Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Loss-of-function mutations in MICU1 cause a brain and muscle disorder linked to primary alterations in mitochondrial calcium signaling

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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Quadriceps biopsies from affected individuals.
Figure 2: Mutations in MICU1 identified in a multiplex consanguineous family.
Figure 3: Loss of MICU1 protein leads to increased mitochondrial Ca2+ load and reduced cytoplasmic Ca2+ transients without altering mitochondrial membrane potential.
Figure 4: Effect of MICU1 protein loss on mitochondrial morphology, basal mitochondrial Ca2+ concentration and mitochondrial energy metabolism.

Similar content being viewed by others

Accession codes

Accessions

NCBI Reference Sequence

References

  1. 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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  3. Millay, D.P. et al. Genetic and pharmacologic inhibition of mitochondrial-dependent necrosis attenuates muscular dystrophy. Nat. Med. 14, 442–447 (2008).

    Article  CAS  Google Scholar 

  4. Boncompagni, S. et al. Characterization and temporal development of cores in a mouse model of malignant hyperthermia. Proc. Natl. Acad. Sci. USA 106, 21996–22001 (2009).

    Article  CAS  Google Scholar 

  5. Duchen, M.R. & Szabadkai, G. Roles of mitochondria in human disease. Essays Biochem. 47, 115–137 (2010).

    Article  CAS  Google Scholar 

  6. 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).

    Article  CAS  Google Scholar 

  7. Szabadkai, G. & Duchen, M.R. Mitochondria: the hub of cellular Ca2+ signaling. Physiology (Bethesda) 23, 84–94 (2008).

    CAS  Google Scholar 

  8. Rizzuto, R. & Pozzan, T. Microdomains of intracellular Ca2+: molecular determinants and functional consequences. Physiol. Rev. 86, 369–408 (2006).

    Article  CAS  Google Scholar 

  9. Giacomello, M., Drago, I., Pizzo, P. & Pozzan, T. Mitochondrial Ca2+ as a key regulator of cell life and death. Cell Death Differ. 14, 1267–1274 (2007).

    Article  CAS  Google Scholar 

  10. Csordás, G. et al. MICU1 controls both the threshold and cooperative activation of the mitochondrial Ca2+ uniporter. Cell Metab. 17, 976–987 (2013).

    Article  Google Scholar 

  11. Plovanich, M. et al. MICU2, a paralog of MICU1, resides within the mitochondrial uniporter complex to regulate calcium handling. PLoS ONE 8, e55785 (2013).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  14. Carr, I.M., Sheridan, E., Hayward, B.E., Markham, A.F. & Bonthron, D.T. IBDfinder and SNPsetter: tools for pedigree-independent identification of autozygous regions in individuals with recessive inherited disease. Hum. Mutat. 30, 960–967 (2009).

    Article  CAS  Google Scholar 

  15. Stevens, E. et al. Mutations in B3GALNT2 cause congenital muscular dystrophy and hypoglycosylation of α-dystroglycan. Am. J. Hum. Genet. 92, 354–365 (2013).

    Article  CAS  Google Scholar 

  16. Zampese, E. et al. Presenilin 2 modulates endoplasmic reticulum (ER)-mitochondria interactions and Ca2+ cross-talk. Proc. Natl. Acad. Sci. USA 108, 2777–2782 (2011).

    Article  CAS  Google Scholar 

  17. Chami, M. et al. Role of SERCA1 truncated isoform in the proapoptotic calcium transfer from ER to mitochondria during ER stress. Mol. Cell 32, 641–651 (2008).

    Article  CAS  Google Scholar 

  18. Bianchi, K., Rimessi, A., Prandini, A., Szabadkai, G. & Rizzuto, R. Calcium and mitochondria: mechanisms and functions of a troubled relationship. Biochim. Biophys. Acta 1742, 119–131 (2004).

    Article  CAS  Google Scholar 

  19. Gerencsér, A.A. & Adam-Vizi, V. Selective, high-resolution fluorescence imaging of mitochondrial Ca2+ concentration. Cell Calcium 30, 311–321 (2001).

    Article  Google Scholar 

  20. Spät, A. & Pitter, J.G. The effect of cytoplasmic Ca2+ signal on the redox state of mitochondrial pyridine nucleotides. Mol. Cell Endocrinol. 215, 115–118 (2004).

    Article  Google Scholar 

  21. Irwin, W.A. et al. Mitochondrial dysfunction and apoptosis in myopathic mice with collagen VI deficiency. Nat. Genet. 35, 367–371 (2003).

    Article  CAS  Google Scholar 

  22. Dubowitz, V., Sewry, C.A. & Oldfors, A. Muscle Biopsy: A Practical Approach 4th edn. (Saunders, Philadelphia, 2013).

  23. McKenna, A. et al. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 20, 1297–1303 (2010).

    Article  CAS  Google Scholar 

  24. Rozen, S. & Skaletsky, H. Primer3 on the WWW for general users and for biologist programmers. Methods Mol. Biol. 132, 365–386 (2000).

    CAS  Google Scholar 

  25. Dawe, H.R. et al. The Meckel-Gruber Syndrome proteins MKS1 and meckelin interact and are required for primary cilium formation. Hum. Mol. Genet. 16, 173–186 (2007).

    Article  CAS  Google Scholar 

  26. Bolte, S. & Cordelieres, F.P. A guided tour into subcellular colocalization analysis in light microscopy. J. Microsc. 224, 213–232 (2006).

    Article  CAS  Google Scholar 

  27. Traba, J., Del Arco, A., Duchen, M.R., Szabadkai, G. & Satrustegui, J. SCaMC-1 promotes cancer cell survival by desensitizing mitochondrial permeability transition via ATP/ADP-mediated matrix Ca2+ buffering. Cell Death Differ. 19, 650–660 (2012).

    Article  CAS  Google Scholar 

  28. Chen, T.W. et al. Ultrasensitive fluorescent proteins for imaging neuronal activity. Nature 499, 295–300 (2013).

    Article  CAS  Google Scholar 

  29. Schindelin, J. et al. Fiji: an open-source platform for biological-image analysis. Nat. Methods 9, 676–682 (2012).

    Article  CAS  Google Scholar 

  30. Maravall, M., Mainen, Z.F., Sabatini, B.L. & Svoboda, K. Estimating intracellular calcium concentrations and buffering without wavelength ratioing. Biophys. J. 78, 2655–2667 (2000).

    Article  CAS  Google Scholar 

  31. Faul, F., Erdfelder, E., Buchner, A. & Lang, A.G. Statistical power analyses using G*Power 3.1: tests for correlation and regression analyses. Behav. Res. Methods 41, 1149–1160 (2009).

    Article  Google Scholar 

Download references

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

Authors and Affiliations

Authors

Consortia

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.

Corresponding authors

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

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Additional information

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

Supplementary information

Supplementary Text and Figures

Supplementary Note, Supplementary Tables 1–4 and Supplementary Figures 1–15 (PDF 7587 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Logan, C., Szabadkai, G., Sharpe, J. et al. Loss-of-function mutations in MICU1 cause a brain and muscle disorder linked to primary alterations in mitochondrial calcium signaling. Nat Genet 46, 188–193 (2014). https://doi.org/10.1038/ng.2851

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

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

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing