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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NCBI Reference Sequence
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).
Supplementary Note, Supplementary Tables 1–4 and Supplementary Figures 1–15