1932

Abstract

Mitochondria are responsible for ATP production but are also known as regulators of cell death, and mitochondrial matrix Ca2+ is a key modulator of both ATP production and cell death. Although mitochondrial Ca2+ uptake and efflux have been studied for over 50 years, it is only in the past decade that the proteins responsible for mitochondrial Ca2+ uptake and efflux have been identified. The identification of the mitochondrial Ca2+ uniporter (MCU) led to an explosion of studies identifying regulators of the MCU. The levels of these regulators vary in a tissue- and disease-specific manner, providing new insight into how mitochondrial Ca2+ is regulated. This review focuses on the proteins responsible for mitochondrial transport and what we have learned from mouse studies with genetic alterations in these proteins.

Keyword(s): Ca2+energeticsmitochondriasodium
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2021-02-10
2024-03-29
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Literature Cited

  1. 1. 
    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
    [Google Scholar]
  2. 2. 
    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
    [Google Scholar]
  3. 3. 
    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
    [Google Scholar]
  4. 4. 
    Deluca HF, Engstrom GW. 1961. Calcium uptake by rat kidney mitochondria. PNAS 47:1744–50
    [Google Scholar]
  5. 5. 
    Vasington FD, Murphy JV. 1962. Ca ion uptake by rat kidney mitochondria and its dependence on respiration and phosphorylation. J. Biol. Chem. 237:2670–77
    [Google Scholar]
  6. 6. 
    Lehninger AL. 1970. Mitochondria and calcium ion transport. Biochem. J. 119:129–38
    [Google Scholar]
  7. 7. 
    Gunter TE, Pfeiffer DR. 1990. Mechanisms by which mitochondria transport calcium. Am. J. Physiol. 258:C755–86
    [Google Scholar]
  8. 8. 
    Rizzuto R, Bernardi P, Favaron M, Azzone GF 1987. Pathways for Ca2+ efflux in heart and liver mitochondria. Biochem. J. 246:271–77
    [Google Scholar]
  9. 9. 
    Nicholls DG, Crompton M. 1980. Mitochondrial calcium transport. FEBS Lett 111:261–68
    [Google Scholar]
  10. 10. 
    Scarpa A, Graziotti P. 1973. Mechanisms for intracellular calcium regulation in heart. I. Stopped-flow measurements of Ca++ uptake by cardiac mitochondria. J. Gen. Physiol. 62:756–72
    [Google Scholar]
  11. 11. 
    Akerman KE, Wikstrom MK, Saris NE 1977. Effect of inhibitors on the sigmoidicity of the calcium ion transport kinetics in rat liver mitochondria. Biochim. Biophys. Acta 464:287–94
    [Google Scholar]
  12. 12. 
    Kirichok Y, Krapivinsky G, Clapham DE 2004. The mitochondrial calcium uniporter is a highly selective ion channel. Nature 427:360–64
    [Google Scholar]
  13. 13. 
    Fieni F, Lee SB, Jan YN, Kirichok Y 2012. Activity of the mitochondrial calcium uniporter varies greatly between tissues. Nat. Commun. 3:1317
    [Google Scholar]
  14. 14. 
    Haworth RA, Hunter DR. 1979. The Ca2+-induced membrane transition in mitochondria: II. Nature of the Ca2+ trigger site. Arch. Biochem. Biophys. 195:460–67
    [Google Scholar]
  15. 15. 
    Murphy E, Steenbergen C. 2011. What makes the mitochondria a killer? Can we condition them to be less destructive. Biochim. Biophys. Acta 1813:1302–8
    [Google Scholar]
  16. 16. 
    Bauer TM, Murphy E. 2020. Role of mitochondrial calcium and the permeability transition pore in regulating cell death. Circ. Res. 126:280–93
    [Google Scholar]
  17. 17. 
    Bernardi P, Vassanelli S, Veronese P, Colonna R, Szabó I, Zoratti M 1992. Modulation of the mitochondrial permeability transition pore. Effect of protons and divalent cations. J. Biol. Chem. 267:2934–39
    [Google Scholar]
  18. 18. 
    Halestrap AP. 2009. What is the mitochondrial permeability transition pore?. J. Mol. Cell. Cardiol. 46:821–31
    [Google Scholar]
  19. 19. 
    Giorgio V, Burchell V, Schiavone M, Bassot C, Minervini G et al. 2017. Ca2+ binding to F‐ATP synthase β subunit triggers the mitochondrial permeability transition. EMBO Rep 18:1065–76
    [Google Scholar]
  20. 20. 
    Amanakis G, Sun J, Fergusson MM, McGinty S, Liu C et al. 2020. Cysteine 202 of cyclophilin D is a site of multiple post-translational modifications and plays a role in cardioprotection. Cardiovasc. Res. In press. https://doi.org/10.1093/cvr/cvaa053
    [Crossref] [Google Scholar]
  21. 21. 
    Glancy B, Willis WT, Chess DJ, Balaban RS 2013. Effect of calcium on the oxidative phosphorylation cascade in skeletal muscle mitochondria. Biochemistry 52:2793–809
    [Google Scholar]
  22. 22. 
    Denton RM, McCormack JG. 1980. The role of calcium in the regulation of mitochondrial metabolism. Biochem. Soc. Trans. 8:266–68
    [Google Scholar]
  23. 23. 
    Brandes R, Bers DM. 2002. Simultaneous measurements of mitochondrial NADH and Ca2+ during increased work in intact rat heart trabeculae. Biophys. J. 83:587–604
    [Google Scholar]
  24. 24. 
    Liu T, O'Rourke B. 2008. Enhancing mitochondrial Ca2+ uptake in myocytes from failing hearts restores energy supply and demand matching. Circ. Res. 103:279–88
    [Google Scholar]
  25. 25. 
    Chalmers S, Nicholls DG. 2003. The relationship between free and total calcium concentrations in the matrix of liver and brain mitochondria. J. Biol. Chem. 278:19062–70
    [Google Scholar]
  26. 26. 
    Nicholls DG. 1978. The regulation of extramitochondrial free calcium ion concentration by rat liver mitochondria. Biochem. J. 176:463–74
    [Google Scholar]
  27. 27. 
    Hansford RG, Castro F. 1982. Intramitochondrial and extramitochondrial free calcium ion concentrations of suspensions of heart mitochondria with very low, plausibly physiological, contents of total calcium. J. Bioenerg. Biomembr. 14:361–76
    [Google Scholar]
  28. 28. 
    O'Rourke B, Blatter LA. 2009. Mitochondrial Ca2+ uptake: Tortoise or hare. J. Mol. Cell. Cardiol. 46:767–74
    [Google Scholar]
  29. 29. 
    Wescott AP, Kao JPY, Lederer WJ, Boyman L 2019. Voltage-energized calcium-sensitive ATP production by mitochondria. Nat. Metab. 1:975–84
    [Google Scholar]
  30. 30. 
    Amoedo ND, Punzi G, Obre E, Lacombe D, De Grassi A et al. 2016. AGC1/2, the mitochondrial aspartate-glutamate carriers. Biochim. Biophys. Acta 1863:2394–412
    [Google Scholar]
  31. 31. 
    Tomar D, Dong Z, Shanmughapriya S, Koch DA, Thomas T et al. 2016. MCUR1 is a scaffold factor for the MCU complex function and promotes mitochondrial bioenergetics. Cell Rep 15:1673–85
    [Google Scholar]
  32. 32. 
    Chaudhuri D, Artiga DJ, Abiria SA, Clapham DE 2016. Mitochondrial calcium uniporter regulator 1 (MCUR1) regulates the calcium threshold for the mitochondrial permeability transition. PNAS 113:E1872–80
    [Google Scholar]
  33. 33. 
    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 21:109–16
    [Google Scholar]
  34. 34. 
    Nguyen NX, Armache JP, Lee C, Yang Y, Zeng W et al. 2018. Cryo-EM structure of a fungal mitochondrial calcium uniporter. Nature 559:570–74
    [Google Scholar]
  35. 35. 
    Baradaran R, Wang C, Siliciano AF, Long SB 2018. Cryo-EM structures of fungal and metazoan mitochondrial calcium uniporters. Nature 559:580–84
    [Google Scholar]
  36. 36. 
    Yoo J, Wu M, Yin Y, Herzik MA Jr. Lander GC. Lee SY 2018. Cryo-EM structure of a mitochondrial calcium uniporter. Science 361:506–11
    [Google Scholar]
  37. 37. 
    Fan M, Zhang J, Tsai CW, Orlando BJ, Rodriguez M et al. 2020. Structure and mechanism of the mitochondrial Ca2+ uniporter holocomplex. Nature 582:129–33
    [Google Scholar]
  38. 38. 
    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
    [Google Scholar]
  39. 39. 
    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
    [Google Scholar]
  40. 40. 
    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
    [Google Scholar]
  41. 41. 
    Rasmussen TP, Wu Y, Joiner ML, 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
    [Google Scholar]
  42. 42. 
    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
    [Google Scholar]
  43. 43. 
    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
    [Google Scholar]
  44. 44. 
    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
    [Google Scholar]
  45. 45. 
    Altamimi TR, Karwi QG, Uddin GM, Fukushima A, Kwong JQ et al. 2019. Cardiac-specific deficiency of the mitochondrial calcium uniporter augments fatty acid oxidation and functional reserve. J. Mol. Cell. Cardiol. 127:223–31
    [Google Scholar]
  46. 46. 
    Kwong JQ, Huo J, Bround MJ, Boyer JG, Schwanekamp JA et al. 2018. The mitochondrial calcium uniporter underlies metabolic fuel preference in skeletal muscle. JCI Insight 3:e121689
    [Google Scholar]
  47. 47. 
    Parks RJ, Menazza S, Holmström KM, Amanakis G, Fergusson M et al. 2019. Cyclophilin D-mediated regulation of the permeability transition pore is altered in mice lacking the mitochondrial calcium uniporter. Cardiovasc. Res. 115:385–94
    [Google Scholar]
  48. 48. 
    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
    [Google Scholar]
  49. 49. 
    Lambert JP, Luongo TS, Tomar D, Jadiya P, Gao E et al. 2019. MCUB regulates the molecular composition of the mitochondrial calcium uniporter channel to limit mitochondrial calcium overload during stress. Circulation 140:1720–33
    [Google Scholar]
  50. 50. 
    Huo J, Lu S, Kwong JQ, Bround MJ, Grimes KM et al. 2020. MCUb induction protects the heart from post-ischemic remodeling. Circ. Res. 127:379–90
    [Google Scholar]
  51. 51. 
    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
    [Google Scholar]
  52. 52. 
    Patron M, Checchetto V, Raffaello A, Teardo E, Reane DV et al. 2014. MICU1 and MICU2 finely tune the mitochondrial Ca2+ uniporter by exerting opposite effects on MCU activity. Mol. Cell 53:726–37
    [Google Scholar]
  53. 53. 
    Paillard M, Csordás G, Huang KT, Varnai P, Joseph SK, Hajnoczky G 2018. MICU1 interacts with the D-ring of the MCU pore to control its Ca2+ flux and sensitivity to Ru360. Mol. Cell 72:778–85.e3
    [Google Scholar]
  54. 54. 
    Paillard M, Csordás G, Szanda G, Golenár T, Debattisti V et al. 2017. Tissue-specific mitochondrial decoding of cytoplasmic Ca2+ signals is controlled by the stoichiometry of MICU1/2 and MCU. Cell Rep 18:2291–300
    [Google Scholar]
  55. 55. 
    Kamer KJ, Grabarek Z, Mootha VK 2017. High-affinity cooperative Ca2+ binding by MICU1-MICU2 serves as an on-off switch for the uniporter. EMBO Rep 18:1397–411
    [Google Scholar]
  56. 56. 
    Patron M, Granatiero V, Espino J, Rizzuto R, De Stefani D 2019. MICU3 is a tissue-specific enhancer of mitochondrial calcium uptake. Cell Death Differ 26:179–95
    [Google Scholar]
  57. 57. 
    Liu JC, Liu J, Holmström KM, Menazza S, Parks RJ et al. 2016. MICU1 serves as a molecular gatekeeper to prevent in vivo mitochondrial calcium overload. Cell Rep 16:1561–73
    [Google Scholar]
  58. 58. 
    Antony AN, Paillard M, Moffat C, Juskeviciute E, Correnti J et al. 2016. MICU1 regulation of mitochondrial Ca2+ uptake dictates survival and tissue regeneration. Nat. Commun. 7:10955
    [Google Scholar]
  59. 59. 
    Csordás G, Golenar 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 17:976–87
    [Google Scholar]
  60. 60. 
    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
    [Google Scholar]
  61. 61. 
    Reane DV, Vallese F, Checchetto V, Acquasaliente L, Butera G et al. 2016. A MICU1 splice variant confers high sensitivity to the mitochondrial Ca2+ uptake machinery of skeletal muscle. Mol. Cell 64:760–73
    [Google Scholar]
  62. 62. 
    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
    [Google Scholar]
  63. 63. 
    Lewis-Smith D, Kamer KJ, Griffin H, Childs AM, Pysden K et al. 2016. Homozygous deletion in MICU1 presenting with fatigue and lethargy in childhood. Neurol. Genet. 2:e59
    [Google Scholar]
  64. 64. 
    Debattisti V, Horn A, Singh R, Seifert EL, Hogarth MW et al. 2019. Dysregulation of mitochondrial Ca2+ uptake and sarcolemma repair underlie muscle weakness and wasting in patients and mice lacking MICU1. Cell Rep 29:1274–86.e6
    [Google Scholar]
  65. 65. 
    Tufi R, Gleeson TP, von Stockum S, Hewitt VL, Lee JJ et al. 2019. Comprehensive genetic characterization of mitochondrial Ca2+ uniporter components reveals their different physiological requirements in vivo. Cell Rep 27:1541–50.e5
    [Google Scholar]
  66. 66. 
    Gottschalk B, Klec C, Leitinger G, Bernhart E, Rost R et al. 2019. MICU1 controls cristae junction and spatially anchors mitochondrial Ca2+ uniporter complex. Nat. Commun. 10:3732
    [Google Scholar]
  67. 67. 
    Bick AG, Wakimoto H, Kamer KJ, Sancak Y, Goldberger O et al. 2017. Cardiovascular homeostasis dependence on MICU2, a regulatory subunit of the mitochondrial calcium uniporter. PNAS 114:E9096–104
    [Google Scholar]
  68. 68. 
    Ashrafi G, de Juan-Sanz J, Farrell RJ, Ryan TA 2020. Molecular tuning of the axonal mitochondrial Ca2+ uniporter ensures metabolic flexibility of neurotransmission. Neuron 105:678–87.e5
    [Google Scholar]
  69. 69. 
    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
    [Google Scholar]
  70. 70. 
    Wang Y, Nguyen NX, She J, Zeng W, Yang Y et al. 2019. Structural mechanism of EMRE-dependent gating of the human mitochondrial calcium uniporter. Cell 177:1252–61.e13
    [Google Scholar]
  71. 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
    [Google Scholar]
  72. 72. 
    Liu J, Syder N, Ghorashi N, Willingham T, Parks RJ et al. 2020. EMRE is essential for mitochondrial calcium uniporter activity in a mouse model. JCI Insight 5:e134063
    [Google Scholar]
  73. 73. 
    Ji L, Liu F, Jing Z, Huang Q, Zhao Y et al. 2017. MICU1 alleviates diabetic cardiomyopathy through mitochondrial Ca2+-dependent antioxidant response. Diabetes 66:1586–600
    [Google Scholar]
  74. 74. 
    Das S, Ferlito M, Kent OA, Fox-Talbot K, Wang R et al. 2012. Nuclear miRNA regulates the mitochondrial genome in the heart. Circ. Res. 110:1596–603
    [Google Scholar]
  75. 75. 
    Banavath HN, Roman B, Mackowski N, Biswas D, Afzal J et al. 2019. miR-181c activates mitochondrial calcium uptake by regulating MICU1 in the heart. J. Am. Heart Assoc. 8:e012919
    [Google Scholar]
  76. 76. 
    Dong Z, Shanmughapriya S, Tomar D, Siddiqui N, Lynch S et al. 2017. Mitochondrial Ca2+ uniporter is a mitochondrial luminal redox sensor that augments MCU channel activity. Mol. Cell 65:1014–28.e7
    [Google Scholar]
  77. 77. 
    Joiner ML, Koval OM, Li J, He BJ, Allamargot C et al. 2012. CaMKII determines mitochondrial stress responses in heart. Nature 491:269–73
    [Google Scholar]
  78. 78. 
    Nickel AG, Kohlhaas M, Bertero E, Wilhelm D, Wagner M et al. 2020. CaMKII does not control mitochondrial Ca2+ uptake in cardiac myocytes. J. Physiol. 598:1361–76
    [Google Scholar]
  79. 79. 
    Bondarenko AI, Jean-Quartier C, Parichatikanond W, Alam MR, Waldeck-Weiermair M et al. 2014. Mitochondrial Ca2+ uniporter (MCU)-dependent and MCU-independent Ca2+ channels coexist in the inner mitochondrial membrane. Pflügers Arch 466:1411–20
    [Google Scholar]
  80. 80. 
    Hamilton J, Brustovetsky T, Rysted JE, Lin Z, Usachev YM, Brustovetsky N 2018. Deletion of mitochondrial calcium uniporter incompletely inhibits calcium uptake and induction of the permeability transition pore in brain mitochondria. J. Biol. Chem. 293:15652–63
    [Google Scholar]
  81. 81. 
    Ryu SY, Beutner G, Kinnally KW, Dirksen RT, Sheu SS 2011. Single channel characterization of the mitochondrial ryanodine receptor in heart mitoplasts. J. Biol. Chem. 286:21324–29
    [Google Scholar]
  82. 82. 
    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
    [Google Scholar]
  83. 83. 
    Brookes PS, Parker N, Buckingham JA, Vidal-Puig A, Halestrap AP et al. 2008. UCPs—unlikely calcium porters. Nat. Cell Biol. 10:1235–37
    [Google Scholar]
  84. 84. 
    Kostic M, Sekler I. 2019. Functional properties and mode of regulation of the mitochondrial Na+/Ca2+ exchanger, NCLX. Semin. Cell Dev. Biol. 94:59–65
    [Google Scholar]
  85. 85. 
    Jung DW, Apel LM, Brierley GP 1992. Transmembrane gradients of free Na+ in isolated heart mitochondria estimated using a fluorescent probe. Am. J. Physiol. 262:C1047–55
    [Google Scholar]
  86. 86. 
    Jung DW, Baysal K, Brierley GP 1995. The sodium-calcium antiport of heart mitochondria is not electroneutral. J. Biol. Chem. 270:672–78
    [Google Scholar]
  87. 87. 
    Dash RK, Beard DA. 2008. Analysis of cardiac mitochondrial Na+-Ca2+ exchanger kinetics with a biophysical model of mitochondrial Ca2+ handling suggests a 3:1 stoichiometry. J. Physiol. 586:3267–85
    [Google Scholar]
  88. 88. 
    Murphy E, Eisner DA. 2009. Regulation of intracellular and mitochondrial sodium in health and disease. Circ. Res. 104:292–303
    [Google Scholar]
  89. 89. 
    Griffiths EJ, Ocampo CJ, Savage JS, Rutter GA, Hansford RG et al. 1998. Mitochondrial calcium transporting pathways during hypoxia and reoxygenation in single rat cardiomyocytes. Cardiovasc. Res. 39:423–33
    [Google Scholar]
  90. 90. 
    Maack C, Cortassa S, Aon MA, Ganesan AN, Liu T, 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
    [Google Scholar]
  91. 91. 
    Luongo TS, Lambert JP, Gross P, Nwokedi M, Lombardi AA et al. 2017. The mitochondrial Na+/Ca2+ exchanger is essential for Ca2+ homeostasis and viability. Nature 545:93–97
    [Google Scholar]
  92. 92. 
    De Stefani D, Rizzuto R, Pozzan T 2016. Enjoy the trip: calcium in mitochondria back and forth. Annu. Rev. Biochem. 85:161–92
    [Google Scholar]
  93. 93. 
    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
    [Google Scholar]
  94. 94. 
    Austin S, Nowikovsky K. 2019. LETM1: Essential for mitochondrial biology and cation homeostasis?. Trends Biochem. Sci. 44:648–58
    [Google Scholar]
  95. 95. 
    Di Marco G, Vallese F, Jourde B, Bergsdorf C, Sturlese M et al. 2020. A high-throughput screening identifies MICU1 targeting compounds. Cell Rep 30:2321–31.e6
    [Google Scholar]
  96. 96. 
    Arduino DM, Wettmarshausen J, Vais H, Navas-Navarro P, Cheng Y et al. 2017. Systematic identification of MCU modulators by orthogonal interspecies chemical screening. Mol. Cell 67:711–23.e7
    [Google Scholar]
  97. 97. 
    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 3:17045
    [Google Scholar]
  98. 98. 
    Woods JJ, Nemani N, Shanmughapriya S, Kumar A, Zhang M et al. 2019. A selective and cell-permeable mitochondrial calcium uniporter (MCU) inhibitor preserves mitochondrial bioenergetics after hypoxia/reoxygenation injury. ACS Cent. Sci. 5:153–66
    [Google Scholar]
  99. 99. 
    Woods JJ, Wilson JJ. 2019. Inhibitors of the mitochondrial calcium uniporter for the treatment of disease. Curr. Opin. Chem. Biol. 55:9–18
    [Google Scholar]
  100. 100. 
    Kohlhaas M, Liu T, Knopp A, Zeller T, Ong MF et al. 2010. Elevated cytosolic Na+ increases mitochondrial formation of reactive oxygen species in failing cardiac myocytes. Circulation 121:1606–13
    [Google Scholar]
  101. 101. 
    Liu T, Takimoto E, Dimaano VL, DeMazumder D, Kettlewell S et al. 2014. Inhibiting mitochondrial Na+/Ca2+ exchange prevents sudden death in a guinea pig model of heart failure. Circ. Res. 115:44–54
    [Google Scholar]
  102. 102. 
    Kohlhaas M, Maack C. 2010. Adverse bioenergetic consequences of Na+-Ca2+ exchanger-mediated Ca2+ influx in cardiac myocytes. Circulation 122:2273–80
    [Google Scholar]
  103. 103. 
    De La Fuente S, Fernandez-Sanz C, Vail C, Agra EJ, Holmstrom K et al. 2016. Strategic positioning and biased activity of the mitochondrial calcium uniporter in cardiac muscle. J. Biol. Chem. 291:23343–62
    [Google Scholar]
  104. 104. 
    Santulli G, Xie W, Reiken SR, Marks AR 2015. Mitochondrial calcium overload is a key determinant in heart failure. PNAS 112:11389–94
    [Google Scholar]
  105. 105. 
    Bertero E, Maack C. 2018. Calcium signaling and reactive oxygen species in mitochondria. Circ. Res. 122:1460–78
    [Google Scholar]
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