title: Loss-of-function mutations in MICU1 cause a brain and muscle disorder linked to primary alterations in mitochondrial calcium signaling.
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.
authors: Clare V
authors: CV
authors: Logan
authors: György
authors: G
authors: Szabadkai
authors: Jenny A
authors: JA
authors: Sharpe
authors: David A
authors: DA
authors: Parry
authors: Silvia
authors: S
authors: Torelli
authors: Anne-Marie
authors: AM
authors: Childs
authors: Marjolein
authors: M
authors: Kriek
authors: Rahul
authors: R
authors: Phadke
authors: Colin A
authors: CA
authors: Johnson
authors: Nicola Y
authors: NY
authors: Roberts
authors: David T
authors: DT
authors: Bonthron
authors: Karen A
authors: KA
authors: Pysden
authors: Tamieka
authors: T
authors: Whyte
authors: Iulia
authors: I
authors: Munteanu
authors: A Reghan
authors: AR
authors: Foley
authors: Gabrielle
authors: G
authors: Wheway
authors: Katarzyna
authors: K
authors: Szymanska
authors: Subaashini
authors: S
authors: Natarajan
authors: Zakia A
authors: ZA
authors: Abdelhamed
authors: Joanne E
authors: JE
authors: Morgan
authors: Helen
authors: H
authors: Roper
authors: Gijs W E
authors: GW
authors: Santen
authors: Erik H
authors: EH
authors: Niks
authors: W Ludo
authors: WL
authors: van der Pol
authors: Dick
authors: D
authors: Lindhout
authors: Anna
authors: A
authors: Raffaello
authors: Diego
authors: D
authors: De Stefani
authors: Johan T
authors: JT
authors: den Dunnen
authors: Yu
authors: Y
authors: Sun
authors: Ieke
authors: I
authors: Ginjaar
authors: Caroline A
authors: CA
authors: Sewry
authors: Matthew
authors: M
authors: Hurles
authors: Rosario
authors: R
authors: Rizzuto
authors: Michael R
authors: MR
authors: Duchen
authors: Francesco
authors: F
authors: Muntoni
authors: Eamonn
authors: E
authors: Sheridan
mesh_terms: D000704:Analysis of Variance; D001483:Base Sequence; D015220:Calcium Channels / Q000378:metabolism; D020013:Calcium Signaling / Q000235:genetics* / Q000502:physiology; D002135:Calcium-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D027682:Cation Transport Proteins / Q000235:genetics* / Q000378:metabolism; D018076:DNA, Complementary / Q000235:genetics; D059472:Exome / Q000235:genetics; D005116:Extrapyramidal Tracts / Q000473:pathology; D005455:Fluorescent Antibody Technique; D006652:Histological Techniques; D006801:Humans; D007150:Immunohistochemistry; D007859:Learning Disabilities / Q000235:genetics*; D053078:Membrane Potential, Mitochondrial / Q000235:genetics; D008928:Mitochondria / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D009069:Movement Disorders / Q000235:genetics*; D009135:Muscular Diseases / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D052097:Quadriceps Muscle / Q000473:pathology; D060888:Real-Time Polymerase Chain Reaction; D017422:Sequence Analysis, DNA
chemical_list: D015220:Calcium Channels; D002135:Calcium-Binding Proteins; D027682:Cation Transport Proteins; D018076:DNA, Complementary; C116241:MICU1 protein, human; D033681:Mitochondrial Membrane Transport Proteins; C034703:mitochondrial calcium uniporter