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MCUR1 is an essential component of mitochondrial Ca2+ uptake that regulates cellular metabolism

A Corrigendum to this article was published on 30 June 2015

A Corrigendum to this article was published on 24 December 2012

This article has been updated

Abstract

Ca2+ flux across the mitochondrial inner membrane regulates bioenergetics, cytoplasmic Ca2+ signals and activation of cell death pathways1,2,3,4,5,6,7,8,9,10,11. Mitochondrial Ca2+ uptake occurs at regions of close apposition with intracellular Ca2+ release sites12,13,14, driven by the inner membrane voltage generated by oxidative phosphorylation and mediated by a Ca2+ selective ion channel (MiCa; ref. 15) called the uniporter16,17,18 whose complete molecular identity remains unknown. Mitochondrial calcium uniporter (MCU) was recently identified as the likely ion-conducting pore19,20. In addition, MICU1 was identified as a mitochondrial regulator of uniporter-mediated Ca2+ uptake in HeLa cells21,22. Here we identified CCDC90A, hereafter referred to as MCUR1 (mitochondrial calcium uniporter regulator 1), an integral membrane protein required for MCU-dependent mitochondrial Ca2+ uptake. MCUR1 binds to MCU and regulates ruthenium-red-sensitive MCU-dependent Ca2+ uptake. MCUR1 knockdown does not alter MCU localization, but abrogates Ca2+ uptake by energized mitochondria in intact and permeabilized cells. Ablation of MCUR1 disrupts oxidative phosphorylation, lowers cellular ATP and activates AMP kinase-dependent pro-survival autophagy. Thus, MCUR1 is a critical component of a mitochondrial uniporter channel complex required for mitochondrial Ca2+ uptake and maintenance of normal cellular bioenergetics.

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Figure 1: RNAi screen identifies MCUR1 as a regulator of mitochondrial Ca2+ uptake.
Figure 2: MCUR1 is required for Ru360-sensitive mitochondrial Ca2+ uptake but is independent of the mitochondrial Ca2+ efflux pathway.
Figure 3: Mitochondrial inner membrane localization and topology of MCUR1 and its interaction with MCU.
Figure 4: MCUR1 is essential for MCU-dependent mitochondrial Ca2+ uptake.
Figure 5: MCUR1 is required for the maintenance of cellular bioenergetics.

Change history

  • 10 June 2015

    In the version of this Letter originally published, a key funding source was omitted from the Acknowledgements. César Cárdenas's credit should have read 'C.C. was supported by the Fondo Nacional de Desarrollo Cientifico y Tecnologico (FONDECYT) grant #1120443 and an award from the American Heart Association'.

References

  1. 1

    Hajnoczky, G., Robb-Gaspers, L. D., Seitz, M. B. & Thomas, A. P. Decoding of cytosolic calcium oscillations in the mitochondria. Cell 82, 415–424 (1995).

    CAS  Article  Google Scholar 

  2. 2

    Orrenius, S., Zhivotovsky, B. & Nicotera, P. Regulation of cell death: the calcium-apoptosis link. Nat. Rev. Mol. Cell Biol. 4, 552–565 (2003).

    CAS  Article  Google Scholar 

  3. 3

    Denton, R. M. & McCormack, J. G. The role of calcium in the regulation of mitochondrial metabolism. Biochem. Soc. Trans. 8, 266–268 (1980).

    CAS  Article  Google Scholar 

  4. 4

    Balaban, R. S. The role of Ca2+ signaling in the coordination of mitochondrial ATP production with cardiac work. Biochim. Biophys. Acta 1787, 1334–1341 (2009).

    CAS  Article  Google Scholar 

  5. 5

    Gunter, K. K. & Gunter, T. E. Transport of calcium by mitochondria. J. Bioenerg. Biomembr. 26, 471–485 (1994).

    CAS  Article  Google Scholar 

  6. 6

    Duchen, M. R., Verkhratsky, A. & Muallem, S. Mitochondria and calcium in health and disease. Cell Calcium 44, 1–5 (2008).

    CAS  Article  Google Scholar 

  7. 7

    McCormack, J. G., Halestrap, A. P. & Denton, R. M. Role of calcium ions in regulation of mammalian intramitochondrial metabolism. Physiol. Rev. 70, 391–425 (1990).

    CAS  Article  Google Scholar 

  8. 8

    Lemasters, J. J., Theruvath, T. P., Zhong, Z. & Nieminen, A. L. Mitochondrial calcium and the permeability transition in cell death. Biochim. Biophys. Acta 1787, 1395–1401 (2009).

    CAS  Article  Google Scholar 

  9. 9

    Szalai, G., Krishnamurthy, R. & Hajnoczky, G. Apoptosis driven by IP(3)-linked mitochondrial calcium signals. EMBO J. 18, 6349–6361 (1999).

    CAS  Article  Google Scholar 

  10. 10

    Hansford, R. G. Physiological role of mitochondrial Ca2+ transport. J. Bioenerg. Biomembr. 26, 495–508 (1994).

    CAS  Article  Google Scholar 

  11. 11

    Herrington, J., Park, Y. B., Babcock, D. F. & Hille, B. Dominant role of mitochondria in clearance of large Ca2+ loads from rat adrenal chromaffin cells. Neuron 16, 219–228 (1996).

    CAS  Article  Google Scholar 

  12. 12

    Rizzuto, R. et al. Close contacts with the endoplasmic reticulum as determinants of mitochondrial Ca2+ responses. Science 280, 1763–1766 (1998).

    CAS  Article  Google Scholar 

  13. 13

    Csordas, G. et al. Imaging interorganelle contacts and local calcium dynamics at the ER-mitochondrial interface. Mol. Cell 39, 121–132 (2010).

    CAS  Article  Google Scholar 

  14. 14

    Giacomello, M. et al. Ca2+ hot spots on the mitochondrial surface are generated by Ca2+ mobilization from stores, but not by activation of store-operated Ca2+ channels. Mol. Cell 38, 280–290 (2010).

    CAS  Article  Google Scholar 

  15. 15

    Kirichok, Y., Krapivinsky, G. & Clapham, D. E. The mitochondrial calcium uniporter is a highly selective ion channel. Nature 427, 360–364 (2004).

    CAS  Article  Google Scholar 

  16. 16

    Santo-Domingo, J. & Demaurex, N. Calcium uptake mechanisms of mitochondria. Biochim. Biophys. Acta 1797, 907–912 (2010).

    CAS  Article  Google Scholar 

  17. 17

    Igbavboa, U. & Pfeiffer, D. R. EGTA inhibits reverse uniport-dependent Ca2+ release from uncoupled mitochondria. Possible regulation of the Ca2+ uniporter by a Ca2+ binding site on the cytoplasmic side of the inner membrane. J. Biol. Chem. 263, 1405–1412 (1988).

    CAS  PubMed  Google Scholar 

  18. 18

    Bernardi, P. Mitochondrial transport of cations: channels, exchangers, and permeability transition. Physiol. Rev. 79, 1127–1155 (1999).

    CAS  Article  Google Scholar 

  19. 19

    Baughman, J. M. et al. Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter. Nature 476, 341–345 (2011).

    CAS  Article  Google Scholar 

  20. 20

    De Stefani, D., Raffaello, A., Teardo, E., Szabo, I. & Rizzuto, R. A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter. Nature 476, 336–340 (2011).

    CAS  Article  Google Scholar 

  21. 21

    Perocchi, F. et al. MICU1 encodes a mitochondrial EF hand protein required for Ca2+ uptake. Nature 467, 291–296 (2010).

    CAS  Article  Google Scholar 

  22. 22

    Mallilankaraman, K et al. MICU1 is an essential gatekeeper for MCU-mediated mitochondrial Ca2+ uptake that regulates cell survival. Cell 151, 630–644 (2012).

    CAS  Article  Google Scholar 

  23. 23

    Babcock, D. F., Herrington, J., Goodwin, P. C., Park, Y. B. & Hille, B. Mitochondrial participation in the intracellular Ca2+ network. J. Cell Biol. 136, 833–844 (1997).

    CAS  Article  Google Scholar 

  24. 24

    Madesh, M. et al. Selective role for superoxide in InsP3 receptor-mediated mitochondrial dysfunction and endothelial apoptosis. J. Cell Biol. 170, 1079–1090 (2005).

    CAS  Article  Google Scholar 

  25. 25

    Moreau, B., Nelson, C. & Parekh, A. B. Biphasic regulation of mitochondrial Ca2+ uptake by cytosolic Ca2+ concentration. Curr. Biol. 16, 1672–1677 (2006).

    CAS  Article  Google Scholar 

  26. 26

    Jiang, D., Zhao, L. & Clapham, D. E. Genome-wide RNAi screen identifies Letm1 as a mitochondrial Ca2+/H+ antiporter. Science 326, 144–147 (2009).

    CAS  Article  Google Scholar 

  27. 27

    Collins, T. J., Lipp, P., Berridge, M. J. & Bootman, M. D. Mitochondrial Ca2+ uptake depends on the spatial and temporal profile of cytosolic Ca2+ signals. J. Biol. Chem. 276, 26411–26420 (2001).

    CAS  Article  Google Scholar 

  28. 28

    Cárdenas, C. et al. Essential regulation of cell bioenergetics by constitutive InsP3 receptor Ca2+ transfer to mitochondria. Cell 142, 270–283 (2010).

    Article  Google Scholar 

  29. 29

    Naldini, L. et al. In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector. Science 272, 263–267 (1996).

    CAS  Article  Google Scholar 

  30. 30

    Greenawalt, J.W. The isolation of outer and inner mitochondrial membranes. Methods Enzymol. 31, 310–323 (1974).

    CAS  Article  Google Scholar 

  31. 31

    Csordas, G. & Hajnoczky, G. Plasticity of mitochondrial calcium signaling. J. Biol. Chem. 278, 42273–42282 (2003).

    CAS  Article  Google Scholar 

  32. 32

    Madesh, M., Antonsson, B., Srinivasula, S. M., Alnemri, E. S. & Hajnoczky, G. Rapid kinetics of tBid-induced cytochrome c and Smac/DIABLO release and mitochondrial depolarization. J. Biol. Chem. 277, 5651–5659 (2002).

    CAS  Article  Google Scholar 

  33. 33

    Madesh, M. & Hajnoczky, G. VDAC-dependent permeabilization of the outer mitochondrial membrane by superoxide induces rapid and massive cytochrome c release. J. Cell Biol. 155, 1003–1015 (2001).

    CAS  Article  Google Scholar 

  34. 34

    Kochanowski, N. et al. Intracellular nucleotide and nucleotide sugar contents of cultured CHO cells determined by a fast, sensitive, and high-resolution ion-pair RP-HPLC. Anal. Biochem. 348, 243–251 (2006).

    CAS  Article  Google Scholar 

  35. 35

    MacAlpine, D. M., Perlman, P. S. & Butow, R. A. The high mobility group protein Abf2p influences the level of yeast mitochondrial DNA recombination intermediates in vivo. Proc. Natl Acad. Sci. USA 95, 6739–6743 (1998).

    CAS  Article  Google Scholar 

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Acknowledgements

This work was supported by the National Institutes of Health grants R01 HL086699, HL086699-01A2S1 and 1S10RR027327-01 to M.M., and GM56328 to J.K.F. C.C. was supported by the Fondo Nacional de Desarrollo Cientifico y Tecnologico (FONDECYT) grant #1120443 and an award from the American Heart Association.

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K.M., M.M. and J.K.F. designed the project. K.M., C.C., P.D., H.C.C., K.M.I., P.M., J.Y., M.M., T.G., G.C. and R.M. performed the experimental work. K.M., C.C., P.D, H.C.C., K.M.I. and M.M. analysed the results. G.H. and G.C. designed the mitopericam experiments and interpreted the results. J.E.K. and B.K. performed mtDNA analysis. J.M. contributed reagents. K.M. M.M. and J.K.F. wrote the manuscript. All authors discussed the results and commented onthe manuscript.

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Correspondence to J. Kevin Foskett or Muniswamy Madesh.

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Mallilankaraman, K., Cárdenas, C., Doonan, P. et al. MCUR1 is an essential component of mitochondrial Ca2+ uptake that regulates cellular metabolism. Nat Cell Biol 14, 1336–1343 (2012). https://doi.org/10.1038/ncb2622

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