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Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
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Structural basis of Ca2+ uptake by mitochondrial calcium uniporter in mitochondria: a brief review

  • Jiho, Yoo (College of Pharmacy, Chung-Ang University)
  • Received : 2022.07.30
  • Accepted : 2022.09.30
  • Published : 2022.11.30
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Abstract

Mitochondria are cellular organelles that perform various functions within cells. They are responsible for ATP production, cell-signal regulation, autophagy, and cell apoptosis. Because the mitochondrial proteins that perform these functions need Ca2+ ions for their activity, mitochondria have ion channels to selectively uptake Ca2+ ions from the cytoplasm. The ion channel known to play the most important role in the Ca2+ uptake in mitochondria is the mitochondrial calcium uniporter (MCU) holo-complex located in the inner mitochondrial membrane (IMM). This ion channel complex exists in the form of a complex consisting of the pore-forming protein through which the Ca2+ ions are transported into the mitochondrial matrix, and the auxiliary protein involved in regulating the activity of the Ca2+ uptake by the MCU holo-complex. Studies of this MCU holo-complex have long been conducted, but we didn't know in detail how mitochondria uptake Ca2+ ions through this ion channel complex or how the activity of this ion channel complex is regulated. Recently, the protein structure of the MCU holo-complex was identified, enabling the mechanism of Ca2+ uptake and its regulation by the MCU holo-complex to be confirmed. In this review, I will introduce the mechanism of action of the MCU holo-complex at the molecular level based on the Cryo-EM structure of the MCU holo-complex to help understand how mitochondria uptake the necessary Ca2+ ions through the MCU holo-complex and how these Ca2+ uptake mechanisms are regulated.

Keywords

Acknowledgement

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No. 2021R1C1C1012076) and by the Chung-Ang University Research Grants in 2020.

References

  1. Di Resta C and Becchetti A (2010) Introduction to ion channels. Adv Exp Med Biol 674, 9-21 https://doi.org/10.1007/978-1-4419-6066-5_2
  2. Clapham DE (1995) Calcium signaling. Cell 80, 259-268 https://doi.org/10.1016/0092-8674(95)90408-5
  3. Hetherington AM and Brownlee C (2004) The generation of Ca(2+) signals in plants. Annu Rev Plant Biol 55, 401-427 https://doi.org/10.1146/annurev.arplant.55.031903.141624
  4. Pandey GK, Cheong YH, Kim KN et al (2004) The calcium sensor calcineurin B-like 9 modulates abscisic acid sensitivity and biosynthesis in Arabidopsis. Plant Cell 16, 1912-1924 https://doi.org/10.1105/tpc.021311
  5. Dodd AN, Kudla J and Sanders D (2010) The language of calcium signaling. Annu Rev Plant Biol 61, 593-620 https://doi.org/10.1146/annurev-arplant-070109-104628
  6. Berridge MJ, Bootman MD and Roderick HL (2003) Calcium signalling: dynamics, homeostasis and remodelling. Nat Rev Mol Cell Biol 4, 517-529 https://doi.org/10.1038/nrm1155
  7. Singh S, Dodt J, Volkers P et al (2019) Structure functional insights into calcium binding during the activation of coagulation factor XIII A. Sci Rep 9, 11324
  8. Cashman KD (2002) Calcium intake, calcium bioavailability and bone health. Br J Nutr 87 Suppl 2, S169-177 https://doi.org/10.1079/BJN/2002534
  9. Balaban RS (2009) The role of Ca2+ signaling in the coordination of mitochondrial ATP production with cardiac work. Biochim Biophys Acta 1787, 1334-1341 https://doi.org/10.1016/j.bbabio.2009.05.011
  10. Denton RM (2009) Regulation of mitochondrial dehydrogenases by calcium ions. Biochim Biophys Acta 1787, 1309-1316 https://doi.org/10.1016/j.bbabio.2009.01.005
  11. Orrenius S, Zhivotovsky B and Nicotera P (2003) Regulation of cell death: the calcium-apoptosis link. Nat Rev Mol Cell Biol 4, 552-565 https://doi.org/10.1038/nrm1150
  12. Szalai G, Krishnamurthy R and Hajnoczky G (1999) Apoptosis driven by IP(3)-linked mitochondrial calcium signals. EMBO J 18, 6349-6361 https://doi.org/10.1093/emboj/18.22.6349
  13. Pinton P, Ferrari D, Rapizzi E, Di Virgilio F, Pozzan T and Rizzuto R (2001) The Ca2+ concentration of the endoplasmic reticulum is a key determinant of ceramide-induced apoptosis: significance for the molecular mechanism of Bcl-2 action. EMBO J 20, 2690-2701 https://doi.org/10.1093/emboj/20.11.2690
  14. Scorrano L, Oakes SA, Opferman JT et al (2003) BAX and BAK regulation of endoplasmic reticulum Ca2+: a control point for apoptosis. Science 300, 135-139 https://doi.org/10.1126/science.1081208
  15. Chernorudskiy AL and Zito E (2017) Regulation of calcium homeostasis by ER redox: a close-up of the ER/mitochondria connection. J Mol Biol 429, 620-632 https://doi.org/10.1016/j.jmb.2017.01.017
  16. Bustos G, Ahumada-Castro U, Silva-Pavez E, Puebla A, Lovy A and Cesar Cardenas J (2021) The ER-mitochondria Ca2+ signaling in cancer progression: Fueling the monster. Int Rev Cell Mol Biol 363, 49-121
  17. Ahumada-Castro U, Puebla-Huerta A, Cuevas-Espinoza V, Lovy A and Cardenas JC (2021) Keeping zombies alive: The ER-mitochondria Ca2+ transfer in cellular senescence. Biochim Biophys Acta Mol Cell Res 1868, 119099
  18. Smaili SS, Pereira GJ, Costa MM et al (2013) The role of calcium stores in apoptosis and autophagy. Curr Mol Med 13, 252-265 https://doi.org/10.2174/156652413804810772
  19. Kaufman RJ and Malhotra JD (2014) Calcium trafficking integrates endoplasmic reticulum function with mitochondrial bioenergetics. Biochim Biophys Acta 1843, 2233-2239 https://doi.org/10.1016/j.bbamcr.2014.03.022
  20. Duchen MR, Verkhratsky A and Muallem S (2008) Mitochondria and calcium in health and disease. Cell Calcium 44, 1-5 https://doi.org/10.1016/j.ceca.2008.02.001
  21. East DA and Campanella M (2013) Ca2+ in quality control: an unresolved riddle critical to autophagy and mitophagy. Autophagy 9, 1710-1719 https://doi.org/10.4161/auto.25367
  22. Gottlieb RA and Bernstein D (2016) Mitochondrial remodeling: Rearranging, recycling, and reprogramming. Cell Calcium 60, 88-101 https://doi.org/10.1016/j.ceca.2016.04.006
  23. Crompton M, Kunzi M and 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, 549-558 https://doi.org/10.1111/j.1432-1033.1977.tb11839.x
  24. Palty R, Silverman WF, Hershfinkel M et al (2010) NCLX is an essential component of mitochondrial Na+/Ca2+ exchange. Proc Natl Acad Sci U S A 107, 436-441 https://doi.org/10.1073/pnas.0908099107
  25. Jiang D, Zhao L and Clapham DE (2009) Genome-wide RNAi screen identifies Letm1 as a mitochondrial Ca2+/H+ antiporter. Science 326, 144-147 https://doi.org/10.1126/science.1175145
  26. Kirichok Y, Krapivinsky G and Clapham DE (2004) The mitochondrial calcium uniporter is a highly selective ion channel. Nature 427, 360-364 https://doi.org/10.1038/nature02246
  27. Baughman JM, Perocchi F, Girgis HS et al (2011) Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter. Nature 476, 341-345 https://doi.org/10.1038/nature10234
  28. De Stefani D, Raffaello A, Teardo E, Szabo I and Rizzuto R (2011) A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter. Nature 476, 336-340 https://doi.org/10.1038/nature10230
  29. Perocchi F, Gohil VM, Girgis HS et al (2010) MICU1 encodes a mitochondrial EF hand protein required for Ca2+ uptake. Nature 467, 291-296 https://doi.org/10.1038/nature09358
  30. Plovanich M, Bogorad RL, Sancak Y et al (2013) MICU2, a paralog of MICU1, resides within the mitochondrial uniporter complex to regulate calcium handling. PLoS One 8, e55785
  31. Sancak Y, Markhard AL, Kitami T et al (2013) EMRE is an essential component of the mitochondrial calcium uniporter complex. Science 342, 1379-1382 https://doi.org/10.1126/science.1242993
  32. Bick AG, Calvo SE and Mootha VK (2012) Evolutionary diversity of the mitochondrial calcium uniporter. Science 336, 886
  33. Kamer KJ and Mootha VK (2015) The molecular era of the mitochondrial calcium uniporter. Nat Rev Mol Cell Biol 16, 545-553 https://doi.org/10.1038/nrm4039
  34. Baradaran R, Wang C, Siliciano AF and Long SB (2018) Cryo-EM structures of fungal and metazoan mitochondrial calcium uniporters. Nature 559, 580-584 https://doi.org/10.1038/s41586-018-0331-8
  35. Fan C, Fan M, Orlando BJ et al (2018) X-ray and cryo-EM structures of the mitochondrial calcium uniporter. Nature 559, 575-579 https://doi.org/10.1038/s41586-018-0330-9
  36. Nguyen NX, Armache JP, Lee C et al (2018) Cryo-EM structure of a fungal mitochondrial calcium uniporter. Nature 559, 570-574 https://doi.org/10.1038/s41586-018-0333-6
  37. Yoo J, Wu M, Yin Y, Herzik MA Jr, Lander GC and Lee SY (2018) Cryo-EM structure of a mitochondrial calcium uniporter. Science 361, 506-511 https://doi.org/10.1126/science.aar4056
  38. Oxenoid K, Dong Y, Cao C et al (2016) Architecture of the mitochondrial calcium uniporter. Nature 533, 269-273 https://doi.org/10.1038/nature17656
  39. Cao C, Wang S, Cui T, Su XC and Chou JJ (2017) Ion and inhibitor binding of the double-ring ion selectivity filter of the mitochondrial calcium uniporter. Proc Natl Acad Sci U S A 114, E2846-E2851
  40. Paillard M, Csordas G, Huang KT, Varnai P, Joseph SK and 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, 778-785 e773
  41. Wang Y, Nguyen NX, She J et al (2019) Structural Mechanism of EMRE-Dependent Gating of the Human Mitochondrial Calcium Uniporter. Cell 177, 1252-1261 e1213
  42. Lee SK, Shanmughapriya S, Mok MCY et al (2016) Structural insights into mitochondrial calcium uniporter regulation by divalent cations. Cell Chem Biol 23, 1157-1169 https://doi.org/10.1016/j.chembiol.2016.07.012
  43. Yuan Y, Cao C, Wen M et al (2020) Structural characterization of the N-terminal domain of the Dictyostelium discoideum mitochondrial calcium uniporter. ACS Omega 5, 6452-6460 https://doi.org/10.1021/acsomega.9b04045
  44. Van Keuren AM, Tsai CW, Balderas E, Rodriguez MX, Chaudhuri D and Tsai MF (2020) Mechanisms of EMRE-dependent MCU opening in the mitochondrial calcium uniporter complex. Cell Rep 33, 108486
  45. Raffaello A, De Stefani D, Sabbadin D et al (2013) The mitochondrial calcium uniporter is a multimer that can include a dominant-negative pore-forming subunit. EMBO J 32, 2362-2376 https://doi.org/10.1038/emboj.2013.157
  46. Lambert JP, Luongo TS, Tomar D et al (2019) MCUB regulates the molecular composition of the mitochondrial calcium uniporter channel to limit mitochondrial calcium overload during stress. Circulation 140, 1720-1733 https://doi.org/10.1161/CIRCULATIONAHA.118.037968
  47. Mallilankaraman K, Cardenas C, Doonan PJ et al (2012) MCUR1 is an essential component of mitochondrial Ca2+ uptake that regulates cellular metabolism. Nat Cell Biol 14, 1336-1343 https://doi.org/10.1038/ncb2622
  48. Patron M, Granatiero V, Espino J, Rizzuto R and De Stefani D (2019) MICU3 is a tissue-specific enhancer of mitochondrial calcium uptake. Cell Death Differ 26, 179-195 https://doi.org/10.1038/s41418-018-0113-8
  49. Paupe V, Prudent J, Dassa EP, Rendon OZ and Shoubridge EA (2015) CCDC90A (MCUR1) is a cytochrome c oxidase assembly factor and not a regulator of the mitochondrial calcium uniporter. Cell Metab 21, 109-116 https://doi.org/10.1016/j.cmet.2014.12.004
  50. Csordas G, Golenar T, Seifert EL et al (2013) MICU1 controls both the threshold and cooperative activation of the mitochondrial Ca2+ uniporter. Cell Metab 17, 976-987 https://doi.org/10.1016/j.cmet.2013.04.020
  51. Mallilankaraman K, Doonan P, Cardenas C et al (2012) MICU1 is an essential gatekeeper for MCU-mediated mitochondrial Ca2+ uptake that regulates cell survival. Cell 151, 630-644 https://doi.org/10.1016/j.cell.2012.10.011
  52. Tsai MF, Phillips CB, Ranaghan M et al (2016) Dual functions of a small regulatory subunit in the mitochondrial calcium uniporter complex. Elife 5, e15545
  53. Pittis AA, Goh V, Cebrian-Serrano A, Wettmarshausen J, Perocchi F and Gabaldon T (2020) Discovery of EMRE in fungi resolves the true evolutionary history of the mitochondrial calcium uniporter. Nat Commun 11, 4031
  54. Kamer KJ and Mootha VK (2014) MICU1 and MICU2 play nonredundant roles in the regulation of the mitochondrial calcium uniporter. EMBO Rep 15, 299-307 https://doi.org/10.1002/embr.201337946
  55. Patron M, Checchetto V, Raffaello A et al (2014) MICU1 and MICU2 finely tune the mitochondrial Ca2+ uniporter by exerting opposite effects on MCU activity. Mol Cell 53, 726-737 https://doi.org/10.1016/j.molcel.2014.01.013
  56. Fan M, Zhang J, Tsai CW et al (2020) Structure and mechanism of the mitochondrial Ca2+ uniporter holocomplex. Nature 582, 129-133 https://doi.org/10.1038/s41586-020-2309-6
  57. Wu W, Shen Q, Zhang R et al (2020) The structure of the MICU1-MICU2 complex unveils the regulation of the mitochondrial calcium uniporter. EMBO J 39, e104285
  58. Wang C, Jacewicz A, Delgado BD, Baradaran R and Long SB (2020) Structures reveal gatekeeping of the mitochondrial Ca2+ uniporter by MICU1-MICU2. Elife 9, e59991