期刊
NATURE GENETICS
卷 46, 期 2, 页码 188-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.2851
关键词
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资金
- Sir Jules Thorn Award for Biomedical Research [JTA/09]
- Medical Research Council [MR/K011154/1]
- Wellcome Trust [WT091310]
- Muscular Dystrophy Association [68762]
- National Specialised Commissioned Team (NSCT)
- Great Ormond Street Children's Charity
- Great Ormond Street Hospital Biomedical Research Centre
- MRC Neuromuscular Centre biobank
- European Union Framework Programme 7 Neuromic grant [HEALTH-F5-2012-305121]
- Parkinson's UK
- British Heart Foundation
- Wellcome Trust-UCL Therapeutic Innovation Fund, Telethon-Italy [GEP1206]
- Italian Association for Cancer Research (AIRC)
- Italian Ministries of Health
- Education, University and Research
- European Union (European Research Council mitoCalcium [294777]
- US National Institutes of Health [1P01AG025532-01A1]
- Cariparo Foundation and the Cariplo Foundations
- European Research Council (ERC) [294777] Funding Source: European Research Council (ERC)
- MRC [MR/K011154/1, MR/K000608/1, G0600717] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [1675658] Funding Source: researchfish
- Great Ormond Street Hospital Childrens Charity [V1217] Funding Source: researchfish
- Medical Research Council [MR/K000608/1, G0600717B, MR/K011154/1, G0600717, MC_UU_12012/5/B] Funding Source: researchfish
- Muscular Dystrophy UK [RA4/0924, RA4/924] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0510-10268, NF-SI-0513-10109] Funding Source: researchfish
- Parkinson's UK [G-0905] Funding Source: researchfish
- Rosetrees Trust [M145] Funding Source: researchfish
- The Sir Jules Thorn Charitable Trust [09JTA] Funding Source: researchfish
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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