Loss-of-function mutations in MICU1 cause a brain and muscle disorder linked to primary alterations in mitochondrial calcium signaling.
Nat Genet
; 46(2): 188-93, 2014 Feb.
Article
em En
| MEDLINE
| ID: mdl-24336167
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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Base de dados:
MEDLINE
Assunto principal:
Fenótipo
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Proteínas de Ligação ao Cálcio
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Sinalização do Cálcio
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Proteínas de Transporte de Cátions
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Proteínas de Transporte da Membrana Mitocondrial
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Deficiências da Aprendizagem
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Mitocôndrias
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Transtornos dos Movimentos
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Doenças Musculares
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article