• A Corrigendum to this article was published on 24 December 2012
  • A Corrigendum to this article was published on 30 June 2015

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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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'.

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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.

Author information

Author notes

    • César Cárdenas
    • , Patrick J. Doonan
    •  & Harish C. Chandramoorthy

    These authors contributed equally to this work

Affiliations

  1. Department of Biochemistry, Temple University, Philadelphia, Pennsylvania 19140, USA

    • Karthik Mallilankaraman
    • , Patrick J. Doonan
    • , Harish C. Chandramoorthy
    • , Krishna M. Irrinki
    • , Priyanka Madireddi
    •  & Muniswamy Madesh
  2. Department of Physiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA

    • César Cárdenas
    • , Jun Yang
    • , Marioly Müller
    •  & J. Kevin Foskett
  3. Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA

    • Tünde Golenár
    • , György Csordás
    •  & György Hajnóczky
  4. Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA

    • Russell Miller
  5. Department of Animal Biology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania 19104, USA

    • Jill E. Kolesar
    •  & Brett Kaufman
  6. CNRS, Institut de Neurobiologie Alfred Fessard, FRC2118, Laboratoire de Neurobiologie et Développement, UPR 3294, 91198 Gif-sur-Yvette cedex, France

    • Jordi Molgó
  7. Center for Translational Medicine, Temple University, Philadelphia, Pennsylvania 19140, USA

    • Karthik Mallilankaraman
    • , Patrick J. Doonan
    • , Harish C. Chandramoorthy
    • , Krishna M. Irrinki
    •  & Muniswamy Madesh
  8. Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA

    • J. Kevin Foskett

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Contributions

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.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to J. Kevin Foskett or Muniswamy Madesh.

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DOI

https://doi.org/10.1038/ncb2622

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