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Publication Detail
Loss-of-function mutations in MICU1 cause a brain and muscle disorder linked to primary alterations in mitochondrial calcium signaling.
  • Publication Type:
    Journal article
  • Publication Sub Type:
    Journal Article
  • Authors:
    Logan CV, Szabadkai G, Sharpe JA, Parry DA, Torelli S, Childs A-M, Kriek M, Phadke R, Johnson CA, Roberts NY, Bonthron DT, Pysden KA, Whyte T, Munteanu I, Foley AR, Wheway G, Szymanska K, Natarajan S, Abdelhamed ZA, Morgan JE, Roper H, Santen GWE, Niks EH, van der Pol WL, Lindhout D, Raffaello A, De Stefani D, den Dunnen JT, Sun Y, Ginjaar I, Sewry CA, Hurles M, Rizzuto R, UK10K Consortium , Duchen MR, Muntoni F, Sheridan E
  • Publication date:
    02/2014
  • Pagination:
    188, 193
  • Journal:
    Nat Genet
  • Volume:
    46
  • Issue:
    2
  • Status:
    Published
  • Country:
    United States
  • PII:
    ng.2851
  • Language:
    eng
  • Keywords:
    Analysis of Variance, Base Sequence, Calcium Channels, Calcium Signaling, Calcium-Binding Proteins, Cation Transport Proteins, DNA, Complementary, Exome, Extrapyramidal Tracts, Fluorescent Antibody Technique, Histological Techniques, Humans, Immunohistochemistry, Learning Disabilities, Membrane Potential, Mitochondrial, Mitochondria, Mitochondrial Membrane Transport Proteins, Molecular Sequence Data, Movement Disorders, Muscular Diseases, Pedigree, Phenotype, Polymorphism, Single Nucleotide, Quadriceps Muscle, Real-Time Polymerase Chain Reaction, Sequence Analysis, DNA
Abstract
Mitochondrial Ca(2+) uptake has key roles in cell life and death. Physiological Ca(2+) signaling regulates aerobic metabolism, whereas pathological Ca(2+) overload triggers cell death. Mitochondrial Ca(2+) uptake is mediated by the Ca(2+) uniporter complex in the inner mitochondrial membrane, which comprises MCU, a Ca(2+)-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 Ca(2+) uptake at low cytosolic Ca(2+) concentrations was increased, and cytosolic Ca(2+) 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 dystrophy and the core myopathies involves abnormal mitochondrial Ca(2+) handling, the phenotype associated with MICU1 deficiency is caused by a primary defect in mitochondrial Ca(2+) signaling, demonstrating the crucial role of mitochondrial Ca(2+) uptake in humans.
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Cell & Developmental Biology
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Developmental Neurosciences Dept
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UCL Queen Square Institute of Neurology
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Cell & Developmental Biology
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Developmental Neurosciences Dept
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