Abstract

Mitochondrial Ca2+ uptake has key roles in cell life and death. Physiological Ca2+ signaling regulates aerobic metabolism, whereas pathological Ca2+ overload triggers cell death. Mitochondrial Ca2+ uptake is mediated by the Ca2+ uniporter complex in the inner mitochondrial membrane1,2, which comprises MCU, a Ca2+-selective ion channel, and its regulator, MICU1. Here we report mutations of MICU1 in individuals with a disease phenotype characterized by proximal myopathy, learning difficulties and a progressive extrapyramidal movement disorder. In fibroblasts from subjects with MICU1 mutations, agonist-induced mitochondrial Ca2+ uptake at low cytosolic Ca2+ concentrations was increased, and cytosolic Ca2+ signals were reduced. Although resting mitochondrial membrane potential was unchanged in MICU1-deficient cells, the mitochondrial network was severely fragmented. Whereas the pathophysiology of muscular dystrophy3 and the core myopathies4 involves abnormal mitochondrial Ca2+ handling, the phenotype associated with MICU1 deficiency is caused by a primary defect in mitochondrial Ca2+ signaling, demonstrating the crucial role of mitochondrial Ca2+ uptake in humans.

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Acknowledgements

This work was supported by a Sir Jules Thorn Award for Biomedical Research (JTA/09 to C.A.J., E.S. and D.T.B.). We acknowledge funding from the Medical Research Council (project grant MR/K011154/1) awarded to C.A.J., E.S. and C.V.L. We are grateful to the UK10K Consortium for making this study possible. This study makes use of data generated by the UK10K Consortium. A full list of the investigators who contributed to the generation of the data is available at http://www.uk10k.org/publications.html. Funding for UK10K was provided by the Wellcome Trust under award WT091310. Muscular Dystrophy Association grant 68762 to F.M. is gratefully acknowledged. National Specialised Commissioned Team (NSCT) funding for the Congenital Muscular Dystrophies and Congenital Myopathy service in London is also gratefully acknowledged. T.W. is a Muscular Dystrophy Campaign PhD student. F.M. is supported by the Great Ormond Street Children's Charity and the Great Ormond Street Hospital Biomedical Research Centre. This study was also partly supported by the MRC Neuromuscular Centre biobank. European Union Framework Programme 7 Neuromic grant to G.-J. van Ommen (FP7-Health-2012-Innovation 1 HEALTH-F5-2012-305121) is also gratefully acknowledged. G.S. is supported by Parkinson's UK, the British Heart Foundation, the Wellcome Trust–UCL Therapeutic Innovation Fund, Telethon-Italy (GEP1206) and the Italian Association for Cancer Research (AIRC). R.R. is supported by the Italian Ministries of Health (Ricerca Finalizzata) and of Education, University and Research (PRIN and FIRB), the European Union (European Research Council mitoCalcium, 294777), the US National Institutes of Health (NIH; grant 1P01AG025532-01A1), the Cariparo Foundation and the Cariplo Foundations (Padua), AIRC and Telethon-Italy (GPP1005A and GPP11082B). J.A.S. is the recipient of a PhD studentship from the Muscular Dystrophy Campaign. The genealogy of family UMCU was constructed by F.A.M. Hennekam (University Medical Center Utrecht).

Author information

Author notes

    • Clare V Logan
    • , György Szabadkai
    •  & Jenny A Sharpe

    These authors contributed equally to this work.

    • Michael R Duchen
    • , Francesco Muntoni
    •  & Eamonn Sheridan

    These authors jointly directed this work.

Affiliations

  1. Leeds Institute of Biomedical and Clinical Science, St. James's University Hospital, Leeds, UK.

    • Clare V Logan
    • , David A Parry
    • , Colin A Johnson
    • , Nicola Y Roberts
    • , David T Bonthron
    • , Gabrielle Wheway
    • , Katarzyna Szymanska
    • , Subaashini Natarajan
    • , Zakia A Abdelhamed
    • , Joanne E Morgan
    •  & Eamonn Sheridan
  2. Department of Cell and Developmental Biology, Consortium for Mitochondrial Research, University College London (UCL), London, UK.

    • György Szabadkai
    • , Jenny A Sharpe
    •  & Michael R Duchen
  3. Department of Biomedical Sciences, University of Padua and Consiglio Nazionale delle Ricerche Neuroscience Institute, Padua, Italy.

    • György Szabadkai
    • , Anna Raffaello
    • , Diego De Stefani
    •  & Rosario Rizzuto
  4. UCL Institute of Child Health, Dubowitz Neuromuscular Centre and Medical Research Council (MRC) Centre for Neuromuscular Diseases, London, UK.

    • Silvia Torelli
    • , Rahul Phadke
    • , Tamieka Whyte
    • , Iulia Munteanu
    • , A Reghan Foley
    • , Caroline A Sewry
    •  & Francesco Muntoni
  5. Department of Paediatric Neurology, Leeds General Infirmary, Leeds, UK.

    • Anne-Marie Childs
    •  & Karen A Pysden
  6. Center for Human and Clinical Genetics, Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.

    • Marjolein Kriek
    • , Gijs W E Santen
    • , Johan T den Dunnen
    • , Yu Sun
    •  & Ieke Ginjaar
  7. UCL Institute of Neurology, MRC Centre for Neuromuscular Diseases, London, UK.

    • Rahul Phadke
  8. Department of Paediatrics, Birmingham Heartlands Hospital, Birmingham, UK.

    • Helen Roper
  9. Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands.

    • Erik H Niks
  10. Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.

    • W Ludo van der Pol
  11. Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.

    • Dick Lindhout
  12. Wolfson Centre for Inherited Neuromuscular Diseases, Robert Jones & Agnes Hunt Orthopaedic Hospital, Oswestry, UK.

    • Caroline A Sewry
  13. Wellcome Trust Sanger Institute, Cambridge, UK.

    • Matthew Hurles

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  1. UK10K Consortium

    A full list of members and affiliations appear in the Supplementary Note.

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Contributions

E.S., F.M., M.R.D. and G.S. designed the study and experiments. E.S., F.M., A.-M.C., K.A.P., D.T.B., M.K., E.H.N., W.L.v.d.P., D.L., G.W.E.S. and H.R. identified, consented and recruited the study subjects and provided clinical information. D.A.P., C.V.L., C.A.J., J.E.M., M.K., I.G., J.T.d.D., Y.S. and M.H. generated and analyzed clonal sequencing data. C.V.L., D.A.P., G.W., N.Y.R., K.S., C.A.J., S.N., Z.A.A., T.W. and S.T. performed genetic analysis, confirmation studies and haplotyping. J.A.S., G.S., D.D.S., A.R., R.R. and M.R.D. performed calcium handling, cellular imaging, oxygen consumption and protein expression studies. C.A.S., R.P., I.M. and A.R.F. undertook muscle immunohistochemistry and analysis of patient muscle biopsies. E.S., C.V.L., D.T.B., F.M., G.S. and M.R.D. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Michael R Duchen or Francesco Muntoni or Eamonn Sheridan.

Supplementary information

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    Supplementary Text and Figures

    Supplementary Note, Supplementary Tables 1–4 and Supplementary Figures 1–15

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DOI

https://doi.org/10.1038/ng.2851

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