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

Logan, CV; Szabadkai, G; Sharpe, JA; Parry, DA; Torelli, S; Childs, AM; Kriek, M; ... Sheridan, E; + view all (2014) Loss-of-function mutations in MICU1 cause a brain and muscle disorder linked to primary alterations in mitochondrial calcium signaling. Nature Genetics , 46 (2) pp. 188-193. 10.1038/ng.2851. Green open access

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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.

Type: Article
Title: Loss-of-function mutations in MICU1 cause a brain and muscle disorder linked to primary alterations in mitochondrial calcium signaling
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1038/ng.2851
Publisher version: http://dx.doi.org/10.1038/ng.2851
Language: English
Additional information: Copyright © 2014 Nature America, Inc. All rights reserved.
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 Disorders, 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
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Cell and Developmental Biology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > UCL GOS Institute of Child Health > ICH Development Bio and Cancer Prog
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > UCL GOS Institute of Child Health > ICH Developmental Neurosciences Prog
URI: http://discovery.ucl.ac.uk/id/eprint/1417546
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