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.
|Number of pages||6|
|Publication status||Published - 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