-89
121. Wollheim CB, Maechler P. 2015. ?cell glutamate receptor antagonists: Novel oral antidiabetic drugs? Nat. Med. 21:310-11
122. Rasola A, Bernardi P. 2011. Mitochondrial permeability transition in Ca2+-dependent apoptosis and necrosis. Cell Calcium 50:222-33
123. Giorgio V, von Stockum S, Antoniel M, Fabbro A, Fogolari F, et al. 2013. Dimers of mitochondrial ATP synthase form the permeability transition pore. PNAS 110:5887-92
124. Bernardi P, Di Lisa F, Fogolari F, Lippe G. 2015. From ATP to PTP and back: A dual function for the mitochondrial ATP synthasE. Circ. Res. 116:1850-62
125. Bonora M, Bononi A, De Marchi E, Giorgi C, Lebiedzinska M, et al. 2013. Role of the c subunit of the FO ATP synthase in mitochondrial permeability transition. Cell Cycle 12:674-83
126. Bonora M, Wieckowski MR, Chinopoulos C, Kepp O, Kroemer G, et al. 2015. Molecular mechanisms of cell death: central implication of ATP synthase in mitochondrial permeability transition. Oncogene 34:1475-86
127. Chinopoulos C, Szabadkai G. 2014. What makes you can also break you, part III: Mitochondrial permeability transition pore formation by an uncoupling channel within the c-subunit ring of the F1FO ATP synthase? Front. Oncol. 4:235
128. Wiederkehr A, Szanda G, Akhmedov D, Mataki C, Heizmann CW, et al. 2011. Mitochondrial matrix calcium is an activating signal for hormone secretion. Cell Metab. 13:601-11
129. Katona D, Rajki A, Di Benedetto G, Pozzan T, Spat A. 2015. Calcium-dependent mitochondrial cAMP production enhances aldosterone secretion. Mol. Cell. Endocrinol. 412:196-204
130. Hansford RG, Zorov D. 1998. Role of mitochondrial calcium transport in the control of substrate oxidation. Mol. Cell. Biochem. 184:359-69
131. Lasorsa FM, Pinton P, Palmieri L, Fiermonte G, Rizzuto R, Palmieri F. 2003. Recombinant expression of the Ca2+-sensitive aspartate/glutamate carrier increases mitochondrial ATP production in agoniststimulated Chinese hamster ovary cells. J. Biol. Chem. 278:38686-92
132. del Arco A, Satrustegui J. 2004. Identification of a novel human subfamily of mitochondrial carriers with calcium-binding domains. J. Biol. Chem. 279:24701-13
133. Satrustegui J, Bak LK. 2015. Fluctuations in cytosolic calcium regulate the neuronal malate-aspartate NADH shuttle: implications for neuronal energy metabolism. Neurochem. Res. 40:2425-30
134. Orrenius S, Zhivotovsky B, Nicotera P. 2003. Regulation of cell death: The calcium-apoptosis link. Nat. Rev. Mol. Cell Biol. 4:552-65
135. HajnoczkyG, Robbgaspers LD, Seitz MB, Thomas AP. 1995. Decoding of cytosolic calcium oscillations in the mitochondria. Cell 82:415-24
136. Pizzo P, Pozzan T. 2007. Mitochondria-endoplasmic reticulum choreography: structure and signaling dynamics. Trends Cell Biol. 17:511-17
137. Csordás G, Thomas AP, Hajnoczky G. 1999. Quasi-synaptic calcium signal transmission between endoplasmic reticulum and mitochondria. EMBO J. 18:96-108
138. Csordás G, Hajnoczky G. 2001. Sorting of calcium signals at the junctions of endoplasmic reticulum and mitochondria. Cell Calcium 29:249-62
139. Bano D, Nicotera P. 2007. Ca2+ signals and neuronal death in brain ischemia. Stroke 38:674-76
140. Werth JL, Thayer SA. 1994. Mitochondria buffer physiological calcium loads in cultured rat dorsal root ganglion neurons. J. Neurosci. 14:348-56
141. Svichar N, Kostyuk P, Verkhratsky A. 1997. Mitochondria buffer Ca2+ entry but not intracellular Ca2+ release in mouse DRG neurones. Neuroreport 8:3929-32
142. Colegrove SL, Albrecht MA, Friel DD. 2000. Quantitative analysis of mitochondrial Ca2+ uptake and release pathways in sympathetic neurons. Reconstruction of the recovery after depolarization-evoked [Ca2+]i elevations. J. Gen. Physiol. 115:371-88
143. Colegrove SL, Albrecht MA, Friel DD. 2000. Dissection ofmitochondrial Ca2+ uptake and release fluxes in situ after depolarization-evoked [Ca2+]i elevations in sympathetic neurons. J. Gen. Physiol. 115:351-70
144. Montero M, Alonso MT, Albillos A, Cuchillo-Ibanez I, Olivares R, et al. 2001. Control of secretion by mitochondria depends on the size of the local [Ca2+] after chromaffin cell stimulation. Eur. J. Neurosci. 13:2247-54
145. Tinel H, Cancela JM, Mogami H, Gerasimenko JV, Gerasimenko OV, et al. 1999. Active mitochondria surrounding the pancreatic acinar granule region prevent spreading of inositol trisphosphate-evoked local cytosolic Ca2+ signals. EMBO J. 18:4999-5008
146. Robert V, Gurlini P, Tosello V, Nagai T, Miyawaki A, et al. 2001. Beat-to-beat oscillations of mitochondrial [Ca2+] in cardiac cells. EMBO J. 20:4998-5007
147. Huser J, Blatter LA, Sheu SS. 2000. Mitochondrial calcium in heart cells: Beat-to-beat oscillations or slow integration of cytosolic transients? J. Bioenerg. Biomembr. 32:27-33
148. Pacher P, Thomas AP, HajnoczkyG. 2002. Ca2+ marks: miniature calcium signals in single mitochondria driven by ryanodine receptors. PNAS 99:2380-85
149. TrollingerDR, Cascio WE, Lemasters JJ. 2000. Mitochondrial calcium transients in adult rabbit cardiac myocytes: inhibition by ruthenium red and artifacts caused by lysosomal loading of Ca2+-indicating fluorophores. Biophys. J. 79:39-50
150. Sedova M, Dedkova EN, Blatter LA. 2006. Integration of rapid cytosolic Ca2+ signals by mitochondria in cat ventricular myocytes. Am. J. Physiol. Cell Physiol. 291:C840-50
151. Maack C, Cortassa S, AonMA, Ganesan AN, LiuT, O'Rourke B. 2006. Elevated cytosolic Na+ decreases mitochondrial Ca2+ uptake during excitation-contraction coupling and impairs energetic adaptation in cardiac myocytes. Circ. Res. 99:172-82
152. Franzini-Armstrong C. 2007. ER-mitochondria communication. How privileged? Physiology 22:261-68
153. Landolfi B, Curci S, Debellis L, Pozzan T, Hofer AM. 1998. Ca2+ homeostasis in the agonist-sensitive internal store: functional interactions between mitochondria and the ER measured in situ in intact cells. J. Cell Biol. 142:1235-43
154. Hajnoczky G, Hager R, Thomas AP. 1999. Mitochondria suppress local feedback activation of inositol 1, 4, 5-trisphosphate receptors by Ca2+. J. Biol. Chem. 274:14157-62
155. Ishii K, Hirose K, Iino M. 2006. Ca2+ shuttling between endoplasmic reticulum and mitochondria underlying Ca2+ oscillations. EMBO Rep. 7:390-96
156. Sanchez JA, Garcia MC, Sharma VK, Young KC, Matlib MA, Sheu SS. 2001. Mitochondria regulate inactivation of L-type Ca2+ channels in rat heart. J. Physiol. 536:387-96
157. Duchen MR. 2004. Mitochondria in health and disease: perspectives on a new mitochondrial biology. Mol. Asp. Med. 25:365-451
158. Hoth M, Fanger CM, Lewis RS. 1997. Mitochondrial regulation of store-operated calcium signaling in T lymphocytes. J. Cell Biol. 137:633-48
159. Quintana A, Schwindling C, Wenning AS, Becherer U, Rettig J, et al. 2007. T cell activation requires mitochondrial translocation to the immunological synapse. PNAS 104:14418-23
160. Parekh AB. 2003. Store-operated Ca2+ entry: dynamic interplay between endoplasmic reticulum, mitochondria and plasma membrane. J. Physiol. 547:333-48
161. GlitschMD, Bakowski D, Parekh AB. 2002. Store-operated Ca2+ entry depends on mitochondrial Ca2+ uptake. EMBO J. 21:6744-54
162. Logan CV, Szabadkai G, Sharpe JA, Parry DA, Torelli S, et al. 2014. Loss-of-function mutations in MICU1 cause a brain and muscle disorder linked to primary alterations in mitochondrial calcium signaling. Nat. Genet. 46:188-93
163. Tarasov AI, Semplici F, Li D, Rizzuto R, Ravier MA, et al. 2013. Frequency-dependent mitochondrial Ca2+ accumulation regulates ATP synthesis in pancreatic ?cells. Pflügers Arch. 465:543-54
164. 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. 17:965-75
165. HuangG, Vercesi AE, Docampo R. 2013. Essential regulation of cell bioenergetics in Trypanosoma brucei by the mitochondrial calcium uniporter. Nat. Commun. 4:2865
166. Prudent J, Popgeorgiev N, Bonneau B, Thibaut J, Gadet R, et al. 2013. Bcl-wav and the mitochondrial calcium uniporter drive gastrula morphogenesis in zebrafish. Nat. Commun. 4:2330
167. Xu S, Chisholm AD. 2014. C. Elegans epidermal wounding induces a mitochondrial ROS burst that promotes wound repair. Dev. Cell 31:48-60
168. Holmstrom KM, Pan X, Liu JC, Menazza S, Liu J, et al. 2015. Assessment of cardiac function in mice lacking the mitochondrial calcium uniporter. J. Mol. Cell. Cardiol. 85:178-82
169. Luongo TS, Lambert JP, Yuan A, Zhang X, Gross P, et al. 2015. The mitochondrial calcium uniporter matches energetic supply with cardiac workload during stress and modulates permeability transition. Cell Rep. 12:23-34
170. Murphy E, Pan X, Nguyen T, Liu J, Holmstrom KM, Finkel T. 2014. Unresolved questions from the analysis of mice lacking MCU expression. Biochem. Biophys. Res. Commun. 449:384-85
171. Wu Y, Rasmussen TP, Koval OM, Joiner ML, Hall DD, et al. 2015. The mitochondrial uniporter controls fight or flight heart rate increases. Nat. Commun. 6:6081
172. Rasmussen TP, Wu Y, Joiner MA, Koval OM, Wilson NR, et al. 2015. Inhibition of MCU forces extramitochondrial adaptations governing physiological and pathological stress responses in heart. PNAS 112:9129-34
173. Kwong JQ, Lu X, Correll RN, Schwanekamp JA, Vagnozzi RJ, et al. 2015. The mitochondrial calcium uniporter selectively matches metabolic output to acute contractile stress in the heart. Cell Rep. 12:15-22
174. Mammucari C, Gherardi G, Zamparo I, Raffaello A, Boncompagni S, et al. 2015. The mitochondrial calcium uniporter controls skeletal muscle trophism in vivo. Cell Rep. 10:1269-79
175. Meeson AP, Radford N, Shelton JM, Mammen PPA, DiMaio JM, et al. 2001. Adaptive mechanisms that preserve cardiac function in mice without myoglobin. Circ. Res. 88:713-20
176. Godecke A, Flogel U, Zanger K, Ding ZP, Hirchenhain J, et al. 1999. Disruption of myoglobin in mice induces multiple compensatory mechanisms. PNAS 96:10495-500
177. Garry DJ, Ordway GA, Lorenz LN, Radford NB, Chin ER, et al. 1998. Mice without myoglobin. Nature 395:905-8
178. De Stefani D, Rizzuto R, 2014. Molecular control of mitochondrial calcium uptake. Biochem. Biophys. Res. Commun. 449(4):373-76