Science China Life Sciences

, Volume 54, Issue 8, pp 763–769

Distinctive characteristics and functions of multiple mitochondrial Ca2+ influx mechanisms

Open Access
Reviews

Abstract

Intracellular Ca2+ is vital for cell physiology. Disruption of Ca2+ homeostasis contributes to human diseases such as heart failure, neuron-degeneration, and diabetes. To ensure an effective intracellular Ca2+ dynamics, various Ca2+ transport proteins localized in different cellular regions have to work in coordination. The central role of mitochondrial Ca2+ transport mechanisms in responding to physiological Ca2+ pulses in cytosol is to take up Ca2+ for regulating energy production and shaping the amplitude and duration of Ca2+ transients in various micro-domains. Since the discovery that isolated mitochondria can take up large quantities of Ca2+ approximately 5 decades ago, extensive studies have been focused on the functional characterization and implication of ion channels that dictate Ca2+ transport across the inner mitochondrial membrane. The mitochondrial Ca2+ uptake sensitive to non-specific inhibitors ruthenium red and Ru360 has long been considered as the activity of mitochondrial Ca2+ uniporter (MCU). The general consensus is that MCU is dominantly or exclusively responsible for the mitochondrial Ca2+ influx. Since multiple Ca2+ influx mechanisms (e.g. L-, T-, and N-type Ca2+ channel) have their unique functions in the plasma membrane, it is plausible that mitochondrial inner membrane has more than just MCU to decode complex intracellular Ca2+ signaling in various cell types. During the last decade, four molecular identities related to mitochondrial Ca2+ influx mechanisms have been identified. These are mitochondrial ryanodine receptor, mitochondrial uncoupling proteins, LETM1 (Ca2+/H+ exchanger), and MCU and its Ca2+ sensing regulatory subunit MICU1. Here, we briefly review recent progress in these and other reported mitochondrial Ca2+ influx pathways and their differences in kinetics, Ca2+ dependence, and pharmacological characteristics. Their potential physiological and pathological implications are also discussed.

Keywords

mitochondrial calcium channels calcium transport mitochondria heart ryanodine receptor 

References

  1. 1.
    Deluca H F, Engstrom G W. Calcium uptake by rat kidney mitochondria. Proc Natl Acad Sci USA, 1961, 47: 1744–1750 13885269, 10.1073/pnas.47.11.1744, 1:STN:280:DyaF38%2Fis1Grsw%3D%3DPubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Harris E J. The uptake and release of calcium by heart mitochondria. Biochem J, 1977, 168: 447–456 204287, 1:CAS:528:DyaE1cXhtlais7w%3DPubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Nicholls D G. Calcium transport and porton electrochemical potential gradient in mitochondria from guinea-pig cerebral cortex and rat heart. Biochem J, 1978, 170: 511–522 348200, 1:CAS:528:DyaE1cXktFyntLg%3DPubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Gunter T E, Pfeiffer D R. Mechanisms by which mitochondria transport calcium. Am J Physiol, 1990, 258: C755–786 2185657, 1:CAS:528:DyaK3cXktlKnu7Y%3DPubMedGoogle Scholar
  5. 5.
    Gunter T E, Gunter K K, Sheu S S, et al. Mitochondrial calcium transport: Physiological and pathological relevance. Am J Physiol, 1994, 267: C313–339 8074170, 1:CAS:528:DyaK2cXlsFCgtL8%3DPubMedGoogle Scholar
  6. 6.
    Gunter T E, Yule D I, Gunter K K, et al. Calcium and mitochondria. FEBS Lett, 2004, 567: 96–102 15165900, 10.1016/j.febslet.2004.03.071, 1:CAS:528:DC%2BD2cXksVGht7g%3DPubMedCrossRefGoogle Scholar
  7. 7.
    Gunter T E, Sheu S S. Characteristics and possible functions of mitochondrial Ca(2+) transport mechanisms. Biochim Biophys Acta, 2009, 1787: 1291–1308 19161975, 10.1016/j.bbabio.2008.12.011, 1:CAS:528:DC%2BD1MXhtVentb%2FNPubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Gunter T E, Buntinas L, Sparagna G, et al. Mitochondrial calcium transport: Mechanisms and functions. Cell Calcium, 2000, 28: 285–296 11115368, 10.1054/ceca.2000.0168, 1:CAS:528:DC%2BD3MXlvFOgtw%3D%3DPubMedCrossRefGoogle Scholar
  9. 9.
    Denton R M. Regulation of mitochondrial dehydrogenases by calcium ions. Biochim Biophys Acta, 2009, 1787: 1309–1316 19413950, 10.1016/j.bbabio.2009.01.005, 1:CAS:528:DC%2BD1MXhtVentb%2FOPubMedCrossRefGoogle Scholar
  10. 10.
    Balaban R S. The role of Ca(2+) signaling in the coordination of mitochondrial atp production with cardiac work. Biochim Biophys Acta, 2009, 1787: 1334–1341 19481532, 10.1016/j.bbabio.2009.05.011, 1:CAS:528:DC%2BD1MXhtVentb%2FKPubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Parekh A B. Mitochondrial regulation of intracellular Ca2+ signaling: More than just simple Ca2+ buffers. News Physiol Sci, 2003, 18: 252–256 14614159, 1:CAS:528:DC%2BD2cXltVSnPubMedGoogle Scholar
  12. 12.
    Ryu S Y, Beutner G, Dirksen R T, et al. Mitochondrial ryanodine receptors and other mitochondrial Ca2+ permeable channels. FEBS Lett, 2010, 584: 1948–1955 20096690, 10.1016/j.febslet.2010.01.032, 1:CAS:528:DC%2BC3cXlvVaruro%3DPubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Ryu S Y, Beutner G, Kinnally K, et al. Single channel characterization of the mitochondrial ryanodine receptor in heart mitoplasts. J Biol Chem, 2011Google Scholar
  14. 14.
    Bernardi P. Mitochondrial transport of cations: Channels, exchangers, and permeability transition. Physiol Rev, 1999, 79: 1127–1155 10508231, 1:CAS:528:DyaK1MXmvVymtLw%3DPubMedGoogle Scholar
  15. 15.
    Sparagna G C, Gunter K K, Sheu S S, et al. Mitochondrial calcium uptake from physiological-type pulses of calcium. A description of the rapid uptake mode. J Biol Chem, 1995, 270: 27510–27515 7499209, 10.1074/jbc.270.46.27510, 1:CAS:528:DyaK2MXpsFShsLc%3DPubMedCrossRefGoogle Scholar
  16. 16.
    Buntinas L, Gunter K K, Sparagna G C, et al. The rapid mode of calcium uptake into heart mitochondria (ram): Comparison to ram in liver mitochondria. Biochim Biophys Acta, 2001, 1504: 248–261 11245789, 10.1016/S0005-2728(00)00254-1, 1:CAS:528:DC%2BD3MXhs1Cisr0%3DPubMedCrossRefGoogle Scholar
  17. 17.
    Altschafl B A, Beutner G, Sharma V K, et al. The mitochondrial ryanodine receptor in rat heart: A pharmaco-kinetic profile. Biochim Biophys Acta, 2007, 1768: 1784–1795 17499575, 10.1016/j.bbamem.2007.04.011, 1:CAS:528:DC%2BD2sXmsFKrtLY%3DPubMedCrossRefGoogle Scholar
  18. 18.
    Beutner G, Sharma V K, Lin L, et al. Type 1 ryanodine receptor in cardiac mitochondria: Transducer of excitation-metabolism coupling. Biochim Biophys Acta, 2005, 1717: 1–10 16246297, 10.1016/j.bbamem.2005.09.016, 1:CAS:528:DC%2BD2MXht1ars7jEPubMedCrossRefGoogle Scholar
  19. 19.
    Beutner G, Sharma V K, Giovannucci D R, et al. Identification of a ryanodine receptor in rat heart mitochondria. J Biol Chem, 2001, 276: 21482–21488 11297554, 10.1074/jbc.M101486200, 1:CAS:528:DC%2BD3MXksFGlurc%3DPubMedCrossRefGoogle Scholar
  20. 20.
    Trenker M, Malli R, Fertschai I, et al. Uncoupling proteins 2 and 3 are fundamental for mitochondrial Ca2+ uniport. Nat Cell Biol, 2007, 9: 445–452 17351641, 10.1038/ncb1556, 1:CAS:528:DC%2BD2sXjs1yqu7Y%3DPubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Jiang D, Zhao L, Clapham D E. Genome-wide rnai screen identifies letm1 as a mitochondrial Ca2+/H+ antiporter. Science, 2009, 326: 144–147 19797662, 10.1126/science.1175145, 1:CAS:528:DC%2BD1MXhtF2hs7nKPubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Palty R, Silverman W F, Hershfinkel M, et al. Nclx is an essential component of mitochondrial Na+/Ca2+ exchange. Proc Natl Acad Sci USA, 2010, 107: 436–441 20018762, 10.1073/pnas.0908099107, 1:CAS:528:DC%2BC3cXnsVGksw%3D%3DPubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Selwyn M J, Dawson A P, Dunnett S J. Calcium transport in mitochondria. FEBS Lett, 1970, 10: 1–5 11945343, 10.1016/0014-5793(70)80402-1, 1:CAS:528:DyaE3MXpsVenuw%3D%3DPubMedCrossRefGoogle Scholar
  24. 24.
    Carafoli E. Active accumulation of Sr2+ by rat-liver mitochondria. Ii. Competition between Ca2+ and Sr2+. Biochim Biophys Acta, 1965, 97: 99–106 14284323, 1:CAS:528:DyaF2MXjslyktg%3D%3DPubMedCrossRefGoogle Scholar
  25. 25.
    Drahota Z, Gazzotti P, Carafoli E, et al. A comparison of the effects of different divalent cations on a number of mitochondrial reactions linked to ion translocation. Arch Biochem Biophys, 1969, 130: 267–273 5778642, 10.1016/0003-9861(69)90033-2, 1:CAS:528:DyaF1MXosVantQ%3D%3DPubMedCrossRefGoogle Scholar
  26. 26.
    Vainio H, Mela L, Chance B. Energy dependent bivalent cation translocation in rat liver mitochondria. Eur J Biochem, 1970, 12: 387–391 5459576, 10.1111/j.1432-1033.1970.tb00863.x, 1:CAS:528:DyaE3cXos1ahuw%3D%3DPubMedCrossRefGoogle Scholar
  27. 27.
    Reed K C, Bygrave F L. Accumulation of lanthanum by rat liver mitochondria. Biochem J, 1974, 138: 239–252 4362742, 1:CAS:528:DyaE2cXktFSjtbc%3DPubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Rossi C S, Vasington F D, Carafoli E. The effect of ruthenium red on the uptake and release of Ca2+ by mitochondria. Biochem Biophys Res Commun, 1973, 50: 846–852 1:CAS:528:DyaE3sXhtF2lsLc%3DGoogle Scholar
  29. 29.
    Noack E, Greeff K. Inhibition of calcium transport in mitochondria by -receptor blocking substances and its reactivation by phospholipids. Experientia, 1971, 27: 810–811 4400390, 10.1007/BF02136879, 1:CAS:528:DyaE3MXkvVKrtLk%3DPubMedCrossRefGoogle Scholar
  30. 30.
    Noack E, Greeff K. The influence of some cardioactive drugs on the energy-dependent uptake of calcium, potassium and adenine nucleotides by mitchondria. J Mol Cell Cardiol, 1971, 2: 145–159 4398856, 10.1016/0022-2828(71)90067-8, 1:CAS:528:DyaE2cXit1Ghuw%3D%3DPubMedCrossRefGoogle Scholar
  31. 31.
    Schellenberg G D, Anderson L, Cragoe E J Jr, et al. Inhibition of brain mitochondrial Ca2+ transport by amiloride analogues. Cell Calcium, 1985, 6: 431–447 4075385, 10.1016/0143-4160(85)90019-3, 1:CAS:528:DyaL28XhtVantL0%3DPubMedCrossRefGoogle Scholar
  32. 32.
    Sastrasinh M, Weinberg J M, Humes H D. The effect of gentamicin on calcium uptake by renal mitochondria. Life Sci, 1982, 30: 2309–2315 6810049, 10.1016/0024-3205(82)90258-2, 1:CAS:528:DyaL38XktleitL8%3DPubMedCrossRefGoogle Scholar
  33. 33.
    Nicchitta C V, Williamson J R. Spermine. A regulator of mitochondrial calcium cycling. J Biol Chem, 1984, 259: 12978–12983 6238031, 1:CAS:528:DyaL2cXlvVKht7w%3DPubMedGoogle Scholar
  34. 34.
    Moreau B, Nelson C, Parekh A B. Biphasic regulation of mitochondrial ca2+ uptake by cytosolic Ca2+ concentration. Curr Biol, 2006, 16: 1672–1677 16920631, 10.1016/j.cub.2006.06.059, 1:CAS:528:DC%2BD28XosVOhtrY%3DPubMedCrossRefGoogle Scholar
  35. 35.
    Putney J W Jr, Thomas A P. Calcium signaling: Double duty for calcium at the mitochondrial uniporter. Curr Biol, 2006, 16: R812–815 16979553, 10.1016/j.cub.2006.08.040, 1:CAS:528:DC%2BD28Xps1Onsbs%3DPubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Kirichok Y, Krapivinsky G, Clapham D E. The mitochondrial calcium uniporter is a highly selective ion channel. Nature, 2004, 427: 360–364 14737170, 10.1038/nature02246, 1:CAS:528:DC%2BD2cXltFCgtw%3D%3DPubMedCrossRefGoogle Scholar
  37. 37.
    Rizzuto R, Bernardi P, Pozzan T. Mitochondria as all-round players of the calcium game. J Physiol, 2000, 529Pt 1: 37–47 11080249, 10.1111/j.1469-7793.2000.00037.x, 1:CAS:528:DC%2BD3cXovVajsrw%3DPubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Montero M, Alonso M T, Carnicero E, et al. Chromaffin-cell stimulation triggers fast millimolar mitochondrial Ca2+ transients that modulate secretion. Nat Cell Biol, 2000, 2: 57–61 10655583, 10.1038/35000001, 1:CAS:528:DC%2BD3cXhtVylt7g%3DPubMedCrossRefGoogle Scholar
  39. 39.
    Rizzuto R, Brini M, Murgia M, et al. Microdomains with high Ca2+ close to ip3-sensitive channels that are sensed by neighboring mitochondria. Science, 1993, 262: 744–747 8235595, 10.1126/science.8235595, 1:CAS:528:DyaK2cXlsVCkPubMedCrossRefGoogle Scholar
  40. 40.
    Neher E. Vesicle pools and Ca2+ microdomains: New tools for understanding their roles in neurotransmitter release. Neuron, 1998, 20: 389–399 9539117, 10.1016/S0896-6273(00)80983-6, 1:CAS:528:DyaK1cXit1Gmsrg%3DPubMedCrossRefGoogle Scholar
  41. 41.
    Baughman J M, Perocchi F, Girgis H S, et al. Integrative genomics identifies mcu as an essential component of the mitochondrial calcium uniporter. Nature, 2011Google Scholar
  42. 42.
    De Stefani D, Raffaello A, Teardo E, et al. A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter. Nature, 2011Google Scholar
  43. 43.
    Perocchi F, Gohil V M, Girgis H S, et al. Micu1 encodes a mitochondrial ef hand protein required for Ca2+ uptake. Nature, 2010, 467: 291–296 20693986, 10.1038/nature09358, 1:CAS:528:DC%2BC3cXpvVWgs70%3DPubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Hajnoczky G, Csordas G. Calcium signalling: Fishing out molecules of mitochondrial calcium transport. Curr Biol, 2010, 20: R888–891 20971432, 10.1016/j.cub.2010.09.035, 1:CAS:528:DC%2BC3cXhtlenurjKPubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Rizzuto R, Simpson A W, Brini M, et al. Rapid changes of mitochondrial Ca2+ revealed by specifically targeted recombinant aequorin. Nature, 1992, 358: 325–327 1322496, 10.1038/358325a0, 1:CAS:528:DyaK38XltVOlsbs%3DPubMedCrossRefGoogle Scholar
  46. 46.
    Rizzuto R, Brini M, Pozzan T. Targeting recombinant aequorin to specific intracellular organelles. Methods Cell Biol, 1994, 40: 339–358 8201984, 10.1016/S0091-679X(08)61121-8, 1:CAS:528:DyaK2cXlsFagt70%3DPubMedCrossRefGoogle Scholar
  47. 47.
    Broekemeier K M, Dempsey M E, Pfeiffer D R. Cyclosporin a is a potent inhibitor of the inner membrane permeability transition in liver mitochondria. J Biol Chem, 1989, 264: 7826–7830 2470734, 1:CAS:528:DyaL1MXktVSnsrc%3DPubMedGoogle Scholar
  48. 48.
    Crompton M, Costi A. A heart mitochondrial Ca2+-dependent pore of possible relevance to re-perfusion-induced injury. Evidence that adp facilitates pore interconversion between the closed and open states. Biochem J, 1990, 266: 33–39 2106875, 1:CAS:528:DyaK3cXhsFClurs%3DPubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Fill M, Copello J A. Ryanodine receptor calcium release channels. Physiol Rev, 2002, 82: 893–922 12270947, 1:CAS:528:DC%2BD38Xot1Ggurk%3DPubMedCrossRefGoogle Scholar
  50. 50.
    Pessah I N, Waterhouse A L, Casida J E. The calcium-ryanodine receptor complex of skeletal and cardiac muscle. Biochem Biophys Res Commun, 1985, 128: 449–456 3985981, 10.1016/0006-291X(85)91699-7, 1:CAS:528:DyaL2MXks1Kgt7s%3DPubMedCrossRefGoogle Scholar
  51. 51.
    Holmberg S R, Williams A J. The cardiac sarcoplasmic reticulum calcium-release channel: Modulation of ryanodine binding and single-channel activity. Biochim Biophys Acta, 1990, 1022: 187–193 2155020, 10.1016/0005-2736(90)90113-3, 1:CAS:528:DyaK3cXhslCiu7k%3DPubMedCrossRefGoogle Scholar
  52. 52.
    Zimanyi I, Pessah I N. Comparison of [3h]ryanodine receptors and Ca2+ release from rat cardiac and rabbit skeletal muscle sarcoplasmic reticulum. J Pharmacol Exp Ther, 1991, 256: 938–946 1848635, 1:CAS:528:DyaK3MXhslyitL4%3DPubMedGoogle Scholar
  53. 53.
    Sharma V K, Ramesh V, Franzini-Armstrong C, et al. Transport of Ca2+ from sarcoplasmic reticulum to mitochondria in rat ventricular myocytes. J Bioenerg Biomembr, 2000, 32: 97–104 11768767, 10.1023/A:1005520714221, 1:CAS:528:DC%2BD3cXisl2itbc%3DPubMedCrossRefGoogle Scholar
  54. 54.
    Franzini-Armstrong C, Protasi F. Ryanodine receptors of striated muscles: A complex channel capable of multiple interactions. Physiol Rev, 1997, 77: 699–729 9234963, 1:CAS:528:DyaK2sXltlWlurs%3DPubMedGoogle Scholar
  55. 55.
    Nowikovsky K, Froschauer E M, Zsurka G, et al. The letm1/yol027 gene family encodes a factor of the mitochondrial K+ homeostasis with a potential role in the wolf-hirschhorn syndrome. J Biol Chem, 2004, 279: 30307–30315 15138253, 10.1074/jbc.M403607200, 1:CAS:528:DC%2BD2cXlsFKiur8%3DPubMedCrossRefGoogle Scholar
  56. 56.
    Dimmer K S, Navoni F, Casarin A, et al. Letm1, deleted in wolf-hirschhorn syndrome is required for normal mitochondrial morphology and cellular viability. Hum Mol Genet, 2008, 17: 201–214 17925330, 10.1093/hmg/ddm297, 1:CAS:528:DC%2BD1cXisVSquw%3D%3DPubMedCrossRefGoogle Scholar
  57. 57.
    McQuibban A G, Joza N, Megighian A, et al. A drosophila mutant of letm1, a candidate gene for seizures in wolf-hirschhorn syndrome. Hum Mol Genet, 2010, 19: 987–1000 20026556, 10.1093/hmg/ddp563, 1:CAS:528:DC%2BC3cXivV2jtb0%3DPubMedCrossRefGoogle Scholar
  58. 58.
    Zotova L, Aleschko M, Sponder G, et al. Novel components of an active mitochondrial K(+)/H(+) exchange. J Biol Chem, 2010, 285: 14399–14414 20197279, 10.1074/jbc.M109.059956, 1:CAS:528:DC%2BC3cXlsVOhsrw%3DPubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Michels G, Khan I F, Endres-Becker J, et al. Regulation of the human cardiac mitochondrial Ca2+ uptake by 2 different voltage-gated Ca2+ channels. Circulation, 2009, 119: 2435–2443 19398664, 10.1161/CIRCULATIONAHA.108.835389, 1:CAS:528:DC%2BD1MXls1Gksrg%3DPubMedCrossRefGoogle Scholar
  60. 60.
    Surmeier D J, Guzman J N, Sanchez-Padilla J. Calcium, cellular aging, and selective neuronal vulnerability in Parkinson’s disease. Cell Calcium, 2010, 47: 175–182 20053445, 10.1016/j.ceca.2009.12.003, 1:CAS:528:DC%2BC3cXjtVSms7s%3DPubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Verkhratsky A, Fernyhough P. Mitochondrial malfunction and Ca2+ dyshomeostasis drive neuronal pathology in diabetes. Cell Calcium, 2008, 44: 112–122 18191198, 10.1016/j.ceca.2007.11.010, 1:CAS:528:DC%2BD1cXntlaitLY%3DPubMedCrossRefGoogle Scholar

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© The Author(s) 2011

Open Access This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution and reproduction in any medium, provided the original author(s) and source are credited.

Authors and Affiliations

  1. 1.Center for Translational Medicine, Department of MedicineThomas Jefferson UniversityPhiladelphiaUSA
  2. 2.Department of PhysiologySeoul National University College of MedicineSeoulRepublic of Korea

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