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

Clare V Logan, Gyorgy Szabadkai, Jenny A Sharpe, David A Parry, Silvia Torelli, Anne-Marie Childs, Marjolein Kriek, Rahul Phadke, Colin A Johnson, Nicola Y Roberts, David T Bonthron, Karen A Pysden, Tamieka Whyte, Iulia Munteanu, A Reghan Foley, Gabrielle Wheway, Katarzyna Szymanska, Subaashini Natarajan, Zakia A Abdelhamed, Joanne E MorganHelen Roper, Gijs W E Santen, Erik H Niks, W Ludo van der Pol, Dick Lindhout, Anna Raffaello, Diego De Stefani, Johan T den Dunnen, Yu Sun, Ieke Ginjaar, Caroline A Sewry, Matthew Hurles, Rosario Rizzuto, Michael R Duchen, Francesco Muntoni, Eamonn Sheridan

Research output: Contribution to journalArticlepeer-review


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.
Original languageEnglish
Pages (from-to)188-193
Number of pages6
JournalNature Genetics
Issue number2
Publication statusPublished - 1 Feb 2014


  • 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,genetics,metabolism,pathology,physiology


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